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J Biol Chem. 2003 Oct 31;278(44):43411-7. Epub 2003 Aug 4.

Tyrosine phosphorylation of the beta2 subunit of clathrin adaptor complex AP-2 reveals the role of a di-leucine motif in the epidermal growth factor receptor trafficking.

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Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.


Tyrosine phosphorylation of the beta2 subunit of clathrin adaptor complex AP-2 was detected in three types of cells treated with epidermal growth factor (EGF). The tyrosine phosphorylation was observed during recruitment of EGF receptors into coated pits at 4 degrees C and reached maximum at 37 degrees C at post-recruitment stages of endocytosis. An inhibitor of EGF receptor kinase completely abolished this phosphorylation in all cell types, whereas the inhibitor of Src family kinases partially inhibited beta2 phosphorylation in A-431 cells but not in HeLa cells. By using beta2 subunit tagged with yellow fluorescent protein that is effectively assembled into AP-2 complex, the major phosphorylation site of beta2 was mapped to Tyr-6. Analysis of cells expressing dominant-interfering mutant mu2 subunit of AP-2 suggested that beta2 phosphorylation is partially mediated by the receptor interaction with the mu2 subunit. Mutation of leucine residues 1010 and 1011 motif in the EGF receptor resulted in the severe inhibition of beta2 tyrosine phosphorylation. From these data, we propose that interactions of the EGF receptor with AP-2 mediated by the receptor 974YRAL and di-leucine motifs may contribute to beta2 tyrosine phosphorylation. Surprisingly, mutation of the Leu-1010/Leu-1011 motif resulted in impaired degradation of EGF receptors, suggesting the role of this motif in lysosomal targeting of the receptor.

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