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  • 1.
    Engelsdorf, Timo
    et al.
    Norwegian Univ Sci & Technol, Hogskoleringen 5, Dept Biol, N-7491 Trondheim, Norway;Philipps Univ Marburg, Dept Biol, Div Plant Physiol, D-35043 Marburg, Germany.
    Gigli-Bisceglia, Nora
    Norwegian Univ Sci & Technol, Hogskoleringen 5, Dept Biol, N-7491 Trondheim, Norway.
    Veerabagu, Manikandan
    Norwegian Univ Sci & Technol, Hogskoleringen 5, Dept Biol, N-7491 Trondheim, Norway;Norwegian Univ Life Sci, Dept Plant Sci, N-1432 As, Norway.
    McKenna, Joseph F.
    Imperial Coll London, Dept Biol, South Kensington Campus, London SW7 2AZ, England;Oxford Brookes Univ, Dept Biol & Med Sci, Plant Cell Biol, Oxford OX3 0BP, England.
    Vaahtera, Lauri
    Norwegian Univ Sci & Technol, Hogskoleringen 5, Dept Biol, N-7491 Trondheim, Norway.
    Augstein, Frauke
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Physiological Botany. Norwegian Univ Sci & Technol, Hogskoleringen 5, Dept Biol, N-7491 Trondheim, Norway;Uppsala Univ, Linnean Ctr Plant Biol, Ullsv 24E, SE-75651 Uppsala, Sweden.
    Van der Does, Dieuwertje
    Norwich Res Pk, Sainsbury Lab, Norwich Res Pk, Norwich NR4 7UH, Norfolk, England;2Blades Fdn BecA ILRI Hub, POB 30709, Nairobi 00100, Kenya.
    Zipfel, Cyril
    Norwich Res Pk, Sainsbury Lab, Norwich Res Pk, Norwich NR4 7UH, Norfolk, England.
    Hamann, Thorsten
    Norwegian Univ Sci & Technol, Hogskoleringen 5, Dept Biol, N-7491 Trondheim, Norway.
    The plant cell wall integrity maintenance and immune signaling systems cooperate to control stress responses in Arabidopsis thaliana2018In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 11, no 536, article id eaao3070Article in journal (Refereed)
    Abstract [en]

    Cell walls surround all plant cells, and their composition and structure are modified in a tightly controlled, adaptive manner to meet sometimes opposing functional requirements during growth and development. The plant cell wall integrity (CWI) maintenance mechanism controls these functional modifications, as well as responses to cell wall damage (CWD). We investigated how the CWI system mediates responses to CWD in Arabidopsis thaliana. CWD induced by cell wall-degrading enzymes or an inhibitor of cellulose biosynthesis elicited similar, turgor-sensitive stress responses. Phenotypic clustering with 27 genotypes identified a core group of receptor-like kinases (RLKs) and ion channels required for the activation of CWD responses. A genetic analysis showed that the RLK FEI2 and the plasma membrane-localized mechanosensitive Ca2+ channel MCA1 functioned downstream of the RLK THE1 in CWD perception. In contrast, pattern-triggered immunity (PTI) signaling components, including the receptors for plant elicitor peptides (AtPeps) PEPR1 and PEPR2, repressed responses to CWD. CWD induced the expression of PROPEP1 and PROPEP3, which encode the precursors of AtPep1 and AtPep3, and the release of PROPEP3 into the growth medium. Application of AtPep1 and AtPep3 repressed CWD-induced phytohormone accumulation in a concentration-dependent manner. These results suggest that AtPep-mediated signaling suppresses CWD-induced defense responses controlled by the CWI mechanism. This suppression was alleviated when PTI signaling downstream of PEPR1 and PEPR2 was impaired. Defense responses controlled by the CWI maintenance mechanism might thus compensate to some extent for the loss of PTI signaling elements.

