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Grb2 mediates negative regulation of stem cell factor receptor/c-Kit signaling by recruitment of Cbl.

Sun, Jianmin LU ; Pedersen, Malin LU ; Bengtsson, Susanne LU and Rönnstrand, Lars LU (2007) In Experimental Cell Research 313(18). p.3935-3942
Abstract
Aberrant activation of c-Kit is involved in a number of human diseases including cancers and leukemias. Certain receptor tyrosine kinases, such as epidermal growth factor receptor, have been shown to indirectly recruit Cbl through the adapter protein Grb2, leading to receptor ubiquitination and degradation. In order to study the role of Grb2 in c-Kit degradation, a series of mutations of the Grb2 binding sites in c-Kit were generated (Y703F, Y936F, and Y703F/Y936F). Since other signal transduction molecules are also known to bind Y703 and Y936, the more selective asparagine-to-alanine (N-to-A) mutants N705A, N938A, and N705A/N938A were generated. We could clearly demonstrate that binding of Grb2 was dependent on intact phosphorylation... (More)
Aberrant activation of c-Kit is involved in a number of human diseases including cancers and leukemias. Certain receptor tyrosine kinases, such as epidermal growth factor receptor, have been shown to indirectly recruit Cbl through the adapter protein Grb2, leading to receptor ubiquitination and degradation. In order to study the role of Grb2 in c-Kit degradation, a series of mutations of the Grb2 binding sites in c-Kit were generated (Y703F, Y936F, and Y703F/Y936F). Since other signal transduction molecules are also known to bind Y703 and Y936, the more selective asparagine-to-alanine (N-to-A) mutants N705A, N938A, and N705A/N938A were generated. We could clearly demonstrate that binding of Grb2 was dependent on intact phosphorylation sites Y703 and Y936. Furthermore, we could demonstrate the presence of Cbl in a complex with Grb2 and c-Kit. Thus, Grb2 is able to indirectly recruit Cbl to c-Kit. In the N-to-A mutants, Cbl phosphorylation was strongly reduced, which correlated with reduced ubiquitination of c-Kit as well as decreased internalization and degradation of the receptor. Taken together, we have demonstrated that, in addition to its role in positive signaling via the Ras/Erk pathway, Grb2 mediates c-Kit degradation through recruitment of Cbl to c-Kit, leading to ubiquitination of c-Kit followed by internalization and degradation. (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
Internalization, Ubiquitination, Grb2, Cbl, c-Kit, Stem cell factor
in
Experimental Cell Research
volume
313
issue
18
pages
3935 - 3942
publisher
Academic Press
external identifiers
  • wos:000250473500013
  • scopus:35248849299
ISSN
1090-2422
DOI
10.1016/j.yexcr.2007.08.021
language
English
LU publication?
yes
id
418b5080-9941-4e86-9e13-3178a18a6aa9 (old id 608180)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17904548&dopt=Abstract
date added to LUP
2007-12-20 14:53:14
date last changed
2017-04-09 03:29:43
@article{418b5080-9941-4e86-9e13-3178a18a6aa9,
  abstract     = {Aberrant activation of c-Kit is involved in a number of human diseases including cancers and leukemias. Certain receptor tyrosine kinases, such as epidermal growth factor receptor, have been shown to indirectly recruit Cbl through the adapter protein Grb2, leading to receptor ubiquitination and degradation. In order to study the role of Grb2 in c-Kit degradation, a series of mutations of the Grb2 binding sites in c-Kit were generated (Y703F, Y936F, and Y703F/Y936F). Since other signal transduction molecules are also known to bind Y703 and Y936, the more selective asparagine-to-alanine (N-to-A) mutants N705A, N938A, and N705A/N938A were generated. We could clearly demonstrate that binding of Grb2 was dependent on intact phosphorylation sites Y703 and Y936. Furthermore, we could demonstrate the presence of Cbl in a complex with Grb2 and c-Kit. Thus, Grb2 is able to indirectly recruit Cbl to c-Kit. In the N-to-A mutants, Cbl phosphorylation was strongly reduced, which correlated with reduced ubiquitination of c-Kit as well as decreased internalization and degradation of the receptor. Taken together, we have demonstrated that, in addition to its role in positive signaling via the Ras/Erk pathway, Grb2 mediates c-Kit degradation through recruitment of Cbl to c-Kit, leading to ubiquitination of c-Kit followed by internalization and degradation.},
  author       = {Sun, Jianmin and Pedersen, Malin and Bengtsson, Susanne and Rönnstrand, Lars},
  issn         = {1090-2422},
  keyword      = {Internalization,Ubiquitination,Grb2,Cbl,c-Kit,Stem cell factor},
  language     = {eng},
  number       = {18},
  pages        = {3935--3942},
  publisher    = {Academic Press},
  series       = {Experimental Cell Research},
  title        = {Grb2 mediates negative regulation of stem cell factor receptor/c-Kit signaling by recruitment of Cbl.},
  url          = {http://dx.doi.org/10.1016/j.yexcr.2007.08.021},
  volume       = {313},
  year         = {2007},
}