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

Voytyuk, Olexandr LU ; Lennartsson, Johan; Mogi, Akira; Caruana, Georgina; Courtneidge, Sara; Ashman, Leonie K. and Rönnstrand, Lars LU (2003) In Journal of Biological Chemistry 278(11). p.9159-9166
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... (More)
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. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
278
issue
11
pages
9159 - 9166
publisher
ASBMB
external identifiers
  • wos:000181524000038
  • pmid:12511554
  • scopus:0037646534
ISSN
1083-351X
DOI
10.1074/jbc.M211726200
language
English
LU publication?
no
id
e394e3b9-e649-40c2-bde5-85dd1fa907dd (old id 112082)
date added to LUP
2007-07-27 12:25:42
date last changed
2018-01-07 05:32:08
@article{e394e3b9-e649-40c2-bde5-85dd1fa907dd,
  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.},
  author       = {Voytyuk, Olexandr and Lennartsson, Johan and Mogi, Akira and Caruana, Georgina and Courtneidge, Sara and Ashman, Leonie K. and Rönnstrand, Lars},
  issn         = {1083-351X},
  language     = {eng},
  number       = {11},
  pages        = {9159--9166},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Src family kinases are involved in the differential signaling from two splice-forms of c-Kit.},
  url          = {http://dx.doi.org/10.1074/jbc.M211726200},
  volume       = {278},
  year         = {2003},
}