RT Journal Article ID 7357906141591275 A1 Miyake, Sachiko A1 Lupher, Jr., Mark L. A1 Andoniou, Christopher E. A1 Lill, Nancy L. A1 Ota, Satoshi A1 Douillard, Patrice A1 Rao, Navin A1 Band, Hamid T1 The Cbl Protooncogene Product: From an Enigmatic Oncogene to Center Stage of Signal Transduction JF Critical Reviews™ in Oncogenesis JO CRO YR 1997 FD 1997-09-01 VO 8 IS 2-3 SP 189 OP 218 K1 protooncogenes K1 protein-tyrosine kinase K1 receptors K1 oncogenesis K1 Src-homology domains K1 phosphotyrosine-binding domains K1 Ras. AB The c-cbl protooncogene was first identified as the cellular homologue of a viral oncogene ν-cbl that induces pre-B lymphomas and myeloid leukemias in mice. Until recently, the biochemical basis for Cbl's transforming potential and its physiological role remained unclear. However, a convergence of biochemical studies in mammalian cells and genetic studies in C. elegans and Drosophila has now identified Cbl as a negative regulator of tyrosine kinase signaling. The N-terminal transforming region of Cbl (Cbl-N) and an adjacent RING finger domain are the elements most conserved during evolution. The Cbl-N region has now been shown to contain a novel phosphotyrosine-binding (PTB) domain that directly interacts with autophosphorylated tyrosine kinases via a D(N/D)XpY motif. A critical role of the PTB domain in Cbl function is demonstrated by the localization of a loss-of-function mutation in C. elegans Cbl homologue SLI-1 within this region. The corresponding mutation in human Cbl inactivates the PTB domain function and abrogates Cbl-mediated regulation of tyrosine kinase function. Recent studies have also identified a novel signaling pathway initiated by the interaction of mammalian Cbl proteins with the SH2 domains of Crk adaptor molecules, which results in Cbl's linkage with C3G, a guanine nucleotide exchange protein for Rap l family of small G-proteins. Presently, Rap l is thought to antagonize Ras function, although Rap l-specific targets have emerged recently. Thus, recent advances have firmly placed the little known protooncoprotein Cbl on the center stage of tyrosine kinase-mediated signal transduction. PB Begell House LK https://www.dl.begellhouse.com/journals/439f422d0783386a,703283381dd19c5b,7357906141591275.html