c-Cbl: An Important Regulator and a Target in Angiogenesis and Tumorigenesis

Cells. 2019 May 23;8(5):498. doi: 10.3390/cells8050498.


Casitas B lineage lymphoma (c-Cbl) is a multifunctional protein with a ubiquitin E3 ligase activity capable of degrading diverse sets of proteins. Although previous work had focused mainly on c-Cbl mutations in humans with hematological malignancies, recent emerging evidence suggests a critical role of c-Cbl in angiogenesis and human solid organ tumors. The combination of its unique structure, modular function, and ability to channelize cues from a rich network of signaling cascades, empowers c-Cbl to assume a central role in these disease models. This review consolidates the structural and functional insights based on recent studies that highlight c-Cbl as a target with tantalizing therapeutic potential in various models of angiogenesis and tumorigenesis.

Keywords: EGFR; FGFR; PDGFR; PLCγ1; RTK; VEGFR; Wnt signaling; angiogenesis; c-Cbl; c-Met; non-RTK; proteasomal degradation; tumors; ubiquitination; β–catenin.

Publication types

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

MeSH terms

  • Animals
  • Carcinogenesis / metabolism*
  • Humans
  • Mice
  • Molecular Targeted Therapy
  • Neovascularization, Pathologic / enzymology*
  • Phospholipase C gamma / metabolism
  • Proto-Oncogene Proteins c-cbl / chemistry
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • Ubiquitination
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Wnt Signaling Pathway
  • beta Catenin / metabolism


  • CTNNB1 protein, human
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • beta Catenin
  • Proto-Oncogene Proteins c-cbl
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2
  • PLCG1 protein, human
  • Phospholipase C gamma
  • CBL protein, human