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  • 1.
    Armulik, Annika
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Velling, Teet
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The integrin beta1 subunit transmembrane domain regulates phosphatidylinositol 3-kinase-dependent tyrosine phosphorylation of Crk-associated substrate.2004In: Mol Biol Cell, ISSN 1059-1524, Vol. 15, no 6, p. 2558-67Article in journal (Refereed)
  • 2.
    Bergström, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Holmqvist, Karin
    Tararuk, Tatsiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Developmentally regulated collagen/integrin interactions confer adhesive properties to early postnatal neural stem cells2014In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1840, no 8, p. 2526-2532Article in journal (Refereed)
    Abstract [en]

    Background:

    It is becoming increasingly apparent that the extracellular matrix acts as an important regulator of the neural stem niche. Previously we found that neural stem and progenitor cells (NSPCs) derived from the early postnatal subventricular zone of mice adhere to a collagen/hyaluronan hydrogel, whereas NSPCs from the adult and embryonic brain do not.

    Methods:

    To examine the specific adhesive properties of young stem cells in more detail, NSPCs isolated from embryonic, postnatal day 6 (P6), and adult mouse brains were cultured on collagen I.

    Results:

    Early postnatal NSPCs formed paxillin-positive focal adhesions on collagen I, and these adhesions could be prevented by an antibody that blocked integrin beta 1. Furthermore, we found the corresponding integrin alpha subunits alpha 2 and alpha 11 levels to be highest at the postnatal stage. Gene ontology analysis of differentially expressed genes showed higher expression of transcripts involved in vasculature development and morphogenesis in P6 stem cells, compared to adult.

    Conclusions:

    The ability to interact with the extracellular matrix differs between postnatal and adult NSPCs.

    General significance:

    Our observations that the specific adhesive properties of early postnatal NSPCs, which are lost in the adult brain, can be ascribed to the integrin subunits expressed by the former furthering our understanding of the developing neurogenic niche. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.  

  • 3. Fässler, R
    et al.
    Pfaff, M
    Murphy, J
    Noegel, A.A.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Timpl, R
    Albrecht, R
    Lack of ß1 integrin gene in embryonic stem cells affects morphology, adhesion, and migration but not integration into the inner cell mass of blastocysts1995In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 128, no 5, p. 979-988Article in journal (Refereed)
    Abstract [en]

    A gene trap-type targeting vector was designed to inactivate the beta 1 integrin gene in embryonic stem (ES) cells. Using this vector more than 50% of the ES cell clones acquired a disruption in the beta 1 integrin gene and a single clone was mutated in both alleles. The homozygous mutant did not produce beta 1 integrin mRNA or protein, while alpha 3, alpha 5, and alpha 6 integrin subunits were transcribed but not detectable on the cell surface. Heterozygous mutants showed reduced beta 1 expression and surface localization of alpha/beta 1 heterodimers. The alpha V subunit expression was not impaired on any of the mutants. Homozygous ES cell mutants lacked adhesiveness for laminin and fibronectin but not for vitronectin and showed a reduced association with a fibroblast feeder layer. Furthermore, they did not migrate towards chemoattractants in fibroblast medium. None of these functions were impaired in heterozygous mutants. Scanning electron microscopy revealed that homozygous cells showed fewer cell-cell junctions and had many microvilli not usually found on wild type and heterozygous cells. This profound change in cell shape is not associated with gross alterations in the expression and distribution of cytoskeletal components. Unexpectedly, microinjection into blastocysts demonstrated full integration of homozygous and heterozygous mutants into the inner cell mass. This will allow studies of the consequences of beta 1 integrin deficiency in several in vivo situations.

  • 4.
    Gupta, Deepesh Kumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Du, Jian
    Kamranvar, Siamak A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tension-induced cytokinetic abscission in human fibroblasts2018In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553Article in journal (Other academic)
  • 5.
    Gupta, Deepesh Kumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kamranvar, Siamak A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Du, Jian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Jilin Univ, Hosp 1, Changchun, Jilin, Peoples R China.
    Liu, Liangwen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Septin and Ras regulate cytokinetic abscission in detached cells2019In: Cell Division, ISSN 1747-1028, E-ISSN 1747-1028, Vol. 14, no 1, article id 8Article in journal (Refereed)
    Abstract [en]

    Background Integrin-mediated adhesion is normally required for cytokinetic abscission, and failure in the process can generate potentially oncogenic tetraploid cells. Here, detachment-induced formation of oncogenic tetraploid cells was analyzed in non-transformed human BJ fibroblasts and BJ expressing SV40LT (BJ-LT) +/- overactive HRas. Results In contrast to BJ and BJ-LT cells, non-adherent BJ-LT-Ras cells recruited ALIX and CHMP4B to the midbody and divided. In detached BJ and BJ-LT cells regression of the cytokinetic furrow was suppressed by intercellular bridge-associated septin; after re-adhesion these cells divided by cytofission, however, some cells became bi-nucleated because of septin reorganization and furrow regression. Adherent bi-nucleated BJ cells became senescent in G1 with p21 accumulation in the nucleus, apparently due to p53 activation since adherent bi-nucleated BJ-LT cells passed through next cell cycle and divided into mono-nucleated tetraploids; the two centrosomes present in bi-nucleated BJ cells fused after furrow regression, pointing to the PIDDosome pathway as a possible mechanism for the p53 activation. Conclusions Several mechanisms prevent detached normal cells from generating tumor-causing tetraploid cells unless they have a suppressed p53 response by viruses, mutation or inflammation. Importantly, activating Ras mutations promote colony growth of detached transformed cells by inducing anchorage-independent cytokinetic abscission in single cells.