  • 2.
    Gordon, Emma J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Fukuhara, Daisuke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Kyorin Univ, Sch Med, Dept Pediat, 6-20-2 Shinkawa, Mitaka, Tokyo 1818611, Japan..
    Weström, Simone
    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, Vascular Biology.
    Sjöström, Elisabet O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    van Meeteren, Laurens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Orsenigo, Fabrizio
    IFOM, FIRC Inst Mol Oncol Fdn, I-20139 Milan, Italy..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. IFOM, FIRC Inst Mol Oncol Fdn, I-20139 Milan, Italy..
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA..
    Spurkland, Anne
    Univ Oslo, Inst Basic Med Sci, Dept Mol Med, N-0317 Oslo, Norway..
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    The endothelial adaptor molecule TSAd is required for VEGF-induced angiogenic sprouting through junctional c-Src activation2016In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 9, no 437, article id ra72Article in journal (Refereed)
    Abstract [en]

    Activation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by VEGF binding is critical for vascular morphogenesis. In addition, VEGF disrupts the endothelial barrier by triggering the phosphorylation and turnover of the junctional molecule VE-cadherin, a process mediated by the VEGFR2 downstream effectors T cell-specific adaptor (TSAd) and the tyrosine kinase c-Src. We investigated whether the VEGFR2-TSAd-c-Src pathway was required for angiogenic sprouting. Indeed, Tsad-deficient embryoid bodies failed to sprout in response to VEGF. Tsad-deficient mice displayed impaired angiogenesis specifically during tracheal vessel development, but not during retinal vasculogenesis, and in VEGF-loaded Matrigel plugs, but not in those loaded with FGF. The SH2 and proline-rich domains of TSAd bridged VEGFR2 and c-Src, and this bridging was critical for the localization of activated c-Src to endothelial junctions and elongation of the growing sprout, but not for selection of the tip cell. These results revealed that vascular sprouting and permeability are both controlled through the VEGFR2-TSAd-c-Src signaling pathway in a subset of tissues, which may be useful in developing strategies to control tissue-specific pathological angiogenesis.

  • 3.
    Hamidi, Anahita
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Song, Jie
    Umea Univ, Dept Med Biosci, Unit Pathol, SE-90185 Umea, Sweden.
    Thakur, Noopur
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Itoh, Susumu
    Showa Pharmaceut Univ, Biochem Lab, Tokyo 1948543, Japan.
    Marcusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergh, Anders
    Umea Univ, Dept Med Biosci, Unit Pathol, SE-90185 Umea, Sweden.
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Landström, Maréne
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Umea Univ, Dept Med Biosci, Unit Pathol, SE-90185 Umea, Sweden.
    TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α2017In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 10, no 486, article id eaal4186Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-b (TGF-beta) is a pluripotent cytokine that regulates cell fate and plasticity in normal tissues and tumors. The multifunctional cellular responses evoked by TGF-beta are mediated by the canonical SMAD pathway and by noncanonical pathways, including mitogen-activated protein kinase (MAPK) pathways and the phosphatidylinositol 3'-kinase (PI3K)-protein kinase B (AKT) pathway. We found that TGF-b activated PI3K in a manner dependent on the activity of the E3 ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6). TRAF6 polyubiquitylated the PI3K regulatory subunit p85 alpha and promoted the formation of a complex between the TGF-beta type I receptor (T beta RI) and p85 alpha, which led to the activation of PI3K and AKT. Lys(63)-linked polyubiquitylation of p85 alpha on Lys(513) and Lys(519) in the iSH2 (inter-Src homology 2) domain was required for TGF-beta-induced activation of PI3K-AKT signaling and cell motility in prostate cancer cells and activated macrophages. Unlike the activation of SMAD pathways, the TRAF6-mediated activation of PI3K and AKT was not dependent on the kinase activity of TbRI. In situ proximity ligation assays revealed that polyubiquitylation of p85a was evident in aggressive prostate cancer tissues. Thus, our data reveal a molecular mechanism by which TGF-b activates the PI3K-AKT pathway to drive cell migration.

