Direct binding of Cbl to Tyr568 and Tyr936 of the stem cell factor receptor/c-Kit is required for ligand-induced ubiquitination, internalization and degradation

Kristina Masson, Elke Heiss, Hamid Band, Lars Rönnstrand

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

The ubiquitin E3 ligase Cbl has been shown to negatively regulate tyrosine kinase receptors, including the stem cell factor receptor/c-Kit. Impaired recruitment of Cbl to c-Kit results in a deregulated positive signalling that eventually can contribute to carcinogenesis. Here, we present results showing that Cbl is activated by the SFKs (Src family kinases) and recruited to c-Kit in order to trigger receptor ubiquitination. We demonstrate that phosphorylated Tyr568 and Tyr936 in c-Kit are involved in direct binding and activation of Cbl and that binding of the TKB domain (tyrosine kinase binding domain) of Cbl to c-Kit is specified by the presence of an isoleucine or leucine residue in position + 3 to the phosphorylated tyrosine residue on c-Kit. Apart from the direct association between Cbl and c-Kit, we show that phosphorylation of Cbl by SFK members is required for activation of Cbl to occur. Moreover, we demonstrate that Cbl mediates monoubiquitination of c-Kit and that the receptor is subsequently targeted for lysosomal degradation. Taken together, our findings reveal novel insights into the mechanisms by which Cbl negatively regulates c-Kit-mediated signalling.

Original languageEnglish (US)
Pages (from-to)59-67
Number of pages9
JournalBiochemical Journal
Volume399
Issue number1
DOIs
StatePublished - Oct 1 2006

Fingerprint

Proto-Oncogene Proteins c-kit
src-Family Kinases
Ubiquitination
Chemical activation
Ligands
Degradation
Phosphorylation
Ubiquitin-Protein Ligases
Isoleucine
Receptor Protein-Tyrosine Kinases
Leucine
Protein-Tyrosine Kinases
Tyrosine
Carcinogenesis
Association reactions

Keywords

  • Cbl
  • Degradation
  • Receptor tyrosine kinase
  • Src family kinase
  • Stem cell factor receptor/c-Kit
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Direct binding of Cbl to Tyr568 and Tyr936 of the stem cell factor receptor/c-Kit is required for ligand-induced ubiquitination, internalization and degradation. / Masson, Kristina; Heiss, Elke; Band, Hamid; Rönnstrand, Lars.

In: Biochemical Journal, Vol. 399, No. 1, 01.10.2006, p. 59-67.

Research output: Contribution to journalArticle

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