  • 6.
    Gupta, Deepesh Kumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University.
    Kamranvar, Siamak A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University.
    Du, Jian
    Lu, Liangwen
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fate of bi-nucleated cells: the role of septin and Ras2018Manuscript (preprint) (Other academic)
    Abstract [en]

    Integrin-mediated adhesion is required to complete cytokinesis, and failure in the process can generate tetraploid cells, which are potentially oncogenic. The effect of cell detachment on the cytokinesis process and on the following cell cycle was analyzed in the non-transformed human fibroblast cell line BJ and in BJ cells expressing SV40 LT (BJ-LT) +/- an oncogenic Ras mutant. In non-adherent BJ and BJ-LT cells, ALIX could not be recruited to the midbody (MB) and cytokinetic abscission did not occur. Based on the results from several approaches, this block was concluded to be overcome in the detached BJ-LT-Ras cells. Non-adherent BJ and BJ-LT cells maintained the septin-associated intercellular bridge (ICB) formed by cleavage furrow ingression, for more than 24 hours. After re-adhesion to fibronectin most such cells divided by cytofission due to tension exerted on the narrow bridge, while a minor fraction of the cell population instead became bi-nucleated because of regression of the intercellular bridge. Adherent bi-nucleated BJ-LT cells progressed through the cell cycle and at mitosis they divided into two mono-nucleated (4N) cells, while adherent bi-nucleated BJ cells were arrested in the G1 phase and became senescent. Thus, p53-dependent mechanism(s) prevented the formation of tetraploid cells from non-transformed bi-nucleated cells. The two centrosomes in the adherent bi-nucleated cells rapidly fused, indicating that p53 was activated via the PIDDosome mechanism. The results show that several mechanisms contribute to prevent detached normal cells from generating tumor-causing tetraploid cells, and that expression of an activating Ras mutation can promote cytokinesis in detached tumor cells. 

  • 7.
    Gupta, Rajesh Kumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    beta 1 Integrins restrict the growth of foci and spheroids2012In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 138, no 6, p. 881-894Article in journal (Refereed)
    Abstract [en]

    Extracellular matrices (ECM) have important roles for tissue architecture, both as structural and signaling components. Members of the integrin family are the main regulators of ECM assembly and transmitters of signals from the ECM to cells. In this study, we have analyzed the role of integrin subunit beta 1 in two-dimensional (2D) and three-dimensional (3D) cell cultures using integrin beta 1 null cells (MEF beta 1(-/-) and GD25) and their beta 1 integrin-expressing counterparts. GD25 and GD25 beta 1 cells proliferated with similar kinetics in sub-confluent 2D cultures, whereas GD25 cells attained higher cell numbers in confluent culture and formed foci with fivefold higher frequency than GD25 beta 1 cells. Fibronectin fibrils were abundantly deposited throughout the GD25 beta 1 colonies but strictly limited to the central multilayered area (focus) of GD25 colonies. During 3D growth as spheroids, GD25 continuously increased in size for > 21 days while the growth of GD25 beta 1 spheroids ceased after 14 days. Similarly, MEF beta 1(-/-) cells formed foci and grew as spheroids, while the beta 1 integrin-expressing MEF did not. Expression levels of the cell cycle markers Ki67, PCNA, and histone H3-pSer10 were similar between GD25 beta 1 and GD25 spheroids. Apoptotic cells accumulated earlier in GD25 spheroids; however, cell death increased with spheroid volumes in both spheroid types. In both cell systems, the presence of beta 1 integrins resulted in higher levels of active myosin light chain and inactive myosin light chain phosphatase, and a more compact spheroid structure. In conclusion, our results reveal that regulation of 3D growth in spheroids and foci is dependent on the beta 1 subfamily of integrins, and suggest that myosin-based spheroid contraction in combination with cell death limits the growth of beta 1-expressing spheroids.

  • 8.
    Gupta, Rajesh Kumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fibronectin Assembly in the Crypts of Cytokinesis-Blocked Multilobular Cells Promotes Anchorage-Independent Growth2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, p. e72933-Article in journal (Refereed)
    Abstract [en]

    Anchorage-independent growth is a characteristic feature of cancer cells. However, it is unclear whether it represents a cause or a consequence of tumorigenesis. For normal cells, integrin-mediated adhesion is required for completion of the G1 and cytokinesis stages of the cell cycle. This study identified a mechanism that can drive anchorage-independent growth if the G1 checkpoint is suppressed. Cells with defective G1 checkpoint progressed through several rounds of the cell cycle in suspension in spite of uncompleted cytokinesis, thereby forming bi- and multilobular cells. Aurora B and CEP55 were localized to midbodies between the lobes, suggesting that the cytokinesis process reached close to abscission. Integrin-mediated re-attachment of such cells induced cytokinesis completion uncoupled from karyokinesis in most cells. However, a portion of the cells instead lost the constriction and became binucleated. Also, long-term suspension culture in soft agar produced colonies where the cytokinesis block was overcome. This process was fibronectin-dependent since fibronectin-deficient cells did not form colonies unless fibronectin was expressed or exogenously added. While fibronectin normally is not deposited on non-adherent single cells, bi/multilobular cells accumulated fibronectin in the intussusceptions. Based on our data we conclude: 1) Suppression of the G1 checkpoint allows multiple rounds of the cell cycle in detached cells and thereby enables matrix formation on their surface. 2) Uncompleted cytokinesis due to cell detachment resumes if integrin interactions are re-formed, allowing colony formation in soft agar 3) Such delayed cell division can generate binucleated cells, a feature known to cause chromosomal instability.

