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J Cell Sci. 2014 Feb 1;127(Pt 3):653-62. doi: 10.1242/jcs.140590. Epub 2013 Nov 27.

Src-like-adaptor protein (SLAP) differentially regulates normal and oncogenic c-Kit signaling.

Author information

1
Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, 22381 Lund, Sweden.

Erratum in

  • J Cell Sci. 2014 May 15;127(Pt 10):2376.

Abstract

The Src-like-adaptor protein (SLAP) is an adaptor protein sharing considerable structural homology with Src. SLAP is expressed in a variety of cells and regulates receptor tyrosine kinase signaling by direct association. In this report, we show that SLAP associates with both wild-type and oncogenic c-Kit (c-Kit-D816V). The association involves the SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitylation which, in turn, is followed by receptor degradation. Although SLAP depletion potentiates c-Kit downstream signaling by stabilizing the receptor, it remains non-functional in c-Kit-D816V signaling. Ligand-stimulated c-Kit or c-Kit-D816V did not alter membrane localization of SLAP. Interestingly oncogenic c-Kit-D816V, but not wild-type c-Kit, phosphorylates SLAP on residues Y120, Y258 and Y273. Physical interaction between c-Kit-D816V and SLAP is mandatory for the phosphorylation to take place. Although tyrosine-phosphorylated SLAP does not affect c-Kit-D816V signaling, mutation of these tyrosine sites to phenylalanine can restore SLAP activity. Taken together the data demonstrate that SLAP negatively regulates wild-type c-Kit signaling, but not its oncogenic counterpart, indicating a possible mechanism by which the oncogenic c-Kit bypasses the normal cellular negative feedback control.

KEYWORDS:

D816V; Kit; Receptor tyrosine kinase; SLA; Signal transduction; Ubiquitylation; c-Kit-D816V

PMID:
24284075
DOI:
10.1242/jcs.140590
[Indexed for MEDLINE]
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