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J. Biol. Chem., Vol. 278, Issue 11, 9159-9166, March 14, 2003
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From the 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
Src Family Kinases Are Involved in the Differential Signaling
from Two Splice Forms of c-Kit*
§¶,§,
,,¶¶¶
Ludwig Institute for Cancer Research,
Biomedical Center, SE-751 24 Uppsala, Sweden, Sweden, the
** Department of Anatomy and Cell Biology, Monash University,
Clayton, Victoria 3800, Australia, the Van
Andel Institute, Grand Rapids, Michigan 49503, and the
§§ School of Biomedical Sciences, University of
Newcastle, Callaghan, New South Wales 2308, Australia
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.
*
This work was in part supported by a grant from the Swedish
Cancer Society.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: First Department of Surgery, Gunma University
School of Medicine, Gunma, Japan.
¶¶
Senior Researcher funded by the Swedish Research
Council. To whom correspondence should be addressed. Present address:
Dept. of Experimental Clinical Chemistry, Lund University, Wallenberg Laboratory, Malmö University Hospital, SE 205 02 Malmö,
Sweden. Tel.: 46-40-33-72-22; Fax: 46-40-92-90-23; E-mail:
Lars.Ronnstrand@klkemi.mas.lu.se.
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