  • 9. Hansen, Berit
    et al.
    Longati, Paola
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Elvevold, Kjetil
    Nedredal, Geir-Ivar
    Schledzewski, Kai
    Olsen, Randi
    Falkowski, Martin
    Kzhyshkowska, Julia
    Carlsson, Fredrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Smedsrød, Bård
    Goerdt, Sergij
    Johansson, Sophie
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    McCourt, Peter
    Stabilin-1 and stabilin-2 are both directed into the early endocytic pathway in hepatic sinusoidal endothelium via interactions with clathrin/AP-2, independent of ligand binding.2005In: Exp Cell Res, ISSN 0014-4827, Vol. 303, no 1, p. 160-73Article in journal (Refereed)
  • 10.
    Hildebrand, Sebastian
    et al.
    Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institutet and Division of Obstetrics and Gynecology, Karolinska University Hospital, Huddinge, Sweden.;Department of Oncology-Pathology, Cancer Centrum Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.
    Hultin, Sara
    Department of Oncology-Pathology, Cancer Centrum Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.
    Subramani, Aravindh
    Department of Oncology-Pathology, Cancer Centrum Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.
    Petropoulos, Sophie
    Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institutet and Division of Obstetrics and Gynecology, Karolinska University Hospital, Huddinge, Sweden.
    Zhang, Yuanyuan
    Department of Oncology-Pathology, Cancer Centrum Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.
    Cao, Xiaofang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mpindi, John
    Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland.;Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
    Kalloniemi, Olli
    Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland.;Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Majumdar, Arindam
    Department of Oncology-Pathology, Cancer Centrum Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.
    Lanner, Fredrik
    Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institutet and Division of Obstetrics and Gynecology, Karolinska University Hospital, Huddinge, Sweden.
    Holmgren, Lars
    Department of Oncology-Pathology, Cancer Centrum Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.
    The E-cadherin/AmotL2 complex organizes actin filaments required for epithelial hexagonal packing and blastocyst hatching2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 9540Article in journal (Refereed)
    Abstract [en]

    Epithelial cells connect via cell-cell junctions to form sheets of cells with separate cellular compartments. These cellular connections are essential for the generation of cellular forms and shapes consistent with organ function. Tissue modulation is dependent on the fine-tuning of mechanical forces that are transmitted in part through the actin connection to E-cadherin as well as other components in the adherens junctions. In this report we show that p100 amotL2 forms a complex with E-cadherin that associates with radial actin filaments connecting cells over multiple layers. Genetic inactivation or depletion of amotL2 in epithelial cells in vitro or zebrafish and mouse in vivo, resulted in the loss of contractile actin filaments and perturbed epithelial packing geometry. We further showed that AMOTL2 mRNA and protein was expressed in the trophectoderm of human and mouse blastocysts. Genetic inactivation of amotL2 did not affect cellular differentiation but blocked hatching of the blastocysts from the zona pellucida. These results were mimicked by treatment with the myosin II inhibitor blebbistatin. We propose that the tension generated by the E-cadherin/AmotL2/actin filaments plays a crucial role in developmental processes such as epithelial geometrical packing as well as generation of forces required for blastocyst hatching.

  • 11. Holmvall, K
    et al.
    Camper, L
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kimura, J.H.
    Lundgren-Åkerlund, E
    Chondrocyte and chondrosarcoma cell integrins with affinity for collagen type II and their response to mechanical stress1995In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 221, no 2, p. 496-503Article in journal (Refereed)
    Abstract [en]

    Mechanical stress is an important regulator of chondrocyte functions but the mechanisms by which chondrocytes sense mechanical signals are unknown. Receptors for matrix molecules are likely involved in the mechanical signaling. In the first part of this study we identified integrins with affinity for the cartilage-specific collagen type II. We report that the collagen-binding integrins alpha 1 beta 1 and alpha 2 beta 1 isolated from bovine chondrocytes or human chondrosarcoma cells bound collagen type II as judged from affinity chromatography. The integrins alpha 3 beta 1 or alpha 9 beta 1 did not bind collagen type II-Sepharose. In the second part of the study we investigated the effect of mechanical stress on expression of matrix molecules and integrin subunits. Chondrocytes and chondrosarcoma cells, cultured on uncoated flexible silicone membranes in the presence of serum, were exposed to mechanical stress by the Flexercell system. Dynamic stimulation of chondrocytes for 3 h increased the mRNA expression of collagen type II and aggrecan as judged by Northern blotting, while the beta 1-integrin subunit was not changed. When chondrosarcoma cells were exposed to mechanical stimulation under the same conditions, mRNA expression of alpha 5 was found to increase while beta 1, alpha 2, and alpha v did not increase to significant levels. In another study the effect of mechanical stress on integrins was investigated when the cells were cultured on collagen type II-coated flex-dishes. Three hours of dynamic stress increased the mRNA expression of alpha 2-integrin subunit while the level of mRNA for integrin subunits beta 1, alpha 1, alpha 5, and alpha v showed no or small changes, indicating that matrix components may modulate the expression of integrins during mechanical stress.

  • 12.
    Kamranvar, Siamak A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gupta, Deepesh Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Biomed Ctr, Dept Med Biochem & Microbiol, Uppsala, Sweden..
    Huang, Ying
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gupta, Rajesh Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Integrin signaling via FAK-Src controls cytokinetic abscission by decelerating PLK1 degradation and subsequent recruitment of CEP55 at the midbody2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 21, p. 30820-30830Article in journal (Refereed)
    Abstract [en]

    Adhesion to extracellular matrix is required for cell cycle progression through the G1 phase and for the completion of cytokinesis in normal adherent cells. Cancer cells acquire the ability to proliferate anchorage-independently, a characteristic feature of malignantly transformed cells. However, the molecular mechanisms underlying this escape of the normal control mechanisms remain unclear. The current study aimed to identify adhesion-induced reactions regulating the cytokinesis of non-transformed human fibroblasts. The adhesion-dependent control of cytokinesis was found to occur at a late stage close to the abscission, during which the endosomal sorting complex required for transport (ESCRT) severs the thin intercellular bridge connecting two nascent daughter cells. CEP55, a key protein involved in the abscission process, was localized at the midbody in both adherent and non-adherent fibroblasts, but it was unable to efficiently recruit ALIX, TSG101, and consequently the ESCRT-III subunit CHMP4B was missing in the non-adherent cells. PLK1, a kinase that prevents premature recruitment of CEP55 to the midbody, disappeared from this site more rapidly in the non-adherent cells. A FAK-Src signaling pathway downstream of integrin-mediated cell adhesion was found to decelerate both PLK1 degradation and CEP55 accumulation at the midbody. These data identify the regulation of PLK1 and CEP55 as steps where integrins exert control over the cytokinetic abscission.

