c-Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCγ1

Oncogene. 2011 May 12;30(19):2198-206. doi: 10.1038/onc.2010.597. Epub 2011 Jan 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division / physiology*
  • Cells, Cultured
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Enzyme Activation
  • Humans
  • Mice
  • Neoplasms / blood supply
  • Neoplasms / pathology*
  • Neovascularization, Pathologic / prevention & control*
  • Phospholipase C gamma / antagonists & inhibitors
  • Phospholipase C gamma / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / physiology*
  • Signal Transduction
  • Tyrosine / metabolism
  • Vascular Endothelial Growth Factor A / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism


  • Vascular Endothelial Growth Factor A
  • Tyrosine
  • Proto-Oncogene Proteins c-cbl
  • Vascular Endothelial Growth Factor Receptor-2
  • Phospholipase C gamma
  • CBL protein, human
  • Cbl protein, mouse