c-Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCγ1.
Angiogenesis is regulated by highly coordinated function of various proteins with pro- and anti-angiogenic functions. Among the many cytoplasmic signaling proteins that are activated by VEGFR-2, activation of PLCγ1 is considered to have a pivotal role in angiogenic signaling. In previous study we have identified c-Cbl as a negative regulator of PLCγ1 in endothelial cells, the biochemical and biological significance of c-Cbl, however, in angiogenesis in vivo and molecular mechanisms involved were remained elusive. In this study, we report that genetic inactivation of c-Cbl in mice results in enhanced tumor angiogenesis and retinal neovascularization. Endothelial cells derived from c-Cbl null mice displayed elevated cell proliferation and tube formation in response to VEGF stimulation. Loss of c-Cbl also resulted in robust activation of PLCγ1 and increased intracellular calcium release. c-Cbl-dependent ubiquitination selectively inhibited tyrosine phosphorylation of PLCγ1 and mostly refrained from ubiquitin-mediated degradation. Hence, we propose c-Cbl as an angiogenic suppressor protein where upon activation it uniquely modulates PLCγ1 activation by ubiquitination and subsequently inhibits VEGF-driven angiogenesis.
Department of Pathology, Boston University Medical Campus, Boston, MA 02118, USA.
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Meyer
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Husain
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Rahimi
D000818:Animals; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D040301:Vascular Endothelial Growth Factor Receptor-2; D051966:Phospholipase C gamma; C067419:CBL protein, human; C493849:Cbl protein, mouse
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