  • 13.
    Kamranvar, Siamak A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gupta, Deepesh Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wasberg, Anishia
    Liu, Liangwen
    Roig, J
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Focal adhesion kinase (FAK) is required for centrosome separation and subsequent bipolar mitotic spindle  assemblyManuscript (preprint) (Other academic)
  • 14. Lannergård, Jonas
    et al.
    Flock, Margareta
    Johansson, Staffan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Flock, Jan-Ingmar
    Guss, Bengt
    Studies of fibronectin-binding proteins of Streptococcus equi.2005In: Infect Immun, ISSN 0019-9567, Vol. 73, no 11, p. 7243-51Article in journal (Refereed)
  • 15.
    Lugano, Roberta
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vemuri, Kalyani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dejana, Elisabetta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Dimberg, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.2018In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 8, p. 3280-3297Article in journal (Refereed)
    Abstract [en]

    Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is up-regulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates integrin-β1-signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytical cleavage. The CD93-MMRN2 complex was required for activation of integrin-β1, phosphorylation of focal adhesion kinase (FAK) and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of integrin-β1 and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy.

  • 16. Lundholm, Carl
    et al.
    Norlen, Bo Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ekman, Peter
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lagerkvist, Mikael
    Lindeborg, Torsten
    Olsson, Jan Olov
    Tveter, Kjell
    Wijkstrom, Hans
    Westberg, Ronny
    Malmstrom, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    A randomized prospective study comparing long-term intravesical instillations of mitomycin-c and BCG in patients with superficial bladder carcinoma1996In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 156, no 2, p. 372-376Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    We compared the efficacy and toxicity of long-term mitomycin C versus bacillus Calmette-Guerin (BCG) instillation in patients at high risk for recurrence and progression of superficial bladder carcinoma.

    MATERIALS AND METHODS:

    Our randomized comparison study included 261 patients with primary dysplasia, or stage Tis, stage T1, grade 3 and multiple recurrent stage Ta/T1, grade 1 or 2 disease. Mitomycin C (40 mg.) or Pasteur strain BCG (120 mg.) was instilled weekly for 6 weeks, then monthly for up to 1 year and every 3 months during year 2.

    RESULTS:

    After a median followup of 39 months 49% of the patients given BCG and 34% given mitomycin C were disease-free (p < 0.03), compared to 48 and 35%, respectively, of those with stage Ta or T1 disease, and 54 and 33%, respectively, of those with dysplasia or stage Tis tumor. Tumor progressed in 13% of patients, with no statistically significant difference observed regarding progression between the mitomycin C and BCG groups. Side effects were more common after BCG instillation, with 5 cases of severe side effects compared to 1 in the mitomycin C group. Treatment was stopped due to toxicity in 10% of the patients.

    CONCLUSIONS:

    The majority of patients tolerated long-term intravesical therapy well. BCG instillation was hampered by more frequent side effects. BCG was superior regarding recurrence prophylaxis, since patients given BCG had fewer recurrences and a significantly longer time to treatment failure compared to those treated with mitomycin C. No statistically significant difference was observed regarding progression.

  • 17. McCourt, Peter
    et al.
    Hansen, Berit
    Svistuonov, Dmitri
    Johansson, Sophie
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Longati, Paola
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Schledzewski, Kai
    Kzhyshkowska, Julia
    Goerdt, Sergij
    Johansson, Staffan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Smedsröd, Bård
    The liver sinusoidal endothelial cell hyaluronan receptor and its homolog, stabilin-1 - Their roles (known and unknown) in endocytosis.2004In: Comp Hepatol, ISSN 1476-5926, Vol. 3 Suppl 1, p. S24-Article in journal (Other scientific)
  • 18.
    Nilsson, Stina
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kaniowska, Dorota
    Brakebusch, Cord
    Fässler, Reinhard
    Johansson, Staffan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Threonine 788 in integrin subunit beta1 regulates integrin activation.2006In: Exp Cell Res, ISSN 0014-4827, Vol. 312, no 6, p. 844-53Article in journal (Refereed)
  • 19.
    Nilsson, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kaniowska, Dorota
    Brakebusch, Cord
    Fässler, Reinhard
    Johansson, Staffan
    Threonine 788 in integrin subunit β1 regulates integrin activation2006In: Exp Cell Res., Vol. 312, no 6, p. 844-853Article in journal (Refereed)
  • 20.
    Nilsson, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wärmegård, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Velling, Teet
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Activation of Erk downstream of β1 integrins independently of FAK and ShcAManuscript (Other academic)
  • 21. Politz, Oliver
    et al.
    Gratchev, Alexei
    McCourt, Peter A. G.
    Schledzewski, Kai
    Guillot, Pierre
    Johansson, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Svineng, Gunborg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Franke, Peter
    Kannicht, Christoph
    Kzhyshkowska, Julia
    Longati, Paola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Velten, Florian W.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Goerdt, Sergij
    Stabilin-1 and -2 constitute a novel family of fasciclin-like hyaluronan receptor homologues2002In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 362, p. 155-164Article in journal (Refereed)
  • 22.
    Prasthofer, T
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Ek, B
    Ekman, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Owens, R
    Hook, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Protein kinase C phosphorylates two of the four known syndecan cytoplasmic domains in vitro1995In: Biochemistry and Molecular Biology International, ISSN 1039-9712, Vol. 36, no 4, p. 793-802Article in journal (Refereed)
    Abstract [en]

