Advanced

The tyrosine kinase CSK associates with FLT3 and c-Kit receptors and regulates downstream signaling.

Kazi, Julhash U. LU ; Vaapil, Marica LU ; Agarwal, Shruti LU ; Bracco, Enrico; Påhlman, Sven LU and Rönnstrand, Lars LU (2013) In Cellular Signalling 25(9). p.1852-1860
Abstract
Type III receptor tyrosine kinases (RTKs), FLT3 and c-Kit play important roles in a variety of cellular processes. A number of SH2-domain containing proteins interact with FLT3 and c-Kit and regulate downstream signaling. The SH2-domain containing non-receptor protein tyrosine kinase CSK is mainly studied in context of regulating Src family kinases. Here we present an addition role of this kinase in RTK signaling. We show that CSK interacts with FLT3 and c-Kit in a phosphorylation dependent manner. This interaction is facilitated through the SH2-domain of CSK. Under basal conditions CSK is mainly localized throughout the cytosolic compartment but upon ligand stimulation it is recruited to the inner side of cell membrane. CSK association... (More)
Type III receptor tyrosine kinases (RTKs), FLT3 and c-Kit play important roles in a variety of cellular processes. A number of SH2-domain containing proteins interact with FLT3 and c-Kit and regulate downstream signaling. The SH2-domain containing non-receptor protein tyrosine kinase CSK is mainly studied in context of regulating Src family kinases. Here we present an addition role of this kinase in RTK signaling. We show that CSK interacts with FLT3 and c-Kit in a phosphorylation dependent manner. This interaction is facilitated through the SH2-domain of CSK. Under basal conditions CSK is mainly localized throughout the cytosolic compartment but upon ligand stimulation it is recruited to the inner side of cell membrane. CSK association did not alter receptor ubiquitination or phosphorylation but disrupted downstream signaling. Selective depletion of CSK using siRNA, or inhibition with CSK inhibitor, led to increased phosphorylation of Akt and Erk, but not p38, upon FLT3 ligand (FL) stimulation. Stem cell factor (SCF)-mediated Akt and Erk activation was also elevated by CSK inhibition. However, siRNA mediated CSK knockdown increased SCF stimulated Akt phosphorylation but decreased Erk phosphorylation. CSK depletion also significantly increased both FL- and SCF-induced SHC, Gab2 and SHP2 phosphorylation. Furthermore, CSK depletion contributed to oncogenic FLT3- and c-Kit-mediated cell proliferation, but not to cell survival. Thus, the results indicate that CSK association with type III RTKs, FLT3 and c-Kit can have differential impact on receptor downstream signaling. (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
Cellular Signalling
volume
25
issue
9
pages
1852 - 1860
publisher
Elsevier
external identifiers
  • wos:000322298800016
  • pmid:23707526
  • scopus:84879260711
ISSN
1873-3913
DOI
10.1016/j.cellsig.2013.05.016
language
English
LU publication?
yes
id
e1ce3d76-2604-4758-9493-532826fec4c6 (old id 3804147)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23707526?dopt=Abstract
date added to LUP
2013-06-06 21:43:08
date last changed
2018-11-21 19:52:18
@article{e1ce3d76-2604-4758-9493-532826fec4c6,
  abstract     = {Type III receptor tyrosine kinases (RTKs), FLT3 and c-Kit play important roles in a variety of cellular processes. A number of SH2-domain containing proteins interact with FLT3 and c-Kit and regulate downstream signaling. The SH2-domain containing non-receptor protein tyrosine kinase CSK is mainly studied in context of regulating Src family kinases. Here we present an addition role of this kinase in RTK signaling. We show that CSK interacts with FLT3 and c-Kit in a phosphorylation dependent manner. This interaction is facilitated through the SH2-domain of CSK. Under basal conditions CSK is mainly localized throughout the cytosolic compartment but upon ligand stimulation it is recruited to the inner side of cell membrane. CSK association did not alter receptor ubiquitination or phosphorylation but disrupted downstream signaling. Selective depletion of CSK using siRNA, or inhibition with CSK inhibitor, led to increased phosphorylation of Akt and Erk, but not p38, upon FLT3 ligand (FL) stimulation. Stem cell factor (SCF)-mediated Akt and Erk activation was also elevated by CSK inhibition. However, siRNA mediated CSK knockdown increased SCF stimulated Akt phosphorylation but decreased Erk phosphorylation. CSK depletion also significantly increased both FL- and SCF-induced SHC, Gab2 and SHP2 phosphorylation. Furthermore, CSK depletion contributed to oncogenic FLT3- and c-Kit-mediated cell proliferation, but not to cell survival. Thus, the results indicate that CSK association with type III RTKs, FLT3 and c-Kit can have differential impact on receptor downstream signaling.},
  author       = {Kazi, Julhash U. and Vaapil, Marica and Agarwal, Shruti and Bracco, Enrico and Påhlman, Sven and Rönnstrand, Lars},
  issn         = {1873-3913},
  language     = {eng},
  number       = {9},
  pages        = {1852--1860},
  publisher    = {Elsevier},
  series       = {Cellular Signalling},
  title        = {The tyrosine kinase CSK associates with FLT3 and c-Kit receptors and regulates downstream signaling.},
  url          = {http://dx.doi.org/10.1016/j.cellsig.2013.05.016},
  volume       = {25},
  year         = {2013},
}