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Vol. 10, Issue 2, 417-434, February 1999
¶ and#
*Dipartimento di Medicina Sperimentale e Patologia, University of
Roma "La Sapienza," Rome 00161, Italy;
Eps15 is a substrate for the tyrosine kinase of the epidermal
growth factor receptor (EGFR) and is characterized by the presence of a
novel protein:protein interaction domain, the EH domain. Eps15 also
stably binds the clathrin adaptor protein complex AP-2. Previous work
demonstrated an essential role for eps15 in receptor-mediated endocytosis. In this study we show that, upon activation of the EGFR
kinase, eps15 undergoes dramatic relocalization consisting of 1)
initial relocalization to the plasma membrane and 2) subsequent colocalization with the EGFR in various intracellular compartments of
the endocytic pathway, with the notable exclusion of coated vesicles.
Relocalization of eps15 is independent of its binding to the EGFR or of
binding of the receptor to AP-2. Furthermore, eps15 appears to undergo
tyrosine phosphorylation both at the plasma membrane and in a
nocodazole-sensitive compartment, suggesting sustained phosphorylation
in endocytic compartments. Our results are consistent with a model in
which eps15 undergoes cycles of association:dissociation with membranes
and suggest multiple roles for this protein in the endocytic pathway.
Istituto San
Gellicano, Rome, Italy;
§Istituto Nazionale Ricerca sul
Cancro di Genova, Sezione di Biotecnologie, Rome, Italy;
Department of Experimental Oncology, European Institute
of Oncology, 20141 Milan, Italy;
¶Istituto di Patologia
Speciale Medica, University of Parma, Italy; and
#Istituto
di Microbiologia, University of Bari, Italy
Corresponding author. E-mail address:
torrisi{at}axrma.uniroma1.it.
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