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

Författare

  • Olexandr Voytyuk
  • Johan Lennartsson
  • Akira Mogi
  • Georgina Caruana
  • Sara Courtneidge
  • Leonie K. Ashman
  • Lars Rönnstrand

Summary, in English

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.

Publiceringsår

2003

Språk

Engelska

Sidor

9159-9166

Publikation/Tidskrift/Serie

Journal of Biological Chemistry

Volym

278

Issue

11

Dokumenttyp

Artikel i tidskrift

Förlag

American Society for Biochemistry and Molecular Biology

Ämne

  • Medicinal Chemistry

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1083-351X