  • 4.
    Hamidi, Anahita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Thakur, Noopur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Marcusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Landstöm, Marene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    TGFβ promotes cancer cell migration via TRAF6-specific ubiquitination of p85α causing activation of the PI3K/AKT pathwayIn: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145Article in journal (Refereed)
  • 5.
    Idevall-Hagren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jakobsson, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Xu, Yunjian
    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.
    Spatial Control of Epac2 Activity by cAMP and Ca2+-Mediated Activation of Ras in Pancreatic beta Cells2013In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 6, no 273, p. ra29-Article in journal (Refereed)
    Abstract [en]

    The cAMP (adenosine 3',5'-monophosphate)-activated guanine nucleotide exchange factor (GEF) Epac2 is an important mediator of cAMP-dependent processes in multiple cell types. We used real-time confocal and total internal reflection fluorescence microscopy to examine the spatiotemporal regulation of Epac2, which is a GEF for the guanosine triphosphatase (GTPase) Rap. We demonstrated that increases in the concentration of cAMP triggered the translocation of Epac2 from the cytoplasm to the plasma membrane in insulin-secreting beta cells. Glucose-induced oscillations of the submembrane concentration of cAMP were associated with cyclic translocation of Epac2, and this translocation could be amplified by increases in the cytoplasmic Ca2+ concentration. Analyses of Epac2 mutants identified the high-affinity cAMP-binding and the Ras association domains as crucial for the translocation. Expression of a dominant-negative Ras mutant reduced Epac2 translocation, and Ca2+-dependent oscillations in Ras activity synchronized with Epac2 translocation in single beta cells. The cyclic translocation of Epac2 was accompanied by oscillations of Rap GTPase activity at the plasma membrane, and expression of an inactive Rap1B mutant decreased insulin secretion. Thus, Epac2 localization is dynamically controlled by cAMP as well as by Ca2+-mediated activation of Ras. These results help to explain how oscillating signals can produce pulses of insulin release from pancreatic b cells.

  • 6.
    Morikawa, Masato
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Tokyo, Grad Sch Med, Dept Mol Med, Bunkyo Ku, Tokyo 1130033, Japan.
    Mitani, Yoshihide
    Mie Univ, Grad Sch Med, Dept Pediat, Tsu, Mie 5148507, Japan.
    Holmborn, Katarina
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kato, Taichi
    Mie Univ, Grad Sch Med, Dept Pediat, Tsu, Mie 5148507, Japan;Nagoya Univ, Grad Sch Med, Dept Pediat Dev Pediat, Nagoya, Aichi 4668550, Japan.
    Koinuma, Daizo
    Univ Tokyo, Grad Sch Med, Dept Mol Med, Bunkyo Ku, Tokyo 1130033, Japan.
    Maruyama, Junko
    Mie Univ, Grad Sch Med, Dept Anesthesiol, Tsu, Mie 5148507, Japan;Suzuka Univ Med Sci, Fac Med Engn, Suzuka, Mie 5100293, Japan.
    Vasilaki, Eleftheria
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sawada, Hirofumi
    Mie Univ, Grad Sch Med, Dept Pediat, Tsu, Mie 5148507, Japan;Mie Univ, Grad Sch Med, Dept Anesthesiol, Tsu, Mie 5148507, Japan.
    Kobayashi, Mai
    Univ Tokyo, Grad Sch Med, Dept Mol Med, Bunkyo Ku, Tokyo 1130033, Japan.
    Ozawa, Takayuki
    Univ Tokyo, Grad Sch Med, Dept Mol Med, Bunkyo Ku, Tokyo 1130033, Japan.
    Morishita, Yasuyuki
    Univ Tokyo, Grad Sch Med, Dept Mol Med, Bunkyo Ku, Tokyo 1130033, Japan.
    Bessho, Yasumasa
    Kyoto Univ, Inst Frontier Life & Med Sci, Sakyo Ku, Kyoto 6068507, Japan;Nara Inst Sci & Technol NAIST, Grad Sch Biol Sci, Dept Syst Biol, Nara 6300101, Japan.
    Maeda, Shingo
    Kagoshima Univ, Dept Med Joint Mat, Kagoshima, Kagoshima 8908544, Japan.
    Ledin, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Aburatani, Hiroyuki
    Univ Tokyo, RCAST, Genome Sci Div, Meguro Ku, Tokyo 1538904, Japan.
    Kageyama, Ryoichiro
    Kyoto Univ, Inst Frontier Life & Med Sci, Sakyo Ku, Kyoto 6068507, Japan.
    Maruyama, Kazuo
    Mie Univ, Grad Sch Med, Dept Anesthesiol, Tsu, Mie 5148507, Japan.
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Miyazono, Kohei
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Tokyo, Grad Sch Med, Dept Mol Med, Bunkyo Ku, Tokyo 1130033, Japan.
    The ALK-1/SMAD/ATOH8 axis attenuates hypoxic responses and protects against the development of pulmonary arterial hypertension2019In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 12, no 607, article id eaay4430Article in journal (Refereed)
    Abstract [en]

