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.

Haploinsufficiency of Casitas B-Lineage Lymphoma Augments the Progression of Colon Cancer in the Background of Adenomatous Polyposis Coli Inactivation

“…c-Cbl has a translational potential in CRC. 39 In combination with previous data, this work supports the notion that c-Cbl down-regulates two key components of CRCepithelial tumorigenesis and tumor-induced angiogenesis. 11,40,41 In CRC cells, c-Cbl suppresses the growth of colon cancer cells by down-regulating Wnt signaling and suppressing nuclear b-catenin.…”

“…45 Together with previously published work, the current study demonstrates c-Cbl as a Wnt inhibitor in the colonic epithelium and a suppressor of CRC tumorigenesis. 8,10,11 Given the versatile role of c-Cbl in the biology of CRC cancer, 39 investigations to examine c-Cbl as a marker for overall prognosis and other aspects of CRC, such as responsiveness to targeted therapeutic agents, will pave the path forward for its translational application.…”

Competitive sgRNA Screen Identifies p38 MAPK as a Druggable Target to Improve HSPC Engraftment

“…In our targeted screen, we also identified Cbl and Lnk as additional candidates to enhance the repopulating capacity of HSPCs. These genes, especially Lnk , were shown to play a role in various forms of leukemia and non-hematologic tumors [ 46 , 47 ]. Thus, we observed an increased number of white blood cells in mice transplanted with these knockout cells.…”

Photocrosslinking Activity-Based Probes for Ubiquitin RING E3 Ligases

“…We next tested photoABP-Bpa31 with a RING E3 that activates via a distinct mechanism. The Cbl proteins are multidomain and multifunctional RING E3 ligases consisting of three homologs: c-Cbl, Cbl-b, and Cbl-c (Lyle et al, 2019). The majority of Cbl function is associated with RING E3 activity and involves regulation of angiogenesis and aberrations in Cbl activity have been implicated with a number of cancers.…”