uu.seUppsala University Publications
Change search
Refine search result
1 - 16 of 16
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1. Cébe-Suarez, Stéphanie
    et al.
    Grünewald, Felix S.
    Jaussi, Rolf
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mercer, Andrew A.
    Prota, Andrea E.
    Ballmer-Hofer, Kurt
    Orf virus VEGF-E NZ2 promotes paracellular NRP-1/VEGFR-2 coreceptor assembly via the peptide RPPR2008In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 22, no 8, p. 3078-3086Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factors (VEGFs) interact with the receptor tyrosine kinases (RTKs) VEGFR-1, -2, and -3; neuropilins (NRPs); and heparan sulfate (HS) proteoglycans. VEGF RTKs signal to downstream targets upon ligand-induced tyrosine phosphorylation, while NRPs and HS act as coreceptors that lack enzymatic activity yet modulate signal output by VEGF RTKs. VEGFs exist in various isoforms with distinct receptor specificity and biological activity. Here, a series of mammalian VEGF-A splice variants and orf virus VEGF-Es, as well as chimeric and mutant VEGF variants, were characterized to determine the motifs required for binding to NRP-1 in the absence (VEGF-E) or presence (VEGF-A(165)) of an HS-binding sequence. We identified the carboxyterminal peptides RPPR and DKPRR as the NRP-1 binding motifs of VEGF-E and VEGF-A, respectively. RPPR had significantly higher affinity for NRP-1 than DKPRR. VEGFs containing an RPPR motif promoted HS-independent coreceptor complex assembly between VEGFR-2 and NRP-1, independent of whether these receptors were expressed on the same or separate cells grown in cocultures. Functional studies showed that stable coreceptor assembly by VEGF correlated with its ability to promote vessel formation in an embryoid body angiogenesis assay.

  • 2.
    Fernandez-Alonso, R.
    et al.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Martin-Lopez, M.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Gonzalez-Cano, L.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Garcia, S.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Castrillo, F.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Diez-Prieto, I.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain.;Univ Leon, Dept Med Cirugia & Anat Vet, E-24071 Leon, Spain..
    Fernandez-Corona, A.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain.;Complejo Hosp Leon, Leon 24071, Spain..
    Lorenzo-Marcos, M. E.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain.;Complejo Hosp Leon, Leon 24071, Spain..
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, S-75185 Uppsala, Sweden.;Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    Marques, M.
    Univ Leon, Inst Desarrollo Ganadero, E-24071 Leon, Spain..
    Marin, M. C.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGF beta signaling2015In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 22, no 8, p. 1287-+Article in journal (Refereed)
    Abstract [en]

    Vasculogenesis, the establishment of the vascular plexus and angiogenesis, branching of new vessels from the preexisting vasculature, involves coordinated endothelial differentiation, proliferation and migration. Disturbances in these coordinated processes may accompany diseases such as cancer. We hypothesized that the p53 family member p73, which regulates cell differentiation in several contexts, may be important in vascular development. We demonstrate that p73 deficiency perturbed vascular development in the mouse retina, decreasing vascular branching, density and stability. Furthermore, p73 deficiency could affect non endothelial cells (ECs) resulting in reduced in vivo proangiogenic milieu. Moreover, p73 functional inhibition, as well as p73 deficiency, hindered vessel sprouting, tubulogenesis and the assembly of vascular structures in mouse embryonic stem cell and induced pluripotent stem cell cultures. Therefore, p73 is necessary for EC biology and vasculogenesis and, in particular, that DNp73 regulates EC migration and tube formation capacity by regulation of expression of pro-angiogenic factors such as transforming growth factor-beta and vascular endothelial growth factors. DNp73 expression is upregulated in the tumor environment, resulting in enhanced angiogenic potential of B16-F10 melanoma cells. Our results demonstrate, by the first time, that differential p73-isoform regulation is necessary for physiological vasculogenesis and angiogenesis and DNp73 overexpression becomes a positive advantage for tumor progression due to its pro-angiogenic capacity.