    Dysregulated bone morphogenetic protein (BMP) signaling in endothelial cells (ECs) is implicated in vascular diseases such as pulmonary arterial hypertension (PAH). Here, we showed that the transcription factor ATOH8 was a direct target of SMAD1/5 and was induced in a manner dependent on BMP but independent of Notch, another critical signaling pathway in ECs. In zebrafish and mice, inactivation of Atoh8 did not cause an arteriovenous malformation-like phenotype, which may arise because of dysregulated Notch signaling. In contrast, Atoh8-deficient mice exhibited a phenotype mimicking PAH, which included increased pulmonary arterial pressure and right ventricular hypertrophy. Moreover, ATOH8 expression was decreased in PAH patient lungs. We showed that in cells, ATOH8 interacted with hypoxia-inducible factor 2 alpha (HIF-2 alpha) and decreased its abundance, leading to reduced induction of HIF-2 alpha target genes in response to hypoxia. Together, these findings suggest that the BMP receptor type II/ALK-1/SMAD/ATOH8 axis may attenuate hypoxic responses in ECs in the pulmonary circulation and may help prevent the development of PAH.

  • 7.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    The mitotic checkpoint protein kinase BUB1 is an engine in the TGF-beta signaling apparatus2015In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 8, no 359, article id fs1Article in journal (Other academic)
    Abstract [en]

    The transforming growth factor-beta (TGF-beta) pathway mediates critical events in cell behavior that contribute to development and disease. The mitotic checkpoint guarantees faithful chromosomal segregation during cell division. In the 6 January 2015 issue of Science Signaling, Nyati et al. reported that the mitotic checkpoint kinase BUB1 promotes the activity of TGF-beta receptors, which adds new molecular links between these fundamental biological processes.

  • 8.
    Okita, Yukari
    et al.
    Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Expt Pathol, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan.;Univ Tsukuba, Fac Med, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan..
    Kimura, Minori
    Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Expt Pathol, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan.;Univ Tsukuba, Fac Med, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan..
    Xie, Rudy
    Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Expt Pathol, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan.;Univ Tsukuba, Fac Med, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan..
    Chen, Chen
    Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Expt Pathol, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan.;Univ Tsukuba, Fac Med, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan..
    Shen, Larina Tzu-Wei
    Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Expt Pathol, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan.;Univ Tsukuba, Fac Med, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan..
    Kojima, Yurika
    Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Expt Pathol, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan.;Univ Tsukuba, Fac Med, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan..
    Suzuki, Hiroyuki
    Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Expt Pathol, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan.;Univ Tsukuba, Fac Med, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan..
    Muratani, Masafumi
    Univ Tsukuba, Fac Med, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan.;Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Genome Biol, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan..
    Saitoh, Masao
    Univ Yamanashi, Grad Sch Med & Engn, Dept Biochem, Chuo Ku, 1110 Shimokato, Yamanashi 4093898, Japan..
    Semba, Kentaro
    Waseda Univ, Sch Adv Sci & Engn, Dept Life Sci & Med Biosci, Shinjuku Ku, 2-2Wakamatsu Cho, Tokyo 1628480, Japan..
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kato, Mitsuyasu
    Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Expt Pathol, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan.;Univ Tsukuba, Fac Med, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan..
    The transcription factor MAFK induces EMT and malignant progression of triple-negative breast cancer cells through its target GPNMB2017In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 10, no 474, article id eaak9397Article in journal (Refereed)
    Abstract [en]

