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Removing Receptors by Ubiquitination

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Science  21 Jan 2000:
Vol. 287, Issue 5452, pp. 393
DOI: 10.1126/science.287.5452.393h

The intracellular adaptor protein c-Cbl has been implicated in the ubiquitination and degradation of growth factor receptors. Levkowitz et al. and Lill et al. have determined that interaction between the src homology 2 (SH2) domain of c-Cbl and the cytoplasmic tail of the epidermal growth factor (EGF) receptor is essential for this effect. Binding of EGF to the receptor is known to activate the cytoplasmic tyrosine kinase domain; Levkowitz et al. showed that a phosphorylated tyrosine residue in the EGF receptor tail serves as the c-Cbl docking site and also that c-Cbl itself becomes phosphorylated on a tyrosine residue. Phosphorylation of c-Cbl was required for ubiquitination of activated EGF receptor, suggesting that the adaptor protein may act as a ubiquitin ligase. Furthermore, ubiquitination may contribute to diverting internalized growth factor receptors to the lysosomal degradation pathway because activated EGF receptors lacking the c-Cbl docking residue were neither ubiquitinated nor degraded. Instead, they were internalized and then recycled to the cell surface. Thus, ubiquitination of growth factor receptors may ensure receptor downregulation by recruiting both proteosomal and lysosomal degradation pathways.—LDC

Mol. Cell4, 1029 (1999); J. Biol. Chem.275, 367 (2000).

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