  • 3.
    Hayashi, Makoto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Majumdar, Arindam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Adler, Jeremy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sun, Zuyue
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Vertuani, Simona
    Hellberg, Carina
    Mellberg, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Koch, Sina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Koh, Gou Young
    Dejana, Elisabetta
    Belting, Heinz-Georg
    Affolter, Markus
    Thurston, Gavin
    Holmgren, Lars
    Vestweber, Dietmar
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    VE-PTP regulates VEGFR2 activity in stalk cells to establish endothelial cell polarity and lumen formation2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 1672-Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF) guides the path of new vessel sprouts by inducing VEGF receptor-2 activity in the sprout tip. In the stalk cells of the sprout, VEGF receptor-2 activity is downregulated. Here, we show that VEGF receptor-2 in stalk cells is dephosphorylated by the endothelium-specific vascular endothelial-phosphotyrosine phosphatase (VE-PTP). VE-PTP acts on VEGF receptor-2 located in endothelial junctions indirectly, via the Angiopoietin-1 receptor Tie2. VE-PTP inactivation in mouse embryoid bodies leads to excess VEGF receptor-2 activity in stalk cells, increased tyrosine phosphorylation of VE-cadherin and loss of cell polarity and lumen formation. Vessels in ve-ptp(-/-) teratomas also show increased VEGF receptor-2 activity and loss of endothelial polarization. Moreover, the zebrafish VE-PTP orthologue ptp-rb is essential for polarization and lumen formation in intersomitic vessels. We conclude that the role of Tie2 in maintenance of vascular quiescence involves VE-PTP-dependent dephosphorylation of VEGF receptor-2, and that VEGF receptor-2 activity regulates VE-cadherin tyrosine phosphorylation, endothelial cell polarity and lumen formation.

  • 4.
    He, Qi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Cyrus Tang Hematology Center, Soochow University, Suzhou, China.
    Singh, Kailash
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Luo, Zhengkang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Meija-Cordova, Mariela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jamalpour, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lindahl, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kriz, Vitezslav
    Vuolteenaho, Reetta
    Ulvmar, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The Cdh5-CreERT2 transgene causes conditional Shb gene deletion in hematopoietic cells with consequences for immune cell responses to tumors2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 7548Article in journal (Refereed)
    Abstract [en]

    The tamoxifen-responsive conditional Cdh5-CreERT2 is commonly used for endothelial cell specific conditional deletion of loxP-flanked gene sequences. To address the role of endothelial cell Shb gene for B16F10 melanoma immune responses, tamoxifen-injected Cdh5-CreERT2/WT and Cdh5-CreERT2/Shbflox/flox mice received subcutaneous tumor cell injections. We observed a decrease of tumor myeloid cell Shb mRNA in the tamoxifen treated Cdh5-CreERT2/Shbflox/flox mice, which was not present when the mice had undergone a preceding bone marrow transplantation using wild type bone marrow. Differences in CD4+/FoxP3+ Tregs were similarly abolished by a preceding bone marrow transplantation. In ROSA26-mTmG mice, Cdh5-CreERT2 caused detectable floxing in certain bone marrow populations and in spleen cells. Floxing in bone marrow could be detected two months after tamoxifen treatment. In the spleen, however, floxing was undetectable two months after tamoxifen treatment, suggesting that Cdh5-CreERT2 is operating in a non-renewable population of hematopoietic cells in this organ. These data suggest that conditional gene deletion in hematopoietic cells is a potential confounder in experiments attempting to assess the role of endothelial specific effects. A cautious approach to achieve an endothelial-specific phenotype would be to adopt a strategy that includes a preceding bone marrow transplantation.