    Triple-negative breast cancer (TNBC) is particularly aggressive and difficult to treat. For example, the transforming growth factor-beta (TGF-beta) pathway is implicated in TNBC progression and metastasis, but its opposing role in tumor suppression in healthy tissues and early-stage lesions makes it a challenging target. Therefore, additional molecular characterization of TNBC may lead to improved patient prognosis by informing the development and optimum use of targeted therapies. We found that musculoaponeurotic fibrosarcoma (MAF) oncogene family protein K (MAFK), a member of the small MAF family of transcription factors that are induced by the TGF-beta pathway, was abundant in human TNBC and aggressive mouse mammary tumor cell lines. MAFK promoted tumorigenic growth and metastasis by 4T1 cells when implanted subcutaneously in mice. Overexpression of MAFK in mouse breast epithelial NMuMG cells induced epithelial-mesenchymal transition (EMT) phenotypes and promoted tumor formation and invasion in mice. MAFK induced the expression of the gene encoding the transmembrane glycoprotein nmb(GPNMB). Similar to MAFK, GPNMB overexpression in NMuMG cells induced EMT, tumor formation, and invasion, in mice, whereas knockdown of MAFK in tumor cells before implantation suppressed tumor growth and progression. MAFK and GPNMB expression correlated with poor prognosis in TNBC patients. These findings suggest that MAFK and its target gene GPNMB play important roles in the malignant progression of TNBC cells, offering potentially new therapeutic targets for TNBC patients.

  • 9.
    Roth, Lise
    et al.
    German Canc Res Ctr DKFZ ZMBH Alliance, Div Vasc Oncol & Metastasis, D-69120 Heidelberg, Germany.;Heidelberg Univ, Med Fac Mannheim, Dept Vasc Biol & Tumor Angiogenesis CBTM, D-68167 Mannheim, Germany..
    Prahst, Claudia
    German Canc Res Ctr DKFZ ZMBH Alliance, Div Vasc Oncol & Metastasis, D-69120 Heidelberg, Germany.;Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02215 USA..
    Ruckdeschel, Tina
    German Canc Res Ctr DKFZ ZMBH Alliance, Div Vasc Oncol & Metastasis, D-69120 Heidelberg, Germany..
    Savant, Soniya
    German Canc Res Ctr DKFZ ZMBH Alliance, Div Vasc Oncol & Metastasis, D-69120 Heidelberg, Germany.;Karolinska Inst, Dept Cell & Mol Biol, SE-171 Stockholm, Sweden..
    Weström, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. German Canc Res Ctr DKFZ ZMBH Alliance, Div Vasc Oncol & Metastasis, D-69120 Heidelberg, Germany..
    Fantin, Alessandro
    UCL, UCL Inst Ophthalmol, London EC1V 9EL, England..
    Riedel, Maria
    German Canc Res Ctr DKFZ ZMBH Alliance, Div Vasc Oncol & Metastasis, D-69120 Heidelberg, Germany..
    Heroult, Melanie
    German Canc Res Ctr DKFZ ZMBH Alliance, Div Vasc Oncol & Metastasis, D-69120 Heidelberg, Germany.;Bayer AG, Innovat Strategy Dept, D-51368 Leverkusen, Germany..
    Ruhrberg, Christiana
    UCL, UCL Inst Ophthalmol, London EC1V 9EL, England..
    Augustin, Hellmut G.
    German Canc Res Ctr DKFZ ZMBH Alliance, Div Vasc Oncol & Metastasis, D-69120 Heidelberg, Germany.;Heidelberg Univ, Med Fac Mannheim, Dept Vasc Biol & Tumor Angiogenesis CBTM, D-68167 Mannheim, Germany..
    Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation2016In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 9, no 425, article id ra42Article in journal (Refereed)
    Abstract [en]

    Neuropilin-1 (NRP1) regulates developmental and pathological angiogenesis, arteriogenesis, and vascular permeability, acting as a coreceptor for semaphorin 3A (Sema3A) and the 165-amino acid isoform of vascular endothelial growth factor A (VEGF-A(165)). NRP1 is also the receptor for the CendR peptides, a class of cell-and tissue-penetrating peptides with a specific R-x-x-R carboxyl-terminal motif. Because the cytoplasmic domain of NRP1 lacks catalytic activity, NRP1 is mainly thought to act through the recruitment and binding to other receptors. We report here that the NRP1 intracellular domain mediates vascular permeability. Stimulation with VEGF-A(165), a ligand-blocking antibody, and a CendR peptide led to NRP1 accumulation at cell-cell contacts in endothelial cell monolayers, increased cellular permeability in vitro and vascular leakage in vivo. Biochemical analyses, VEGF receptor-2 (VEGFR-2) silencing, and the use of a specific VEGFR blocker established that the effects induced by the CendR peptide and the antibody were independent of VEGFR-2. Moreover, leakage assays in mice expressing a mutant NRP1 lacking the cytoplasmic domain revealed that this domain was required for NRP1-induced vascular permeability in vivo. Hence, these data define a vascular permeability pathway mediated by NRP1 but independent of VEGFR-2 activation.