    The transmembrane heparan sulfate proteoglycans of the syndecan family are implicated to participate in several cellular reactions which are dependent on protein kinase C. We have used an in vitro assay to assess whether any of the Peptides corresponding to the complete cytoplasmic domains of rat syndecans 1 through 4 were used as substrates for the enzyme. The syndecan-2 (fibroglycan) and syndecan-3 (N-syndecan) peptides were both found to be phosphorylated by protein kinase C with Kms of 15 +/- 3 microM and 85 +/- 25 microM, respectively, while the syndecan-1 and -4 peptides were not phosphorylated under the conditions used. The sites of in vitro phosphorylation for syndecans-2 and -3 were localized to ser-197 and ser-339, respectively. Thus, among 13 available sites (serines and threonines) in the four peptides, two were selectively modified by the enzyme. The specificity and the kinetics of the reactions indicate that the cytoplasmic domains of syndecan-2 and -3 are likely to be physiological substrates for protein kinase C.

  • 23. Qian, Hong
    et al.
    Johansson, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    McCourt, Peter
    Smedsrød, Bård
    Ekblom, Marja
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stabilins are expressed in bone marrow sinusoidal endothelial cells and mediate scavenging and cell adhesive functions2009In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 390, no 3, p. 883-886Article in journal (Refereed)
    Abstract [en]

    Bone marrow sinusoidal endothelial cells have a specific function as a site of transmigration of hematopoietic stem and progenitor cells and mature blood cells between bone marrow and blood stream. However, the specific characteristics of bone marrow sinusoidal endothelial cells are still largely unclear. We here report that these cells express stabilin-1 and stabilin-2, which in liver sinusoidal endothelial cells have been identified as endocytic scavenger receptors for several ligands, including SPARC and hyaluronan. We show here that intravenously injected formaldehyde-treated serum albumin, advanced glycation end-products, and collagen I alpha-chains were taken up by bone marrow sinusoidal endothelial cells, showing that these cells have a scavenging function and thereby may modulate bone marrow vascular stem cell niches. Importantly, we show hyaluronan mediated adhesion of hematopoietic stem and progenitor cells to stabilin-2-transfected cells, suggesting that stabilin-2 contributes to adhesion and homing of circulating stem and progenitor cells to bone marrow.

  • 24.
    Retamal, Jaime
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Borges, Joao Batista
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Bruhn, A
    Cao, Xiaofang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Feinstein, R
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Suarez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    High respiratory rate is associated with early reduction of lung edema clearance in an experimental model of ARDS2016In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 60, no 1, p. 79-92Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The independent impact of respiratory rate on ventilator-induced lung injury has not been fully elucidated. The aim of this study was to investigate the effects of two clinically relevant respiratory rates on early ventilator-induced lung injury evolution and lung edema during the protective ARDSNet strategy. We hypothesized that the use of a higher respiratory rate during a protective ARDSNet ventilation strategy increases lung inflammation and, in addition, lung edema associated to strain-induced activation of transforming growth factor beta (TGF-β) in the lung epithelium.

    METHODS: Twelve healthy piglets were submitted to a two-hit lung injury model and randomized into two groups: LRR (20 breaths/min) and HRR (40 breaths/min). They were mechanically ventilated during 6 h according to the ARDSNet strategy. We assessed respiratory mechanics, hemodynamics, and extravascular lung water (EVLW). At the end of the experiment, the lungs were excised and wet/dry ratio, TGF-β pathway markers, regional histology, and cytokines were evaluated.

    RESULTS: No differences in oxygenation, PaCO2 levels, systemic and pulmonary arterial pressures were observed during the study. Respiratory system compliance and mean airway pressure were lower in LRR group. A decrease in EVLW over time occurred only in the LRR group (P < 0.05). Wet/dry ratio was higher in the HRR group (P < 0.05), as well as TGF-β pathway activation. Histological findings suggestive of inflammation and inflammatory tissue cytokines were higher in LRR.

    CONCLUSION: HRR was associated with more pulmonary edema and higher activation of the TGF-β pathway. In contrast with our hypothesis, HRR was associated with less lung inflammation.

  • 25.
    Riaz, Anjum
    et al.
    Univ Punjab, Inst Biochem & Biotechnol, Lahore 54590, Pakistan..
    Huang, Ying
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    G-Protein-Coupled Lysophosphatidic Acid Receptors and Their Regulation of AKT Signaling2016In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 17, no 2Article, review/survey (Refereed)
    Abstract [en]

    A hallmark of G-protein-coupled receptors (GPCRs) is their ability to recognize and respond to chemically diverse ligands. Lysophospholipids constitute a relatively recent addition to these ligands and carry out their biological functions by activating G-proteins coupled to a large family of cell-surface receptors. This review aims to highlight salient features of cell signaling by one class of these receptors, known as lysophosphatidic acid (LPA) receptors, in the context of phosphatidylinositol 3-kinase (PI3K)-AKT pathway activation. LPA moieties efficiently activate AKT phosphorylation and activation in a multitude of cell types. The interplay between LPA, its receptors, the associated Gi/o subunits, PI3K and AKT contributes to the regulation of cell survival, migration, proliferation and confers chemotherapy-resistance in certain cancers. However, detailed information on the regulation of PI3K-AKT signals induced by LPA receptors is missing from the literature. Here, some urgent issues for investigation are highlighted.

