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.
Highlights
The formation of new blood vessels is fundamental to health and disease[1,2,3,4,5]
New vessels are created from angioblasts or other precursor cell, which differentiate into endothelial cells forming lumens and primordial blood vessels
Angiogenesis is a dynamic process orchestrated by endothelial cells (ECs), their associated perivascular supporting cells, and immune cells
Summary
The formation of new blood vessels is fundamental to health and disease[1,2,3,4,5]. This formation can occur by two processes: vasculogenesis or angiogenesis. Studies have shown that the ubiquitin activity of c-Cbl is regulated by Tyr371, a key tyrosine residue. C-Cbl is a RING finger E3 ubiquitin ligase and targets several pro-angiogenic mediator proteins for degradation including receptor and non-receptor tyrosine kinases (c-Src, c-MET, EGFR, PDGFR, etc), mediators of Wnt signaling (β-catenin) [21,22,47,48], and VEGF signaling (PLCγ1) [25,38].
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