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

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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, 2003, p. 9159-9166.

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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

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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.

RIS

TY - JOUR

T1 - Src family kinases are involved in the differential signaling from two splice-forms of c-Kit.

AU - Voytyuk, Olexandr

AU - Lennartsson, Johan

AU - Mogi, Akira

AU - Caruana, Georgina

AU - Courtneidge, Sara

AU - Ashman, Leonie K.

AU - Rönnstrand, Lars

N1 - 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)

PY - 2003

Y1 - 2003

N2 - 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.

AB - 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.

U2 - 10.1074/jbc.M211726200

DO - 10.1074/jbc.M211726200

M3 - Article

VL - 278

SP - 9159

EP - 9166

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 11

ER -