  • 26.
    Riaz, Anjum
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ilan, Neta
    Vlodavsky, Israel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Characterization of Heparanase-induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 17, p. 12366-12375Article in journal (Refereed)
    Abstract [en]

    Heparanase functions as a heparan sulfate-degrading enzyme and as a ligand for an unidentified signaling receptor(s). Here, several reactions involved in the activation of the PI3K-AKT pathway by latent heparanase were characterized. Protein suppression using specific siRNAs revealed that heparanase-induced phosphorylation of AKT at Ser-473 was RICTOR-mTOR-dependent, whereas ILK and PAK1/2 were dispensable. p110 alpha was the PI3K catalytic isoform preferred by heparanase for AKT activation and cell proliferation because the p110 alpha inhibitor YM024 blocked these processes. Heparanase-induced AKT phosphorylation was low in mouse embryonic fibroblast cells expressing a RAS interaction-defective p110 alpha compared with wild type cells, indicating that RAS has an important role in the PI3K-AKT activation. The response to heparanase was also inefficient in suspension cultures of several cell lines, suggesting a requirement of integrins in this pathway. Adhesion via either alpha V beta 3 or alpha 5 beta 1 promoted heparanase-induced AKT phosphorylation, and a stronger effect was seen when both integrins were engaged. Simultaneous inhibition of FAK and PYK2 using a chemical inhibitor, or suppression of their expression, inhibited heparanase-induced AKT activation and cell proliferation. Stimulation of cells with heparanase enhanced their resistance against oxidative stress-or growth factor starvation-induced apoptosis. These results demonstrate that there is an intimate crosstalk between the heparanase receptor(s) and integrins during induction of the prosurvival PI3K-AKT pathway by heparanase.

  • 27.
    Riaz, Anjum
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zeller, Kathrin Stephanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Receptor-Specific Mechanisms Regulate Phosphorylation of AKT at Ser473: Role of RICTOR in β1 Integrin-Mediated Cell Survival2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2, p. e32081-Article in journal (Refereed)
    Abstract [en]

    A tight control over AKT/PKB activation is essential for cells, and they realise this in part by regulating the phosphorylation of Ser473 in the "hydrophobic motif" of the AKT carboxy-terminal region. The RICTOR-mTOR complex (TORC2) is a major kinase for AKT Ser473 phosphorylation after stimulation by several growth factors, in a reaction proposed to require p21-activated kinase (PAK) as a scaffold. However, other kinases may catalyse this reaction in stimuli-specific manners. Here we characterised the requirement of RICTOR, ILK, and PAK for AKT Ser473 phosphorylation downstream of selected family members of integrins, G protein-coupled receptors, and tyrosine-kinase receptors and analysed the importance of this phosphorylation site for adhesion-mediated survival. siRNA-mediated knockdown in HeLa and MCF7 cells showed that RICTOR-mTOR was required for phosphorylation of AKT Ser473, and for efficient phosphorylation of the downstream AKT targets FOXO1 Thr24 and BAD Ser136, in response to β1 integrin-stimulation. ILK and PAK1/2 were dispensable for these reactions. RICTOR knockdown increased the number of apoptotic MCF7 cells on β1 integrin ligands up to 2-fold after 24 h in serum-free conditions. β1 integrin-stimulation induced phosphorylation of both AKT1 and AKT2 but markedly preferred AKT2. RICTOR-mTOR was required also for LPA-induced AKT Ser473 phosphorylation in MCF7 cells, but, interestingly, not in HeLa cells. PAK was needed for the AKT Ser473 phosphorylation in response to LPA and PDGF, but not to EGF. These results demonstrate that different receptors utilise different enzyme complexes to phosphorylate AKT at Ser473, and that AKT Ser473 phosphorylation significantly contributes to β1 integrin-mediated anchorage-dependent survival of cells.

  • 28.
    Roche, Francis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sipilä, Kalle
    Honjo, Satoshi
    Staffan, Johansson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tugues, Sonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Heino, Jyrki
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Histidine-rich glycoprotein blocks collagen-binding integrins and adhesion of endothelial cells through low-affinity interaction with alpha 2 integrin2015In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 48, p. 89-99Article in journal (Refereed)
    Abstract [en]

    The plasma protein histidine-rich glycoprotein (HRG) affects the morphology and function of both endothelial cells (ECs) and monocytes/macrophages in cancer. Here, we examined the mechanism of action of HRG's effect on ECs. HRG suppressed adhesion, spreading and migration of ECs specifically on collagen I (COL I) whereas ECs seeded on other extracellular matrix proteins were insensitive to HRG. HRG did not bind specifically to COL I or to the α-integrin binding site on collagen, GFOGER. Furthermore, HRG's inhibition of EC adhesion was not dependent upon heparan sulfate (HS) moieties as heparitinase-treated ECs remained sensitive to HRG. C2C12 cells expressing α2 integrin, the major collagen-binding α-integrin subunit in ECs, showed increased binding of HRG compared with wild type C2C12 cells lacking the α2 subunit. Recombinant α2 I-domain protein bound HRG and to a higher extent when in active conformation. However, the α2 I-domain bound weakly to HRG compared with COL I and the purified α2β1 ectodomain complex failed to retain HRG. We conclude that HRG binds to α2 integrin through low-affinity interactions in a HS-independent manner, thereby blocking EC-adhesion to COL I.

