c-Cbl proto-oncogene is a ubiquitously expressed cytoplasmic adaptor protein that is especially predominant in hematopoietic cells. c-Cbl possesses a highly conserved amino-terminal phosphotyrosine binding domain and a C3HC4 RING finger motif. c-Cbl is rapidly tyrosine phosphorylated in response to stimulation of a variety of cell-surface receptors and becomes associated with a number of intracellular signaling molecules such as protein tyrosine kinases, phosphatidylinositol 3 kinase (PI3K), Crk and 14-3-3 proteins. In human cancer tissues, c-Cbl is frequently tyrosine phosphorylated in a tumor-specific manner. Src-family kinases primarily phosphorylate c-Cbl at Tyr-700, Tyr-731, and Tyr-774. These sites of phosphorylation provide docking sites for downstream signaling components, such as Grb-2, PI3K, and Fyn.
