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
Författare
Summary, in English
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.
Avdelning/ar
Publiceringsår
2006
Språk
Engelska
Sidor
59-67
Publikation/Tidskrift/Serie
Biochemical Journal
Volym
399
Dokumenttyp
Artikel i tidskrift
Förlag
Portland Press
Ämne
- Biochemistry and Molecular Biology
Nyckelord
- ubiquitin ligase
- receptor tyrosine kinase
- stem cell factor receptor/c-Kit
- Src family kinase
- Cbl
- degradation
Status
Published
ISBN/ISSN/Övrigt
- ISSN: 0264-6021