  • 5.
    Jamalpour, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gustafsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mostoslavsky, Gustavo
    Center for Regenerative Medicine (CReM), Department of Medicine, School of Medicine, Boston University..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tumor SHB gene expression affects disease characteristics in human acute myeloid leukemia2017In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 39, no 10Article in journal (Refereed)
    Abstract [en]

    Objective: The mouse Shb gene coding for the Src Homology 2-domain containing adapter protein B has recently been placed in context of BCRABL1-induced myeloid leukemia in mice and the current study was performed in order to relate SHB to human acute myeloid leukemia (AML). Methods: Publicly available AML databases were mined for SHB gene expression and patient survival. SHB gene expression was determined in the Uppsala cohort of AML patients by qPCR. Cell proliferation was determined after SHB gene knockdown in leukemic cell lines. Results: Despite a low frequency of SHB gene mutations, many tumors overexpressed SHB mRNA compared with normal myeloid blood cells. AML patients with tumors expressing low SHB mRNA displayed longer survival times. A subgroup of AML exhibiting a favorable prognosis, acute promyelocytic leukemia (APL) with a PMLRARA translocation, expressed less SHB mRNA than AML tumors in general. When examining genes co-expressed with SHB in AML tumors, four other genes (PAX5, HDAC7, BCORL1, TET1) related to leukemia were identified. A network consisting of these genes plus SHB was identified that relates to certain phenotypic characteristics, such as immune cell, vascular and apoptotic features. SHB knockdown in the APL PMLRARA cell line NB4 and the monocyte/macrophage cell line MM6 adversely affected proliferation, linking SHB gene expression to tumor cell expansion and consequently to patient survival. Conclusions: It is concluded that tumor SHB gene expression relates to AML survival and its subgroup APL. Moreover, this gene is included in a network of genes that plays a role for an AML phenotype exhibiting certain immune cell, vascular and apoptotic characteristics.

  • 6.
    Jamalpour, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Gustafsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mostoslavsky, Gustavo
    Center for Regenerative Medicine (CReM), Department of Medicine, School of Medicine, Boston University, Boston, MA, USA.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tumor SHB gene expression affects disease characteristics in human acute myeloid leukemia2017In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 39, no 10, article id 1010428317720643Article in journal (Refereed)
    Abstract [en]

    The mouse Shb gene coding for the Src Homology 2-domain containing adapter protein B has recently been placed in context of BCRABL1-induced myeloid leukemia in mice and the current study was performed in order to relate SHB to human acute myeloid leukemia (AML). Publicly available AML databases were mined for SHB gene expression and patient survival. SHB gene expression was determined in the Uppsala cohort of AML patients by qPCR. Cell proliferation was determined after SHB gene knockdown in leukemic cell lines. Despite a low frequency of SHB gene mutations, many tumors overexpressed SHB mRNA compared with normal myeloid blood cells. AML patients with tumors expressing low SHB mRNA displayed longer survival times. A subgroup of AML exhibiting a favorable prognosis, acute promyelocytic leukemia (APL) with a PMLRARA translocation, expressed less SHB mRNA than AML tumors in general. When examining genes co-expressed with SHB in AML tumors, four other genes (PAX5, HDAC7, BCORL1, TET1) related to leukemia were identified. A network consisting of these genes plus SHB was identified that relates to certain phenotypic characteristics, such as immune cell, vascular and apoptotic features. SHB knockdown in the APL PMLRARA cell line NB4 and the monocyte/macrophage cell line MM6 adversely affected proliferation, linking SHB gene expression to tumor cell expansion and consequently to patient survival. It is concluded that tumor SHB gene expression relates to AML survival and its subgroup APL. Moreover, this gene is included in a network of genes that plays a role for an AML phenotype exhibiting certain immune cell, vascular and apoptotic characteristics.

  • 7.
    Jamalpour, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gustafsson, Karin
    Harvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.;Center for Regenerative Medicine and the Cancer Center, Massachusetts General Hospital, MA, USA.
    Tyner, Jeffrey
    Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Disparate effects of Shb-gene deficiency on disease characteristics in murine models of myeloid, B-cell and T-cell leukemia2018In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 40, no 4, p. 1-13Article in journal (Refereed)
    Abstract [en]

