Alix facilitates the interaction between c-Cbl and platelet-derived growth factor beta-receptor and thereby modulates receptor down-regulation.

Alix (ALG-2-interacting protein X) is an adaptor protein involved in down-regulation and sorting of cell surface receptors through the endosomal compartments toward the lysosome. In this study, we show that Alix interacts with the C-terminal region of the platelet-derived growth factor (PDGF) beta-receptor (PDGFRbeta) and becomes transiently tyrosine-phosphorylated in response ...
to PDGF-BB stimulation. Increased expression levels of Alix resulted in a reduced rate of PDGFRbeta removal from the cell surface following receptor activation, and this was associated with decreased receptor degradation. Furthermore, Alix was found to co-immunoprecipitate with the ubiquitin ligase c-Cbl, and elevated Alix levels increased the interaction between c-Cbl and PDGFRbeta. Interestingly, Alix interacted constitutively with both c-Cbl and PDGFRbeta. Moreover, c-Cbl was found to be hyperphosphorylated in cells engineered to overexpress Alix compared with control cells. The increased c-Cbl phosphorylation correlated with enhanced proteasomal degradation of c-Cbl, which in turn correlated with a decreased ubiquitination of PDGFRbeta. Our data suggest that Alix inhibits down-regulation of PDGFRbeta by modulating the interaction between c-Cbl and the receptor, thereby affecting the ubiquitination of the receptor.
Mesh Terms:
Amino Acid Sequence, Animals, Calcium-Binding Proteins, Carrier Proteins, Cell Cycle Proteins, Cell Membrane, Down-Regulation, Endosomal Sorting Complexes Required for Transport, Humans, Molecular Sequence Data, Phosphorylation, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-cbl, Receptor, Platelet-Derived Growth Factor beta, Sequence Homology, Amino Acid, Swine, Tyrosine, Ubiquitin
J. Biol. Chem.
Date: Dec. 22, 2006
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