  • 29.
    Sandberg, Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Johansson, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Q Med AB, Uppsala, Sweden..
    Sagulin, Lisbeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Scavenging Endothelium of Pancreatic Islets Differential Expression of Stabilin-1 and Stabilin-2 in Mice and Humans2017In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 46, no 1, p. E4-E5Article in journal (Other academic)
  • 30. Smedsröd, Bård
    et al.
    Johansson, Staffan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Goerdt, Sergij
    Shooting HARE.2003In: Glycobiology, ISSN 0959-6658, Vol. 13, no 5, p. 11G-12G; author reply 12GArticle in journal (Other scientific)
  • 31.
    Snis, Niklas
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Technology, Department of Engineering Sciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Physics, Department of Physics and Materials Science, Materials Science.
    Simu, Urban
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Technology, Department of Engineering Sciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Physics, Department of Physics and Materials Science, Materials Science.
    Johansson, Staffan
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Technology, Department of Engineering Sciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Physics, Department of Physics and Materials Science, Materials Science.
    Piezoelectric Drive Platform for cm3-sized Autonomous Robot2004In: ACTUATOR, Bremen, Germany, 2004Conference paper (Refereed)
  • 32.
    Stefansson, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Armulik, Annika
    Nilsson, IngMarie
    von Heijne, Gunnar
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Determination of N- and C-terminal Borders of the Transmembrane Domain of Integrin Subunits2004In: The Journal of Biological Chemistry, ISSN 0021-9258, Vol. 279, no 20, p. 21200-21205Article in journal (Refereed)
  • 33.
    Stefansson, Anne
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Armulik, Annika
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nilsson, IngMarie
    von Heijne, Gunnar
    Johansson, Staffan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Determination of N- and C-terminal borders of the transmembrane domain of integrin subunits.2004In: J Biol Chem, ISSN 0021-9258, Vol. 279, no 20, p. 21200-5Article in journal (Refereed)
  • 34.
    Stefansson, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Idevall Hagren, Olof
    Velling, Teet
    Tengholm, Anders
    Johansson, Staffan
    Rapid integrin-induced cell spreading requires actin polymerisation mediated by PI3-kinase p110αManuscript (Other academic)
  • 35.
    Velling, Teet
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nilsson, Stina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stefansson, Anne
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    beta1-Integrins induce phosphorylation of Akt on serine 473 independently of focal adhesion kinase and Src family kinases.2004In: EMBO Rep, ISSN 1469-221X, Vol. 5, no 9, p. 901-5Article in journal (Refereed)
  • 36. Velling, Teet
    et al.
    Stefansson, Anne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    EGFR and beta1 integrins utilize different signaling pathways to activate Akt.2008In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 314, no 2, p. 309-316Article in journal (Refereed)
    Abstract [en]

    Akt, also called PKB, is a serine/threonine kinase that plays a major role in cell survival. It can be activated by several cellular receptors, including integrins and growth factor receptors, in PI3K-dependent manners. In this study, we analyzed the two current models for Akt activation upon beta1 integrin-mediated adhesion: via focal adhesion kinase and via transactivation of the EGF receptor. Distinct differences in the pathways leading to phosphorylation and activation of Akt from stimulated beta1 integrins and EGF receptor were observed, including opposing sensitivity to the tyrosine kinase inhibitors PP2 and Gefitinib. Using knockout cells and integrin mutant cells, we show that beta1 integrins can induce phosphorylation of Akt at Ser473 and Thr308 and Akt kinase activity independently of the EGF receptor activity, focal adhesion kinase, and the Src family members. In contrast to stimulation with EGF, beta1 integrin-mediated adhesion did not induce Akt tyrosine phosphorylation. Moreover, tyrosine phosphorylation of Akt was found not to be required for its catalytic activity. The results identify a previously unrecognized mechanism by which beta1 integrins activate the PI3K/Akt pathway.

  • 37.
    Velling, Teet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stefansson, Anne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    EGFR and β1-Integrins utilise different signalling pathways to activate Akt2008In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 314, no 2, p. 309-316Article in journal (Refereed)
    Abstract [en]

    Akt, also called PKB, is a serine/threonine kinase that plays a major role in cell survival. It can be activated by several cellular receptors, including integrins and growth factor receptors, in PI3K-dependent manners. In this study, we analyzed the two current models for Akt activation upon β1 integrin-mediated adhesion: via focal adhesion kinase and via transactivation of the EGF receptor. Distinct differences in the pathways leading to phosphorylation and activation of Akt from stimulated β1 integrins and EGF receptor were observed, including opposing sensitivity to the tyrosine kinase inhibitors PP2 and Gefitinib. Using knockout cells and integrin mutant cells, we show that β1 integrins can induce phosphorylation of Akt at Ser473 and Thr308 and Akt kinase activity independently of the EGF receptor activity, focal adhesion kinase, and the Src family members. In contrast to stimulation with EGF, β1 integrin-mediated adhesion did not induce Akt tyrosine phosphorylation. Moreover, tyrosine phosphorylation of Akt was found not to be required for its catalytic activity. The results identify a previously unrecognized mechanism by which β1 integrins activate the PI3K/Akt pathway.

  • 38.
    Wu, Cheng Jun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Öberg, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rashid, Asif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gupta, Rajesh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mignardi, Marco
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Svensson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A mouse mammary epithelial cell line permissive for highly efficient human adenovirus growth2013In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 435, no 2, p. 363-371Article in journal (Refereed)
    Abstract [en]

    Although a few immunocompetent animal models to study the immune response against human adenoviruses (HAdV) are available, such as Syrian hamsters and cotton rats, HAdV replication is several logs lower compared to human control cells. We have identified a non-transformed mouse epithelial cell line (NMuMG) where HAdV-2 gene expression and progeny formation was as efficient as in the highly permissive human A549 cells. HAdV from species, D and E (HAdV-37 and HAdV-4, respectively) also caused a rapid cytopathic effect in NMuMG cells, while HAdV from species A, B1, B2 and F (HAdV-12, HAdV-3, HAdV-11 and HAdV-41, respectively) failed to do so. NMuMG cells might therefore be useful in virotherapy research and the analysis of antiviral defense mechanisms and the determination of toxicity, biodistribution and specific antitumour activity of oncolytic HAdV vectors.