    The Src homology-2 domain protein B is an adaptor protein operating downstream of tyrosine kinases. The Shb gene knockout has been found to accelerate p210 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase-induced leukemia. In human myeloid leukemia were tumors with high Src homology-2 domain protein B mRNA content, tumors were, however, associated with decreased latency and myeloid leukemia exhibiting immune cell characteristics. Thus, the aim of this study was to investigate the effects of Shb knockout on the development of leukemia in three additional models, that is, colony stimulating factor 3 receptor-T618I–induced neutrophilic leukemia, p190 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase-induced B-cell leukemia, and G12D-Kras-induced T-cell leukemia/thymic lymphoma. Wild-type or Shb knockout bone marrow cells expressing the oncogenes were transplanted to bone marrow–deficient recipients. Organs from moribund mice were collected and further analyzed. Shb knockout increased the development of CSF3RT618I-induced leukemia and increased the white blood cell count at the time of death. In the p190 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase B-cell model, Shb knockout reduced white blood cell counts without affecting latency, whereas in the G12D-Kras T-cell model, thymus size was increased without major effects on latency, suggesting that Shb knockout accelerates the development thymic lymphoma. Cytokine secretion plays a role in the progression of leukemia, and consequently Shb knockout bone marrows exhibited lower expression of granulocyte colony stimulating factor and interleukin 6 in the neutrophilic model and interleukin 7 and chemokine C-X-C motif ligand 12 (C-X-C motif chemokine 12) in the B-cell model. It is concluded that in experimental mouse models, the absence of the Shb gene exacerbates the disease in myeloid leukemia, whereas it alters the disease characteristics without affecting latency in B- and T-cell leukemia. The results suggest a role of Shb in modulating the disease characteristics depending on the oncogenic insult operating on hematopoietic cells. These findings help explain the outcome of human disease in relation to Src homology-2 domain protein B mRNA content.

  • 8.
    Kawamura, Harukiyo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Harper, Steven J
    Bates, David O
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Vascular endothelial growth factor (VEGF)-A165b is a weak in vitro agonist for VEGF receptor-2 due to lack of coreceptor binding and deficient regulation of kinase activity2008In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 68, no 12, p. 4683-4692Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF)-A165b is a COOH-terminal splice variant of VEGF-A that has been implicated in negative regulation of angiogenesis. We compared the properties of VEGF-A165b with those of VEGF-A121, VEGF-A145, and VEGF-A165. Induction of tyrosine phosphorylation sites in VEGFR-2 differed between the VEGF ligands as determined by tryptic phosphopeptide mapping and by use of phosphosite-specific antibodies. VEGF-A165b was considerably poorer in inducing phosphorylation of the positive regulatory site Y1052 in VEGFR-2. Whereas this did not affect activation of VEGFR-2 in vitro, we show that VEGF-A165b failed to induce vasculogenesis and sprouting angiogenesis in differentiating embryonic stem cells and vascularization of s.c. Matrigel plugs. In addition, the ability of the different VEGF ligands to induce angiogenesis correlated with their abilities to bind the VEGF coreceptor neuropilin 1 (NRP1). Our data indicate that loss of VEGFR-2/NRP1 complex formation and Y1052 phosphorylation contribute to the lack of angingenic properties of VEGF-A165b.

  • 9. Lanner, Fredrik
    et al.
    Lee, Kian Leong
    Ortega, German C.
    Sohl, Marcus
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Jin, Shaobo
    Hansson, Emil M.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Poellinger, Lorenz
    Lendahl, Urban
    Farnebo, Filip
    Hypoxia-Induced Arterial Differentiation Requires Adrenomedullin and Notch Signaling2013In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 22, no 9, p. 1360-1369Article in journal (Refereed)
    Abstract [en]

    Hypoxia (low oxygen) and Notch signaling are 2 important regulators of vascular development, but how they interact in controlling the choice between arterial and venous fates for endothelial cells during vasculogenesis is less well understood. In this report, we show that hypoxia and Notch signaling intersect in promotion of arterial differentiation. Hypoxia upregulated expression of the Notch ligand Dll4 and increased Notch signaling in a process requiring the vasoactive hormone adrenomedullin. Notch signaling also upregulated Dll4 expression, leading to a positive feedback loop sustaining Dll4 expression and Notch signaling. In addition, hypoxia-mediated upregulation of the arterial marker genes Depp, connexin40 (Gja5), Cxcr4, and Hey1 required Notch signaling. In conclusion, the data reveal an intricate interaction between hypoxia and Notch signaling in the control of endothelial cell differentiation, including a hypoxia/adrenomedullin/Dll4 axis that initiates Notch signaling and a requirement for Notch signaling to effectuate hypoxia-mediated induction of the arterial differentiation program.

