Src family kinases are involved in the differential signaling from two splice-forms of c-Kit.

Research output: Contribution to journalArticle

Abstract

In both mice and humans alternate splicing results in isoforms of c-Kit characterized by the presence or the absence of a tetrapeptide sequence, GNNK, in the juxtamembrane region of the extracellular domain. Dramatic differences in the kinetics and magnitude of activation of the intrinsic tyrosine kinase activity of c-Kit between the GNNK and GNNK+ isoforms has previously been shown. Here we report the analysis of downstream targets of receptor signaling, which revealed that the signaling was differentially regulated in the two splice forms. The kinetics of phosphorylation of Shc, previously demonstrated to be phosphorylated by Src downstream of c-Kit, was stronger and more rapid in the GNNK form, whereas it showed slower kinetics in the GNNK+ form. Inhibition of Src family kinases with the specific Src family kinase inhibitor SU6656 altered the kinetics of activation of the GNNK form of c-Kit so that it resembled that of the GNNK+ form. In cells expressing the GNNK form, SCF was rapidly degraded, whereas in cells expressing the GNNK+ form only showed a very slow rate of degradation of SCF. In the GNNK+ form the Src inhibitor SU6656 only had a weak effect on degradation, whereas in the GNNK form it dramatically inhibited degradation. In summary, the two splice forms show, despite only a four-amino acid sequence difference, remarkable differences in their signaling capabilities.

Details

Authors
  • Olexandr Voytyuk
  • Johan Lennartsson
  • Akira Mogi
  • Georgina Caruana
  • Sara Courtneidge
  • Leonie K. Ashman
  • Lars Rönnstrand
External organisations
  • Ludwig Institute for Cancer Research, Uppsala branch
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medicinal Chemistry
Original languageEnglish
Pages (from-to)9159-9166
JournalJournal of Biological Chemistry
Volume278
Issue number11
Publication statusPublished - 2003
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)

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