  • 39.
    Wu, Chengjun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Lund Univ, Div Med Microbiol, S-22100 Lund, Sweden..
    Cao, Xiaofang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Huijbers, Elisabeth J. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, Angiogenesis Lab, Amsterdam, Netherlands..
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Svensson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    HAdV-2-suppressed growth of SV40 T antigen-transformed mouse mammary epithelial cell-induced tumours in SCID mice2016In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 489, p. 44-50Article in journal (Refereed)
    Abstract [en]

    Human adenovirus (HAdV) vectors are promising tools for cancer therapy, but the shortage of efficient animal models for productive HAdV infections has restricted the evaluation of systemic effects to mainly immunodeficient mice. Previously, we reported a highly efficient replication of HAdV-2 in a non-tumorigenic mouse mammary epithelial cell line, NMuMG. Here we show that HAdV-2 gene expression and progeny formation in NMuMG cells transformed with the SV40 T antigen (NMuMG-T cells) were as efficient as in the parental NMuMG cells. Injection of HAdV-2 into tumours established by NMuMG-T in SCID mice caused reduced tumour growth and signs of intratumoural lesions. HAdV-2 replicated within the NMuMG-T-established tumours, but not in interspersed host-derived tissues within the tumours. The specific infection of NMuMG-T-derived tumours was verified by the lack of viral DNA in kidney, lung or spleen although low levels of viral DNA was occasionally found in liver.

  • 40.
    Zeller, Kathrin S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Idevall Hagren, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Stefansson, Anne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Velling, Teet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jackson, Shaun P.
    Downward, Julian
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    PI3-kinase p110 alpha mediates beta 1 integrin-induced Akt activation and membrane protrusion during cell attachment and initial spreading2010In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 22, no 12, p. 1838-1848Article in journal (Refereed)
    Abstract [en]

    Integrin-mediated cell adhesion activates several signaling effectors, including phosphatidylinositol 3-kinase (PI3K), a central mediator of cell motility and survival. To elucidate the molecular mechanisms of this important pathway the specific members of the PI3K family activated by different integrins have to be identified. Here, we studied the role of PI3K catalytic isoforms in beta 1 integrin-induced lamellipodium protrusion and activation of Akt in fibroblasts. Real-time total internal reflection fluorescence imaging of the membrane substrate interface demonstrated that beta 1 integrin-mediated attachment induced rapid membrane spreading reaching essentially maximal contact area within 5-10 min. This process required actin polymerization and involved activation of PI3K. Isoform-selective pharmacological inhibition identified p110 alpha as the PI3K catalytic isoform mediating both beta 1 integrin-induced cell spreading and Akt phosphorylation. A K756L mutation in the membrane-proximal part of the beta 1 integrin subunit, known to cause impaired Akt phosphorylation after integrin stimulation, induced slower cell spreading. The initial beta 1 integrin-regulated cell spreading as well as Akt phosphorylation were sensitive to the tyrosine kinase inhibitor PP2, but were not dependent on Src family kinases, FAK or EGF/PDGF receptor transactivation. Notably, cells expressing a Ras binding-deficient p110 alpha mutant were severely defective in integrin-induced Akt phosphorylation, but exhibited identical membrane spreading kinetics as wild-type p110 alpha cells. We conclude that p110 alpha mediates beta 1 integrin-regulated activation of Akt and actin polymerization important for survival and lamellipodia dynamics. This could contribute to the tumorigenic properties of cells expressing constitutively active p110 alpha.

  • 41. Zeller, Kathrin Stephanie
    et al.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Common and Diverging Integrin Signals Downstreamof Adhesion and Mechanical Stimuli and TheirInterplay with Reactive Oxygen Species2014In: Biophysical Reviews and Letters, ISSN 1793-0480, Vol. 9, no 2, p. 159-171Article in journal (Refereed)
    Abstract [en]

    The integrin family of adhesion receptors regulates basic functions of cells, and the signalsthey induce are altered in tumor cells. In this review we discuss how different integrindependentsignals are generated during cell adhesion and by physical forces acting oncells.We also describe how reactive oxygen species are integral parts of integrin signalingand highlight a few important questions in the field. Answers to those may improve ourunderstanding of integrins and their role in the development of cancer.

  • 42.
    Zeller, Kathrin Stephanie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Riaz, Anjum
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sarve, Hamid
    SLU, Centrum för bildanalys.
    Li, Jia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The role of mechanical force and ROS in integrin-dependent signals2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, article id e64897Article in journal (Refereed)
    Abstract [en]

    Cells are exposed to several types of integrin stimuli, which generate responses generally referred to as "integrin signals", but the specific responses to different integrin stimuli are poorly defined. In this study, signals induced byintegrin ligation during cell attachment, mechanical force from intracellular contraction, or cell stretching by external force were compared. The elevated phosphorylation levels of several proteins during the early phase of cell attachment and spreading of fibroblast cell lines were not affected by inhibition ofROCK and myosin II activity, i.e. the reactions occurred independently ofintracellular contractile force acting on the adhesion sites. The contraction-independent phosphorylation sites included ERK1/2 T202/Y204, AKT S473, p130CAS Y410, and cofilin S3. In contrast to cell attachment, cyclic stretching ofthe adherent cells induced a robust phosphorylation only of ERK1/2 and thephosphorylation levels of the other investigated proteins were not or only moderately affected by stretching. No major differences between signaling via alpha 5 beta 1 or alpha v beta 3 integrins were detected. The importance ofmitochondrial ROS for the integrin-induced signaling pathways was investigated using rotenone, a specific inhibitor of complex I in the respiratory chain. While rotenone only moderately reduced ATP levels and hardly affected the signalsinduced by cyclic cell stretching, it abolished the activation of AKT and reduced theactin polymerization rate in response to attachment in both cell lines. In contrast, scavenging of extracellular ROS with catalase or the vitamin C analog Asc-2P did not significantly influence the attachment-derived signaling, but caused a selective and pronounced enhancement of ERK1/2 phosphorylation in response to stretching. In conclusion, the results showed that "integrin signals" are composedof separate sets of reactions triggered by different types of integrin stimulation. Mitochondrial ROS and extracellular ROS had specific and distinct effects on theintegrin signals induced by cell attachment and mechanical stretching.

1 - 42 of 42
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