  • 10.
    Li, Xiujuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Shibuya, Masabumi
    Department of Molecular Oncology, Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University, Tokyo, Japan .
    VEGF receptor signal transduction2008In: Angiogenesis: in vitro systems, San Diego, USA: Elsevier, 2008, p. 261-284Chapter in book (Other academic)
    Abstract [en]

    Signal transduction by vascular endothelial growth factors (VEGFs) through their cognate VEGF receptor tyrosine kinases follows the consensus scheme for receptor tyrosine kinases. Thus, binding of ligand induces receptor dimerization and activation of the tyrosine kinase through transphosphorylation between receptor molecules, leading to initiation of intracellular signal transduction pathways. Certain signal transduction pathways are shared with most, if not all, receptor tyrosine kinases, whereas some may be unique (e.g., transduced only by VEGF receptors). Indications that such unique signaling pathways may be discerned only when VEGF receptors are expressed in their proper context (i.e., in endothelial cells of microcapillary origin). In this chapter, we describe a number of methods for the study of signal transduction in endothelial cells. We describe how to isolate and examine endothelial cell lines. We also describe the embryoid body model representing vasculogenesis and angiogenesis, the procedure for subcutaneous Matrigel plugs, and, finally, how to construct gene-targeted mouse models. We emphasize the need for validation of in vitro data in more complex models, where endothelial cells reside in their proper three-dimensional context.

  • 11.
    Li, Xiujuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Edholm, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lanner, Fredrik
    Breier, Georg
    Farnebo, Filip
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lentiviral rescue of vascular endothelial growth factor receptor-2 expression in flk1-/- embryonic stem cells shows early priming of endothelial precursors2007In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 25, no 12, p. 2987-2995Article in journal (Refereed)
    Abstract [en]

    The vascular endothelial growth factor ( VEGF) family and its receptors are important for vascular development and maintenance of blood vessels, as well as for angiogenesis, the formation of new vessels. Loss of VEGF receptor-2 (VEGFR-2; designated Flk-1 in mouse) results in arrest of vascular and hematopoietic development in vivo. We used lentiviral transduction to reconstitute VEGFR-2 expression in flk1-/- embryonic stem (ES) cells. VEGF-induced vasculogenesis and sprouting angiogenesis were rescued in transduced ES cultures differentiating in vitro as EBs. Although the transgene was expressed in the pluripotent stem cells and lacked linage restriction during differentiation, the extent of endothelial recruitment was similar to that in wild-type EBs. Reconstitution of VEGFR-2 in flk1-/- ES cells allowed only precommitted precursors to differentiate into functional endothelial cells able to organize into vascular structures. Chimeric EB cultures composed of wild-type ES cells mixed with flk1-/- ES cells or reconstituted VEGFR-2expressing ES cells were created. In the chimeric cultures, flk1-/- endothelial precursors were excluded from wild-type vessel structures, whereas reconstituted VEGFR-2-expressing precursors became integrated together with wild-type endothelial cells to form chimeric vessels. We conclude that maturation of endothelial precursors, as well as organization into vascular structures, requires expression of VEGFR-2.

  • 12.
    Li, Xiujuan
    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.
    Padhan, Narendra
    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. Uppsala Univ, Sci Life Lab, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Sjöström, Elisabet O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Sci Life Lab, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Roche, Francis P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Testini, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Honkura, Naoki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sainz-Jaspeado, Miguel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gordon, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, 330 Brookline Ave, Boston, MA 02215 USA..
    Philippides, Andrew
    Univ Sussex, Ctr Computat Neurosci & Robot, Chichester 1 CI 104, Brighton BN1 9RH, E Sussex, England..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. IFOM IEO Campus, Via Adamello 16, I-20139 Milan, Italy..
    Stan, Radu V.
    Dartmouth Coll, Dept Pathol, Geisel Sch Med Dartmouth, Lebanon, NH 03756 USA..
    Vestweber, Dietmar
    Max Planck Inst Mol Biomed, Dept Vasc Cell Biol, Rontgenstr 20, D-48149 Munster, Germany..
    Ballmer-Hofer, Kurt
    Paul Scherrer Inst, Biomol Res, Mol Cell Biol, CH-5232 Villigen, Switzerland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Pietras, Kristian
    Lund Univ, Medicon Village, Translat Canc Res, Bldg 404-A3, S-22381 Lund, Sweden..
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11017Article in journal (Refereed)
    Abstract [en]

