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(Received for publication, December 13, 1995, and in revised form, February 26, 1996)
From the § Department of Pharmacology, University of
Colorado Health Sciences Center, Denver, Colorado 80262 and the
¶ Laboratorio di Oncologia Molecolare, DIBIT and The carboxyl-terminal regulatory domain of the
epidermal growth factor (EGF) receptor is essential for its endocytosis
and interaction with the clathrin-associated protein complex AP-2. To
identify AP-2 binding motif in the receptor, several single and
multiple-point mutations within the region between residues 966 and 977 of the human EGF receptor were made, and the mutant receptors were
expressed in NIH3T3 cells. Mutation of tyrosine 974 alone or together
with surrounding residues and the deletion of residues 973-975
essentially eliminated AP-2 co-immunoprecipitation with the EGF
receptor. Furthermore, a synthetic peptide corresponding to receptor
residues 964-978 blocked AP-2 association with the wild-type EGF
receptor. These data suggest that AP-2 has only one high-affinity
binding site in the EGF receptor composed of
Tyr974-containing motif. Receptor mutants that did not bind
AP-2 displayed a lower rate of internalization, down-regulation, and
turnover compared to wild-type receptors when expressed at high levels.
However, similar receptor mutants expressed at low levels were
internalized and down-regulated as efficiently as wild-type receptors.
Internalization of the mutant receptors lacking the high-affinity
binding site for AP-2 was inhibited by K+-depletion of the
cells, indicating that their endocytosis required intact coated pits.
We suggest that whereas one mechanism of EGF receptor recruitment into
coated pits involves high-affinity binding of AP-2 to
Tyr974-containing motif, another pathway may be mediated by
weak receptor/AP-2 interactions or by proteins other than AP-2.
Volume 271, Number 23,
Issue of June 7, 1996
pp. 13377-13384
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
Instituto
di Neuroscienze e Biommagini del CNR, H.S. Raffaele,
Milano 20132, Italy
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