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Phosphorylation of the activation loop tyrosine 823 in c-Kit is crucial for cell survival and proliferation.

Agarwal, Shruti LU ; Kazi, Julhash U. LU and Rönnstrand, Lars LU (2013) In Journal of Biological Chemistry 288(31). p.22460-22468
Abstract
The receptor tyrosine kinase c-Kit, also known as the stem cell factor receptor, plays a key role in several developmental processes. Activating mutations in c-Kit lead to alteration of these cellular processes and have been implicated in many human cancers such as gastrointestinal stromal tumors (GISTs), acute myeloid leukemia (AML), testicular seminomas and mastocytosis. Regulation of the catalytic activity of several kinases is known to be governed by phosphorylation of tyrosine residues in the activation loop of the kinase domain. However, in the case of c-Kit phosphorylation of Y823 has been demonstrated to be a late event that is not required for kinase activation. However, since phosphorylation of Y823 is a ligand-activated event,... (More)
The receptor tyrosine kinase c-Kit, also known as the stem cell factor receptor, plays a key role in several developmental processes. Activating mutations in c-Kit lead to alteration of these cellular processes and have been implicated in many human cancers such as gastrointestinal stromal tumors (GISTs), acute myeloid leukemia (AML), testicular seminomas and mastocytosis. Regulation of the catalytic activity of several kinases is known to be governed by phosphorylation of tyrosine residues in the activation loop of the kinase domain. However, in the case of c-Kit phosphorylation of Y823 has been demonstrated to be a late event that is not required for kinase activation. However, since phosphorylation of Y823 is a ligand-activated event, we sought to investigate the functional consequences of Y823 phosphorylation. By using a tyrosine to phenylalanine mutant of tyrosine 823 we investigated the impact of Y823 on c-Kit signaling. We here demonstrate that Y823 is crucial for cell survival and proliferation and mutation of Y823 to phenylalanine leads to decreased sustained phosphorylation and ubiquitination of c-Kit as compared to the wild-type receptor. Furthermore, the mutated receptor was upon ligand-stimulation quickly internalized and degraded. Phosphorylation of the E3 ubiquitin ligase, Cbl was transient followed by a substantial reduction in phosphorylation of downstream signaling molecules such as Akt, Erk, Shc and Gab2. Thus, we propose that activation loop tyrosine 823 is crucial for activation of both the MAPK and PI3K pathways and that its disruption leads to a destabilization of the c-Kit receptor and decreased survival of cells. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
288
issue
31
pages
22460 - 22468
publisher
ASBMB
external identifiers
  • pmid:23803604
  • wos:000330596300027
  • scopus:84881229551
ISSN
1083-351X
DOI
10.1074/jbc.M113.474072
language
English
LU publication?
yes
id
d2287880-15bb-4f17-a323-bd4d668eb5eb (old id 3912965)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23803604?dopt=Abstract
date added to LUP
2013-07-01 15:45:53
date last changed
2018-11-21 19:55:21
@article{d2287880-15bb-4f17-a323-bd4d668eb5eb,
  abstract     = {The receptor tyrosine kinase c-Kit, also known as the stem cell factor receptor, plays a key role in several developmental processes. Activating mutations in c-Kit lead to alteration of these cellular processes and have been implicated in many human cancers such as gastrointestinal stromal tumors (GISTs), acute myeloid leukemia (AML), testicular seminomas and mastocytosis. Regulation of the catalytic activity of several kinases is known to be governed by phosphorylation of tyrosine residues in the activation loop of the kinase domain. However, in the case of c-Kit phosphorylation of Y823 has been demonstrated to be a late event that is not required for kinase activation. However, since phosphorylation of Y823 is a ligand-activated event, we sought to investigate the functional consequences of Y823 phosphorylation. By using a tyrosine to phenylalanine mutant of tyrosine 823 we investigated the impact of Y823 on c-Kit signaling. We here demonstrate that Y823 is crucial for cell survival and proliferation and mutation of Y823 to phenylalanine leads to decreased sustained phosphorylation and ubiquitination of c-Kit as compared to the wild-type receptor. Furthermore, the mutated receptor was upon ligand-stimulation quickly internalized and degraded. Phosphorylation of the E3 ubiquitin ligase, Cbl was transient followed by a substantial reduction in phosphorylation of downstream signaling molecules such as Akt, Erk, Shc and Gab2. Thus, we propose that activation loop tyrosine 823 is crucial for activation of both the MAPK and PI3K pathways and that its disruption leads to a destabilization of the c-Kit receptor and decreased survival of cells.},
  author       = {Agarwal, Shruti and Kazi, Julhash U. and Rönnstrand, Lars},
  issn         = {1083-351X},
  language     = {eng},
  number       = {31},
  pages        = {22460--22468},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Phosphorylation of the activation loop tyrosine 823 in c-Kit is crucial for cell survival and proliferation.},
  url          = {http://dx.doi.org/10.1074/jbc.M113.474072},
  volume       = {288},
  year         = {2013},
}