  • 10.
    Uhlen, Mathias
    et al.
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden;Tech Univ Denmark, Ctr Biosustainabil, Lyngby, Denmark;Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Karlsson, Max J.
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Hober, Andreas
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Svensson, Anne-Sophie
    KTH Royal Inst Technol, Albanova Univ Ctr, Dept Prot Sci, Stockholm, Sweden.
    Scheffel, Julia
    KTH Royal Inst Technol, Albanova Univ Ctr, Dept Prot Sci, Stockholm, Sweden.
    Kotol, David
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Zhong, Wen
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Tebani, Abdellah
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Strandberg, Linnea
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Edfors, Fredrik
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden;Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
    Sjostedt, Evelina
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Mardinoglu, Adil
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Berling, Anna
    KTH Royal Inst Technol, Albanova Univ Ctr, Dept Prot Sci, Stockholm, Sweden.
    Ekblad, Siri
    KTH Royal Inst Technol, Albanova Univ Ctr, Dept Prot Sci, Stockholm, Sweden.
    Dannemeyer, Melanie
    KTH Royal Inst Technol, Albanova Univ Ctr, Dept Prot Sci, Stockholm, Sweden.
    Kanje, Sara
    KTH Royal Inst Technol, Albanova Univ Ctr, Dept Prot Sci, Stockholm, Sweden.
    Rockberg, Johan
    KTH Royal Inst Technol, Albanova Univ Ctr, Dept Prot Sci, Stockholm, Sweden.
    Lundqvist, Magnus
    KTH Royal Inst Technol, Albanova Univ Ctr, Dept Prot Sci, Stockholm, Sweden.
    Malm, Magdalena
    KTH Royal Inst Technol, Albanova Univ Ctr, Dept Prot Sci, Stockholm, Sweden.
    Volk, Anna-Luisa
    KTH Royal Inst Technol, Albanova Univ Ctr, Dept Prot Sci, Stockholm, Sweden.
    Nilsson, Peter
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Manberg, Anna
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Dodig-Crnkovic, Tea
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Pin, Elisa
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Zwahlen, Martin
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Oksvold, Per
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    von Feilitzen, Kalle
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Haussler, Ragna S.
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Hong, Mun-Gwan
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Katona, Borbala
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Vuu, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Lindström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nielsen, Jens
    Chalmers Univ Technol, Dept Chem & Biol Engn, Gothenburg, Sweden.
    Robinson, Jonathan
    Chalmers Univ Technol, Dept Chem & Biol Engn, Gothenburg, Sweden.
    Ayoglu, Burcu
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Mahdessian, Diana
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Sullivan, Devin
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Thul, Peter
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Danielsson, Frida
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Stadler, Charlotte
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Lundberg, Emma
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Bergstrom, Goran
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden;Sahlgrens Univ Hosp, Dept Clin Physiol, Gothenburg, Region Vastra G, Sweden.
    Gummesson, Anders
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden.
    Voldborg, Bjorn G.
    Tech Univ Denmark, Ctr Biosustainabil, Lyngby, Denmark.
    Tegel, Hanna
    KTH Royal Inst Technol, Albanova Univ Ctr, Dept Prot Sci, Stockholm, Sweden.
    Hober, Sophia
    KTH Royal Inst Technol, Albanova Univ Ctr, Dept Prot Sci, Stockholm, Sweden.
    Forsstrom, Bjorn
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Fagerberg, Linn
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    Sivertsson, Asa
    KTH Royal Inst Technol, Sci Life Lab, Dept Prot Sci, Stockholm, Sweden.
    The human secretome2019In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 12, no 609, article id eaaz0274Article in journal (Refereed)
    Abstract [en]

