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

Abstract

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.

Figure 1

The primary structure and domain organization of human Casitas b-lineage lymphoma family proteins. c-Cbl, Cbl-b and Cbl-c proteins contain highly conserved tyrosine kinase-binding (TKB), linker (L), RING finger (RF) and proline-rich (PR) domains. 4H: Four-helix bundle; EF: EF hand, SH2: Src-homology 2; UBA: Ubiquitin-associated domain.

Figure 2

c-Cbl regulates angiogenesis through Wnt signaling. Constitutively Wnt signaling is suppressed in endothelial cells. In absence of Wnt ligand, β-Catenin is downregulated by in a destruction complex in the cytosol consisting of Adenomatous Polyposis Coli (APC), where β-Catenin gets phosphorylated by GSK3β. This results in β-catenin ubiquitination and proteasomal degradation by E3 ligases such as c-Cbl and β-TrCP, etc. Wnt ligand activates Frz receptors, which dissociates the destruction complex, β-catenin undergoes nuclear translocation and activates the Wnt target genes such as IL-8 and VEGF-A to induce angiogenesis. Wnt activation results in phosphorylation of c-Cbl, its nuclear translocation, wherein it ubiquitinates nuclear β-catenin to switch-off the Wnt signaling and angiogenesis.

Figure 3

c-Cbl is an attractive therapeutic target for angiogenesis and tumorigenesis. In the endothelial cells of vessels supplying the tumor, Wnt activation results in secretion of pro-angiogenic cytokines IL-8 and VEGF-A that augment tumor-induced angiogenesis. In colon cancer epithelial cells, inactivating mutations in APC tumor suppressor stabilizes β-Catenin and allows its nuclear translocation. This event results in the transcription of pro-proliferative and pro-oncogenic genes such as Cylin D1 and c-Myc to augment oncogenic activity. c-Cbl, by ubiquitinating nuclear β-Catenin in endothelial cells and in colon cancer cells, suppresses the growth of blood vessles and tumors. In addition, c-Cbl suppresses these processes by downregulating other pathways such VEGF signaling (PLCγ1) and mitogenic signaling (RTK and non-RTKs).