    The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.

  • 13.
    Li, Xiujuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Soochow University, Suzhou, China.
    Singh, Kailash
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Luo, Zhengkang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mejia Cordova, Mariela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jamalpour, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lindahl, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Zhang, Ganlin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pro-tumoral immune cell alterations in wild type and Shb-deficient mice in response to 4T1 breast carcinomas2018In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 27, p. 18720-18733Article in journal (Refereed)
    Abstract [en]

    To assess mechanisms responsible for breast carcinoma metastasis, 4T1 breast carcinomas were grown orthotopically in wild type or Shb knockout mice. Tumor growth, metastasis, vascular characteristics and immune cell properties were analyzed. Absence of Shb did not affect tumor growth although it increased lung metastasis. Shb knockout mouse tumors showed decreased redness and less developed vascular plexa located at the periphery of the tumors. No difference in overall tumor vascular density, leakage or pericyte coverage was noted between the genotypes although the average vessel size was smaller in the knockout. Tumors induced an increase of CD11b+ cells in spleen, lymph node, thymus, bone marrow and blood. Numbers of Shb knockout CD11b/CD8+ cells were decreased in lymph nodes and bone marrow of tumor bearing mice. Mice with tumors had reduced numbers of CD4+ lymphocytes in blood/lymphoid organs, whereas in most of these locations the proportion of CD4+ cells co-expressing FoxP3 was increased, suggesting a relative increase in Treg cells. This finding was reinforced by increased blood interleukin-35 (IL-35) in wild type tumor bearing mice. Shb knockout blood showed in addition an increased proportion of IL-35 expressing Treg cells, supporting the notion that absence of Shb further promotes tumor evasion from immune cell recognition. This could explain the increased number of lung metastases observed under these conditions. In conclusion, 4T1 tumors alter immune cell responses that promote tumor expansion, metastasis and escape from T cell recognition in an Shb dependent manner. 

  • 14.
    Rolny, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Mazzone, Massimiliano
    Tugues, Sònia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Laoui, Damya
    Johansson, Irja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Coulon, Cathy
    Squadrito, Mario Leonardo
    Segura, Inmaculada
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Knevels, Ellen
    Costa, Sandra
    Vinckier, Stefan
    Dresselaer, Tom
    Åkerud, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    De Mol, Maria
    Salomäki, Henriikka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Wyns, Sabine
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Buysschaert, Ian
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Himmelreich, Uwe
    Van Ginderachter, Jo A.
    De Palma, Michele
    Dewerchin, Mieke
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Carmeliet, Peter
    HRG Inhibits Tumor Growth and Metastasis by Inducing Macrophage Polarization and Vessel Normalization through Downregulation of PIGF2011In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 19, no 1, p. 31-44Article in journal (Refereed)
    Abstract [en]

    Polarization of tumor-associated macrophages (TAMs) to a proangiogenic/immune-suppressive (M2-like) phenotype and abnormal, hypoperfused vessels are hallmarks of malignancy, but their molecular basis and interrelationship remains enigmatic. We report that the host-produced histidine-rich glycoprotein (HRG) inhibits tumor growth and metastasis, while improving chemotherapy. By skewing TAM polarization away from the M2- to a tumor-inhibiting M1-like phenotype, HRG promotes antitumor immune responses and vessel normalization, effects known to decrease tumor growth and metastasis and to enhance chemotherapy. Skewing of TAM polarization by HAG relies substantially on downregulation of placental growth factor (PIGF). Besides unveiling an important role for TAM polarization in tumor vessel abnormalization, and its regulation by HRG/PIGF, these findings offer therapeutic opportunities for anticancer and antiangiogenic treatment.

