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Src-Like Adaptor Protein (SLAP) differentially regulates normal and oncogenic c-Kit signaling

Kazi, Julhash U. LU ; Agarwal, Shruti LU ; Sun, Jianmin LU ; Baracco, Enrico and Rönnstrand, Lars LU (2014) In Journal of Cell Science 127(3). p.653-662
Abstract
The Src-Like Adaptor Protein (SLAP) is an adaptor protein sharing considerable structural homology with Src. SLAP is expressed in variety of cells regulating 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 SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitination 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... (More)
The Src-Like Adaptor Protein (SLAP) is an adaptor protein sharing considerable structural homology with Src. SLAP is expressed in variety of cells regulating 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 SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitination 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 Y120, Y258 and Y273 residues. 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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Kit, c-Kit-D816V, D816V, Receptor tyrosine kinase, Signal transduction, SLA, Ubiquitylation
in
Journal of Cell Science
volume
127
issue
3
pages
653 - 662
publisher
The Company of Biologists Ltd
external identifiers
  • wos:000331201600016
  • scopus:84894031893
ISSN
0021-9533
DOI
10.1242/jcs.140590
language
English
LU publication?
yes
id
934c3a17-6176-4a67-a10a-4b31c921a5aa (old id 4250289)
alternative location
http://jcs.biologists.org/content/early/2013/11/21/jcs.140590
date added to LUP
2014-01-31 07:34:39
date last changed
2017-11-05 03:09:38
@article{934c3a17-6176-4a67-a10a-4b31c921a5aa,
  abstract     = {The Src-Like Adaptor Protein (SLAP) is an adaptor protein sharing considerable structural homology with Src. SLAP is expressed in variety of cells regulating 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 SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitination 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 Y120, Y258 and Y273 residues. 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.},
  author       = {Kazi, Julhash U. and Agarwal, Shruti and Sun, Jianmin and Baracco, Enrico and Rönnstrand, Lars},
  issn         = {0021-9533},
  keyword      = {Kit,c-Kit-D816V,D816V,Receptor tyrosine kinase,Signal transduction,SLA,Ubiquitylation},
  language     = {eng},
  number       = {3},
  pages        = {653--662},
  publisher    = {The Company of Biologists Ltd},
  series       = {Journal of Cell Science},
  title        = {Src-Like Adaptor Protein (SLAP) differentially regulates normal and oncogenic c-Kit signaling},
  url          = {http://dx.doi.org/10.1242/jcs.140590},
  volume       = {127},
  year         = {2014},
}