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GAB2 is involved in differential pi3-kinase signaling by two splice forms of C-kit.

Sun, Jianmin LU ; Pedersen, Malin LU and Rönnstrand, Lars LU (2008) In Journal of Biological Chemistry 283(41). p.27444-27451
Abstract
The stem cell factor receptor/c-Kit plays an important physiological role in hematopoesis, melanogenesis and gametogenesis. It has also been implicated in numerous human malignancies. Signal transduction pathways shown to be of importance for c-Kit mediated transformation include the PI3-kinase/Akt pathway. We have previously shown that two alternative splice forms of c-Kit, denoted GNNK- and GNNK+ respectively, mediate distinctively different signals. In this study we find that in the hematopoietic cell line Ba/F3, the GNNK- c-Kit mediates a substantially stronger activation of PI3-kinase/Akt than the GNNK+ c-Kit. This difference in signaling was shown to be dependent on the association of the scaffolding protein Gab2 to c-Kit and... (More)
The stem cell factor receptor/c-Kit plays an important physiological role in hematopoesis, melanogenesis and gametogenesis. It has also been implicated in numerous human malignancies. Signal transduction pathways shown to be of importance for c-Kit mediated transformation include the PI3-kinase/Akt pathway. We have previously shown that two alternative splice forms of c-Kit, denoted GNNK- and GNNK+ respectively, mediate distinctively different signals. In this study we find that in the hematopoietic cell line Ba/F3, the GNNK- c-Kit mediates a substantially stronger activation of PI3-kinase/Akt than the GNNK+ c-Kit. This difference in signaling was shown to be dependent on the association of the scaffolding protein Gab2 to c-Kit and Src-mediated phosphorylation of Gab2, to be independent of the direct association of PI3-kinase with c-Kit. Furthermore, proliferation and survival of Ba/F3 cells expressing a mutant of c-Kit that fails to bind to PI3-kinase directly was slightly decreased compared to wild-type c-Kit expressing cells. Using siRNA technology we further verified a role of Gab2 in inducing activation of PI3-kinase/Akt downstream of c-Kit. To summarize, we show that PI3-kinase activation by c-Kit is both splice form dependent and cell type specific. Furthermore, activation of PI3-kinase by c-Kit is dependent both on the direct PI3-kinase binding site in c-Kit as well as on the phosphorylation of Gab2. The fact that c-Kit has been found mutated in numerous human malignancies including acute myeloid leukemia and that Gab2 often is overexpressed in acute myeloid leukemia suggests a potential role of Gab2 mediated PI3-kinase activation in transformation. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
283
issue
41
pages
27444 - 27451
publisher
ASBMB
external identifiers
  • wos:000259719200014
  • pmid:18697750
  • scopus:55549092077
ISSN
1083-351X
DOI
10.1074/jbc.M709703200
language
English
LU publication?
yes
id
cea698a4-a3f9-4770-9c36-e6b2244aa7b2 (old id 1223272)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18697750?dopt=Abstract
date added to LUP
2008-09-02 13:42:48
date last changed
2017-05-14 04:22:49
@article{cea698a4-a3f9-4770-9c36-e6b2244aa7b2,
  abstract     = {The stem cell factor receptor/c-Kit plays an important physiological role in hematopoesis, melanogenesis and gametogenesis. It has also been implicated in numerous human malignancies. Signal transduction pathways shown to be of importance for c-Kit mediated transformation include the PI3-kinase/Akt pathway. We have previously shown that two alternative splice forms of c-Kit, denoted GNNK- and GNNK+ respectively, mediate distinctively different signals. In this study we find that in the hematopoietic cell line Ba/F3, the GNNK- c-Kit mediates a substantially stronger activation of PI3-kinase/Akt than the GNNK+ c-Kit. This difference in signaling was shown to be dependent on the association of the scaffolding protein Gab2 to c-Kit and Src-mediated phosphorylation of Gab2, to be independent of the direct association of PI3-kinase with c-Kit. Furthermore, proliferation and survival of Ba/F3 cells expressing a mutant of c-Kit that fails to bind to PI3-kinase directly was slightly decreased compared to wild-type c-Kit expressing cells. Using siRNA technology we further verified a role of Gab2 in inducing activation of PI3-kinase/Akt downstream of c-Kit. To summarize, we show that PI3-kinase activation by c-Kit is both splice form dependent and cell type specific. Furthermore, activation of PI3-kinase by c-Kit is dependent both on the direct PI3-kinase binding site in c-Kit as well as on the phosphorylation of Gab2. The fact that c-Kit has been found mutated in numerous human malignancies including acute myeloid leukemia and that Gab2 often is overexpressed in acute myeloid leukemia suggests a potential role of Gab2 mediated PI3-kinase activation in transformation.},
  author       = {Sun, Jianmin and Pedersen, Malin and Rönnstrand, Lars},
  issn         = {1083-351X},
  language     = {eng},
  number       = {41},
  pages        = {27444--27451},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {GAB2 is involved in differential pi3-kinase signaling by two splice forms of C-kit.},
  url          = {http://dx.doi.org/10.1074/jbc.M709703200},
  volume       = {283},
  year         = {2008},
}