Cbl was originally discovered in 1989 as the cellular homolog of the v-Cbl oncogene, the transforming gene of the Cas NS-1 murine retrovirus that causes myeloid leukemia and lymphomas in mice. Cbl is a member of a family of RING finger ubiquitin ligases that negatively regulate signaling by tyrosine kinases and that function as adaptor proteins to regulate signaling positively. Until the past 2 years, there was little evidence that Cbl proteins were involved in human malignancies. Recent publications have shown homozygous mutations in Cbl in human myeloid neoplasms. Although in vitro and animal transformation models suggested that mutant forms of Cbl acted as an oncogene, the cellular role suggested that the protein could serve as a tumor suppressor gene. The recent data begin to reconcile this paradox as the loss of ubiquitin ligase function (the tumor suppressor function) is coupled to the maintenance of the positive signaling function (the oncogene function). These data also provide insight into potential therapeutic approaches to myeloid disorders harboring Cbl mutations. Cancer Res; 70(12); 4789-94. ©2010 AACR. The Cbl FamilyCbl proteins are a highly conserved family of RING finger (RF) ubiquitin ligases (E3) that regulate signaling by tyrosine kinases (TK) in many pathways (for a comprehensive review of the structure and function of Cbl proteins, see ref. 1 and the chapters therein). There are three mammalian Cbl proteins encoded by separate genes: Cbl (a.k.a., c-Cbl, CBL2, RNF55), Cbl-b (a.k.a., RNF56), and Cbl-c (a.k.a., Cbl-3, Cbl-SL, RNF57; Fig. 1A). Cbl and Cbl-b are widely expressed in mammalian cells, and data from Cbl and Cbl-b null mice indicate a prominent role in T-and B-cell function (1). The expression of Cbl-c is restricted to epithelial cells (2). Cbl-c null mice have no overt phenotype, and thus the physiological function of Cbl-c is not known (2).Cbl proteins are tyrosine phosphorylated upon activation of a variety of growth factor and immune receptors and they associate with many proteins containing SH2 and SH3 domains (1). They have been implicated as regulators of signaling by receptor and nonreceptor TKs (RTK and non-RTK, respectively), immune receptors such as the T-cell receptor, B-cell receptors, and Fc receptors. Mechanistic studies using transfected proteins and mammalian cell lines have shown that Cbl proteins negatively regulate RTKs and non-RTKs by functioning as E3s that mediate the ubiquitination and degradation of activated TKs ( Fig. 1C; ref. 1). In addition, Cbl proteins can serve as adaptor proteins and through this function serve as positive regulators of signal transduction (1). For example, phosphorylation of Cbl on Y731 in the C-terminus has been shown to recruit the p85 subunit of phosphoinositide 3 kinase (PI3K), leading to activation of PI3K and downstream signaling pathways ( Fig. 1C; ref. 1).Ubiquitination of proteins is a multi-enzyme process that regulates the degradation, trafficking, and activity of many proteins (reviewed in refs. 3-5). Ubiquitinatio...
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