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

Research output: Contribution to journalReview article

77 Citations (Scopus)

Abstract

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 (US)
Pages (from-to)189-218
Number of pages30
JournalCritical Reviews in Oncogenesis
Volume8
Issue number2-3
DOIs
StatePublished - Jan 1 1997
Externally publishedYes

Fingerprint

Oncogenes
Protein-Tyrosine Kinases
Phosphotyrosine
Signal Transduction
RING Finger Domains
Mutation
Myeloid Leukemia
Guanine Nucleotides
src Homology Domains
Monomeric GTP-Binding Proteins
Drosophila
Lymphoma
Proteins

Keywords

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

ASJC Scopus subject areas

  • Cancer Research

Cite this

The Cbl protooncogene product : From an enigmatic oncogene to center stage of signal transduction. / Miyake, Sachiko; Lupher, Mark L.; Andoniou, Christopher E.; Lill, Nancy L.; Ota, Satoshi; Douillard, Patrice; Rao, Navin; Band, Hamid.

In: Critical Reviews in Oncogenesis, Vol. 8, No. 2-3, 01.01.1997, p. 189-218.

Research output: Contribution to journalReview article

Miyake, Sachiko ; Lupher, Mark L. ; Andoniou, Christopher E. ; Lill, Nancy L. ; Ota, Satoshi ; Douillard, Patrice ; Rao, Navin ; Band, Hamid. / The Cbl protooncogene product : From an enigmatic oncogene to center stage of signal transduction. In: Critical Reviews in Oncogenesis. 1997 ; Vol. 8, No. 2-3. pp. 189-218.
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