  • 15. Sun, Zuyue
    et al.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Massena, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Kutschera, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Padhan, Narendra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Gualandi, Laura
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sundvold-Gjerstad, Vibeke
    Gustafsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Choy, Wing Wen
    Zang, Guangxiang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Quach, My
    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.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Abid, Md Ruhul
    Spurkland, Anne
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    VEGFR2 induces c-Src signaling and vascular permeability in vivo via the adaptor protein TSAd2012In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 209, no 7, p. 1363-1377Article in journal (Refereed)
    Abstract [en]

    Regulation of vascular endothelial (VE) growth factor (VEGF)-induced permeability is critical in physiological and pathological processes. We show that tyrosine phosphorylation of VEGF receptor 2 (VEGFR2) at Y951 facilitates binding of VEGFR2 to the Rous sarcoma (Src) homology 2-domain of T cell-specific adaptor (TSAd), which in turn regulates VEGF-induced activation of the c-Src tyrosine kinase and vascular permeability. c-Src was activated in vivo and in vitro in a VEGF/TSAd-dependent manner, and was regulated via increased phosphorylation at pY418 and reduced phosphorylation at pY527. Tsad silencing blocked VEGF-induced c-Src activation, but did not affect pathways involving phospholipase C gamma, extracellular regulated kinase, and endothelial nitric oxide. VEGF-induced rearrangement of VE-cadherin-positive junctions in endothelial cells isolated from mouse lungs, or in mouse cremaster vessels, was dependent on TSAd expression, and TSAd formed a complex with VE-cadherin, VEGFR2, and c-Src at endothelial junctions. Vessels in tsad(-/-) mice showed undisturbed flow and pressure, but impaired VEGF-induced permeability, as measured by extravasation of Evans blue, dextran, and microspheres in the skin and the trachea. Histamine-induced extravasation was not affected by TSAd deficiency. We conclude that TSAd is required for VEGF-induced, c-Src-mediated regulation of endothelial cell junctions and for vascular permeability.

  • 16.
    Tugues, Sonia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Honjo, Satoshi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    König, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Padhan, Narendra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Kroon, Jeffrey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gualandi, Laura
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Barkefors, Irmeli
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Thijssen, Victor L.
    Griffioen, Arjan W.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Tetraspanin CD63 Promotes Vascular Endothelial Growth Factor Receptor 2-beta 1 Integrin Complex Formation, Thereby Regulating Activation and Downstream Signaling in Endothelial Cells in Vitro and in Vivo2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 26, p. 19060-19071Article in journal (Refereed)
    Abstract [en]

    CD63 is a member of the transmembrane-4 glycoprotein superfamily (tetraspanins) implicated in the regulation of membrane protein trafficking, leukocyte recruitment, and adhesion processes. We have investigated the involvement of CD63 in endothelial cell (EC) signaling downstream of beta 1 integrin and VEGF. We report that silencing of CD63 in primary ECs arrested capillary sprouting and tube formation in vitro because of impaired adhesion and migration of ECs. Mechanistically, CD63 associated with both beta 1 integrin and the main VEGF receptor on ECs, VEGFR2. Our data suggest that CD63 serves to bridge between beta 1 integrin and VEGFR2 because CD63 silencing disrupted VEGFR2-beta 1 integrin complex formation identified using proximity ligation assays. Signaling downstream of beta 1 integrin and VEGFR2 was attenuated in CD63-silenced cells, although their cell surface expression levels remained unaffected. CD63 was furthermore required for efficient internalization of VEGFR2 in response to VEGF. Importantly, systemic delivery of VEGF failed to potently induce VEGFR2 phosphorylation and downstream signaling in CD63-deficient mouse lungs. Taken together, our findings demonstrate a previously unrecognized role for CD63 in coordinated integrin and receptor tyrosine kinase signaling in vitro and in vivo.

1 - 16 of 16
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf