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

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

Research output: Contribution to journalArticle

69 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)9159-9166
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number11
DOIs
StatePublished - Mar 14 2003
Externally publishedYes

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src-Family Kinases
Kinetics
Degradation
Protein Isoforms
Chemical activation
Cells
Phosphorylation
Alternative Splicing
Corrosion inhibitors
Protein-Tyrosine Kinases
Amino Acid Sequence
Amino Acids
SU 6656

ASJC Scopus subject areas

  • Biochemistry

Cite this

Src family kinases are involved in the differential signaling from two splice forms of c-Kit. / Voytyuk, Olexandr; Lennartsson, Johan; Mogi, Akira; Caruana, Georgina; Courtneidge, Sara; Ashman, Leonie K.; Rönnstrand, Lars.

In: Journal of Biological Chemistry, Vol. 278, No. 11, 14.03.2003, p. 9159-9166.

Research output: Contribution to journalArticle

Voytyuk, O, Lennartsson, J, Mogi, A, Caruana, G, Courtneidge, S, Ashman, LK & Rönnstrand, L 2003, 'Src family kinases are involved in the differential signaling from two splice forms of c-Kit', Journal of Biological Chemistry, vol. 278, no. 11, pp. 9159-9166. https://doi.org/10.1074/jbc.M211726200
Voytyuk, Olexandr ; Lennartsson, Johan ; Mogi, Akira ; Caruana, Georgina ; Courtneidge, Sara ; Ashman, Leonie K. ; Rönnstrand, Lars. / Src family kinases are involved in the differential signaling from two splice forms of c-Kit. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 11. pp. 9159-9166.
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