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Direct binding of Cbl to Tyr(568) and Tyr(936) of the stem cell factor receptor/c-Kit is required for ligand-induced ubiquitination, internalization and degradation

Masson, Kristina LU ; Heiss, Elke LU ; Band, Hamid and Rönnstrand, Lars LU orcid (2006) In Biochemical Journal 399. p.59-67
Abstract
The ubiquitin E3 ligase Cbl has been shown to negatively regulate tyrosine kinase receptors, including the stem cell factor receptor/c-Kit. Impaired recruitment of Cbl to c-Kit results in a deregulated positive signalling that eventually can contribute to carcinogenesis. Here, we present results showing that Cbl is activated by the SFKs (Src family kinases) and recruited to c-Kit in order to trigger receptor ubiquitination. We demonstrate that phosphorylated Tyr(568) and Tyr(936) in c-Kit are involved in direct binding and activation of Cbl and that binding of the TKB domain (tyrosine kinase binding domain) of Cbl to c-Kit is specified by the presence of an isoleucine or leucine residue in position +3 to the phosphorylated tyrosine residue... (More)
The ubiquitin E3 ligase Cbl has been shown to negatively regulate tyrosine kinase receptors, including the stem cell factor receptor/c-Kit. Impaired recruitment of Cbl to c-Kit results in a deregulated positive signalling that eventually can contribute to carcinogenesis. Here, we present results showing that Cbl is activated by the SFKs (Src family kinases) and recruited to c-Kit in order to trigger receptor ubiquitination. We demonstrate that phosphorylated Tyr(568) and Tyr(936) in c-Kit are involved in direct binding and activation of Cbl and that binding of the TKB domain (tyrosine kinase binding domain) of Cbl to c-Kit is specified by the presence of an isoleucine or leucine residue in position +3 to the phosphorylated tyrosine residue on c-Kit. Apart from the direct association between Cbl and c-Kit, we show that phosphorylation of Cbl by SFK members is required for activation of Cbl to occur. Moreover, we demonstrate that Cbl mediates mono-ubiquitination of c-Kit and that the receptor is subsequently targeted for lysosomal degradation. Taken together, our findings reveal novel insights into the mechanisms by which Cbl negatively regulates c-Kit-mediated signalling. (Less)
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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ubiquitin ligase, receptor tyrosine kinase, stem cell factor receptor/c-Kit, Src family kinase, Cbl, degradation
in
Biochemical Journal
volume
399
pages
59 - 67
publisher
Portland Press
external identifiers
  • wos:000240972900007
  • pmid:16780420
  • scopus:33749390318
ISSN
0264-6021
DOI
10.1042/BJ20060464
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)
id
e949a66c-c34c-422a-b3ac-f2ed2038f172 (old id 389778)
date added to LUP
2016-04-01 16:16:48
date last changed
2021-07-27 03:02:32
@article{e949a66c-c34c-422a-b3ac-f2ed2038f172,
  abstract     = {The ubiquitin E3 ligase Cbl has been shown to negatively regulate tyrosine kinase receptors, including the stem cell factor receptor/c-Kit. Impaired recruitment of Cbl to c-Kit results in a deregulated positive signalling that eventually can contribute to carcinogenesis. Here, we present results showing that Cbl is activated by the SFKs (Src family kinases) and recruited to c-Kit in order to trigger receptor ubiquitination. We demonstrate that phosphorylated Tyr(568) and Tyr(936) in c-Kit are involved in direct binding and activation of Cbl and that binding of the TKB domain (tyrosine kinase binding domain) of Cbl to c-Kit is specified by the presence of an isoleucine or leucine residue in position +3 to the phosphorylated tyrosine residue on c-Kit. Apart from the direct association between Cbl and c-Kit, we show that phosphorylation of Cbl by SFK members is required for activation of Cbl to occur. Moreover, we demonstrate that Cbl mediates mono-ubiquitination of c-Kit and that the receptor is subsequently targeted for lysosomal degradation. Taken together, our findings reveal novel insights into the mechanisms by which Cbl negatively regulates c-Kit-mediated signalling.},
  author       = {Masson, Kristina and Heiss, Elke and Band, Hamid and Rönnstrand, Lars},
  issn         = {0264-6021},
  language     = {eng},
  pages        = {59--67},
  publisher    = {Portland Press},
  series       = {Biochemical Journal},
  title        = {Direct binding of Cbl to Tyr(568) and Tyr(936) of the stem cell factor receptor/c-Kit is required for ligand-induced ubiquitination, internalization and degradation},
  url          = {http://dx.doi.org/10.1042/BJ20060464},
  doi          = {10.1042/BJ20060464},
  volume       = {399},
  year         = {2006},
}