    The proteins secreted by human cells (collectively referred to as the secretome) are important not only for the basic understanding of human biology but also for the identification of potential targets for future diagnostics and therapies. Here, we present a comprehensive analysis of proteins predicted to be secreted in human cells, which provides information about their final localization in the human body, including the proteins actively secreted to peripheral blood. The analysis suggests that a large number of the proteins of the secretome are not secreted out of the cell, but instead are retained intracellularly, whereas another large group of proteins were identified that are predicted to be retained locally at the tissue of expression and not secreted into the blood. Proteins detected in the human blood by mass spectrometry-based proteomics and antibody-based immuno-assays are also presented with estimates of their concentrations in the blood. The results are presented in an updated version 19 of the Human Protein Atlas in which each gene encoding a secretome protein is annotated to provide an open-access knowledge resource of the human secretome, including body-wide expression data, spatial localization data down to the single-cell and subcellular levels, and data about the presence of proteins that are detectable in the blood.

  • 11.
    Vasilaki, Eleftheria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Morikawa, Masato
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Koinuma, Daizo
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Bunkyo Ku, Tokyo 1130033, Japan..
    Mizutani, Anna
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Bunkyo Ku, Tokyo 1130033, Japan..
    Hirano, Yudai
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Bunkyo Ku, Tokyo 1130033, Japan..
    Ehata, Shogo
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Bunkyo Ku, Tokyo 1130033, Japan..
    Sundqvist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kawasaki, Natsumi
    Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Bunkyo Ku, Tokyo 1130033, Japan..
    Cedervall, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Aburatani, Hiroyuki
    Univ Tokyo, Genome Sci Div, Res Ctr Adv Sci & Technol, Meguro Ku, Tokyo 1538904, Japan..
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Miyazono, Kohei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Bunkyo Ku, Tokyo 1130033, Japan..
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ras and TGF-beta signaling enhance cancer progression by promoting the Delta Np63 transcriptional program2016In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 9, no 442, article id ra84Article in journal (Refereed)
    Abstract [en]

    The p53 family of transcription factors includes p63, which is a master regulator of gene expression in epithelial cells. Determining whether p63 is tumor-suppressive or tumorigenic is complicated by isoform-specific and cellular context-dependent protein associations, as well as antagonism from mutant p53. Delta Np63 is an amino-terminal-truncated isoform, that is, the predominant isoform expressed in cancer cells of epithelial origin. In HaCaT keratinocytes, which have mutant p53 and Delta Np63, we found that mutant p53 antagonized Delta Np63 transcriptional activity but that activation of Ras or transforming growth factor-beta (TGF-beta) signaling pathways reduced the abundance of mutant p53 and strengthened target gene binding and activity of Delta Np63. Among the products of Delta Np63-induced genes was dual-specificity phosphatase 6 (DUSP6), which promoted the degradation of mutant p53, likely by dephosphorylating p53. Knocking down all forms of p63 or DUSP6 and DUSP7 (DUSP6/7) inhibited the basal or TGF-beta-induced or epidermal growth factor (which activates Ras)-induced migration and invasion in cultures of p53-mutant breast cancer and squamous skin cancer cells. Alternatively, overexpressing Delta Np63 in the breast cancer cells increased their capacity to colonize various tissues upon intracardiac injection in mice, and this was inhibited by knocking down DUSP6/7 in these Delta Np63-overexpressing cells. High abundance of Delta Np63 in various tumors correlated with poor prognosis in patients, and this correlation was stronger in patients whose tumors also had a mutation in the gene encoding p53. Thus, oncogenic Ras and TGF-beta signaling stimulate cancer progression through activation of the Delta Np63 transcriptional program.

