| First Author | Meyer RD | Year | 2011 |
| Journal | Oncogene | Volume | 30 |
| Issue | 19 | Pages | 2198-206 |
| PubMed ID | 21242968 | Mgi Jnum | J:173717 |
| Mgi Id | MGI:5050046 | Doi | 10.1038/onc.2010.597 |
| Citation | Meyer RD, et al. (2011) c-Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCgamma1. Oncogene 30(19):2198-206 |
| abstractText | 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 PLCgamma1 is considered to have a pivotal role in angiogenic signaling. In previous study we have identified c-Cbl as a negative regulator of PLCgamma1 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 PLCgamma1 and increased intracellular calcium release. c-Cbl-dependent ubiquitination selectively inhibited tyrosine phosphorylation of PLCgamma1 and mostly refrained from ubiquitin-mediated degradation. Hence, we propose c-Cbl as an angiogenic suppressor protein where upon activation it uniquely modulates PLCgamma1 activation by ubiquitination and subsequently inhibits VEGF-driven angiogenesis. |
