Threonine phosphorylation diverts internalized epidermal growth factor receptors from a degradative pathway to the recycling endosome

Transregulation of the epidermal growth factor receptor (EGFR) by protein k inase C (PKC) serves as a model for heterologous desensitization of recepto r tyrosine kinases, but the underlying mechanism remained unknown. By using c-Cbl-induced ubiquitination of EGFR as a marker for transfer from early t o late endosomes, we provide evidence that PKC can inhibit this process. In parallel, receptor down-regulation and degradation are significantly reduc ed. The inhibitory effects of PKC are mediated by a single threonine residu e (threonine 654) of EGFR, which serves as a major PKC phosphorylation site . Biochemical and morphological analyses indicate that threonine-phosphoryl ated EGFR molecules undergo normal internalization, but instead of sorting to lysosomal degradation, they recycle back to the cell surface. In conclus ion, by sorting EGFR to the recycling endosome, heterologous desensitizatio n restrains ligand-induced down-regulation of EGFR.