The Cbl protooncogene product: From an enigmatic oncogene to center stage of signal transduction

Sachiko Miyake, Mark L. Lupher, Christopher E. Andoniou, Nancy L. Lill, Satoshi Ota, Patrice Douillard, Navin Rao, Hamid Band

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13 Citations (Scopus)


The c-cbl protooncogene was first identified as the cellular homologue of a viral oncogene v-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 Rap1 family of small G-proteins. Presently, Rapl is thought to antagonize Ras function, although Rap 1-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.

Original languageEnglish
Pages (from-to)189-218
Number of pages30
JournalCritical Reviews in Oncogenesis
Issue number2-3
Publication statusPublished - 1 Jan 1997


  • Oncogenesis
  • Phosphotyrosine-binding domains
  • Protein-tyrosine kinase
  • Protooncogenes
  • Ras
  • Receptors
  • Src- homology domains

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