  • 12.
    Wright, Shane C.
    et al.
    Karolinska Inst, Sect Receptor Biol & Signaling, Dept Physiol & Pharmacol, S-17165 Stockholm, Sweden;Univ Montreal, Inst Res Immunol & Canc, Dept Biochem & Mol Med, Montreal, PQ H3C 3J7, Canada.
    Canizal, Maria Consuelo Alonso
    Univ Wurzburg, Inst Pharmacol & Toxicol, Versbacher Str 9, D-97078 Wurzburg, Germany;Friedrich Schiller Univ Jena, Univ Hosp Jena, Inst Mol Cell Biol, Ctr Mol Biomed, Hans Knoll Str 2, D-07745 Jena, Germany.
    Benkel, Tobias
    Univ Bonn, Inst Pharmaceut Biol, D-53115 Bonn, Germany.
    Simon, Katharina
    Univ Bonn, Inst Pharmaceut Biol, D-53115 Bonn, Germany.
    Le Gouill, Christian
    Univ Montreal, Inst Res Immunol & Canc, Dept Biochem & Mol Med, Montreal, PQ H3C 3J7, Canada.
    Matricon, Pierre
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Namkung, Yoon
    McGill Univ, Ctr Hlth, Res Inst, Dept Med, Montreal, PQ H4A 3J1, Canada.
    Lukasheva, Viktoria
    Univ Montreal, Inst Res Immunol & Canc, Dept Biochem & Mol Med, Montreal, PQ H3C 3J7, Canada.
    Koenig, Gabriele M.
    Univ Bonn, Inst Pharmaceut Biol, D-53115 Bonn, Germany.
    Laporte, Stephane A.
    McGill Univ, Ctr Hlth, Res Inst, Dept Med, Montreal, PQ H4A 3J1, Canada;McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 1Y6, Canada.
    Carlsson, Jens
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Kostenis, Evi
    Univ Bonn, Inst Pharmaceut Biol, D-53115 Bonn, Germany.
    Bouvier, Michel
    Univ Montreal, Inst Res Immunol & Canc, Dept Biochem & Mol Med, Montreal, PQ H3C 3J7, Canada.
    Schulte, Gunnar
    Karolinska Inst, Sect Receptor Biol & Signaling, Dept Physiol & Pharmacol, S-17165 Stockholm, Sweden.
    Hoffmann, Carsten
    Univ Wurzburg, Inst Pharmacol & Toxicol, Versbacher Str 9, D-97078 Wurzburg, Germany;Friedrich Schiller Univ Jena, Univ Hosp Jena, Inst Mol Cell Biol, Ctr Mol Biomed, Hans Knoll Str 2, D-07745 Jena, Germany.
    FZD(5) is a G alpha(q)-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs2018In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 11, no 559, article id eaar5536Article in journal (Refereed)
    Abstract [en]

    Frizzleds (FZDs) are a group of seven transmembrane-spanning (7TM) receptors that belong to class F of the G protein-coupled receptor (GPCR) superfamily. FZDs bind WNT proteins to stimulate diverse signaling cascades involved in embryonic development, stem cell regulation, and adult tissue homeostasis. Frizzled 5 (FZD(5)) is one of the most studied class F GPCRs that promote the functional inactivation of the beta-catenin destruction complex in response to WNTs. However, whether FZDs function as prototypical GPCRs has been heavily debated and, in particular, FZD(5) has not been shown to activate heterotrimeric G proteins. Here, we show that FZD(5) exhibited a conformational change after the addition of WNT-5A, which is reminiscent of class A and class B GPCR activation. In addition, we performed several live-cell imaging and spectrometric-based approaches, such as dual-color fluorescence recovery after photobleaching (dcFRAP) and resonance energy transfer (RET)-based assays that demonstrated that FZD(5) activated G alpha(q) and its downstream effectors upon stimulation with WNT-5A. Together, these findings suggest that FZD(5) is a 7TM receptor with a bona fide GPCR activation profile and suggest novel targets for drug discovery in WNT-FZD signaling.

  • 13.
    Zhang, Lei
    et al.
    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.
    Kundu, Soumi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Feenstra, Tjerk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jin, Chuan
    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.
    Laaniste, Liisi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    El Hassan, Tamador Elsir Abu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Ohlin, K Elisabet
    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.
    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.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Magnusson, Peetra U
    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.
    Forsberg, Karin Nilsson
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    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.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Dieterich, Lothar C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    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.
    Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.2015In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 8, no 406Article in journal (Refereed)
    Abstract [en]

    Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization.

1 - 13 of 13
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