The epidermal growth factor receptor is covalently linked to ubiquitin.

Incubation of cultured human fibroblasts with epidermal growth factor (EGF) causes a proliferative response that is mediated by the binding of the growth factor to specific cell surface receptors. One event that occurs rapidly following EGF binding is the covalent modification of the EGF receptor (EGF-R) by phosphorylation on Ser, Thr, and Tyr residues. Here we report the identification of ubiquitination as a second form of EGF-stimulated covalent modification of the receptor. The LGF receptor was not ubiquitinated in serum-starved cells. However, treatment with EGF caused a rapid increase in EGF-R ubiquitination. In contrast, no EGF-stimulated ubiquitination was found in experiments using cells that express a mutant tyrosine kinase-negative EGF-R. Similarly, ubiquitination of the EGF-R was not observed at 4 degrees C or if the cells are depleted of intracellular K+. Together, these data establish ubiquitination as a form of EGF-stimulated covalent modification of the EGF-R.