The Cbl family of signal transduction molecules.
This review summarizes the current knowledge about the structure, expression, and signaling function of Cbl. A mutant Cbl form (v-Cbl) was first identified as the product of the Cas-NS-1 murine retrovirus that induces lymphomas and leukemias. Two members of the Cbl family have since been defined in mammals (c-Cbl and Cbl-b), one in C. elegans (Sli-1) and one in Drosophila (D-Cbl). There is high conservation between Cbl species in the amino-terminal region that contains a putative phosphotyrosine binding domain and a Ring finger motif. In the carboxy-terminal region, mammalian Cbl forms share a proline-rich stretch, conserved tyrosine residues, and a leucine zipper. Cbl participates in signaling by receptor protein tyrosine kinases, as well as antigen and cytokine receptors that signal via associated cytoplasmic protein tyrosine kinases. Cbl is recruited to the tyrosine kinase module of these receptors and tyrosine phosphorylated after cellular activation. It functions as a scaffold protein and associates with SH2 and SH3 domain containing molecules, including the Crk adaptor family and Vav. By analogy with the C. elegans homologue Sli-1, Cbl is proposed to be a negative regulator of receptor tyrosine kinase signaling. After deletion mutation in a region close to the Ring finger, c-Cbl becomes oncogenic. Such mutations are suggested to result in a structural alteration, allowing oncogenic mutants to displace wild-type c-Cbl from the receptor complex and to abrogate its negative regulatory function.
Smit
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Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam.
Borst
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J
D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D005810:Multigene Family; D050722:Oncogene Protein v-cbl; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D011519:Proto-Oncogenes; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases
D050722:Oncogene Protein v-cbl; D011518:Proto-Oncogene Proteins; D015682:Retroviridae Proteins, Oncogenic; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C067419:CBL protein, human