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Molecular and Cellular Biology, October 2000, p. 7685-7692, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Endosomal Localization and Receptor Dynamics Determine Tyrosine Phosphorylation of Hepatocyte Growth Factor-Regulated Tyrosine Kinase Substrate

Sylvie Urbé,1,* Ian G. Mills,1 Harald Stenmark,2 Naomi Kitamura,3 and Michael J. Clague1,*

Physiological Laboratory, University of Liverpool, Liverpool L69 3BX, United Kingdom1; Department of Biochemistry, The Norwegian Radium Hospital, Montebello, N0310 Oslo, Norway2; and Department of Life Science, Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226, Japan3

Received 20 March 2000/Returned for modification 15 May 2000/Accepted 21 July 2000

Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is a prominent substrate for activated tyrosine kinase receptors that has been proposed to play a role in endosomal membrane trafficking. The protein contains a FYVE domain, which specifically binds to the lipid phosphatidylinositol (PI) 3-phosphate (PI 3-P). We show that this interaction is required both for correct localization of the protein to endosomes that only partially coincides with early endosomal autoantigen 1 and for efficient tyrosine phosphorylation of the protein in response to epidermal growth factor stimulation. Treatment with wortmannin reveals that Hrs phosphorylation also requires PI 3-kinase activity, which is necessary to generate the PI 3-P required for localization. We have used both hypertonic media and expression of a dominant-negative form of dynamin (K44A) to inhibit endocytosis; under which conditions, receptor stimulation fails to elicit phosphorylation of Hrs. Our results provide a clear example of the coupling of a signal transduction pathway to endocytosis, from which we propose that activated receptor (or associated factor) must be delivered to the appropriate endocytic compartment in order for Hrs phosphorylation to occur.

* Corresponding author. Mailing address: Physiological Laboratory, University of Liverpool, Crown St., Liverpool L69 3BX, United Kingdom. Phone: 44 151 794 5308. Fax: 44 151 794 5321. E-mail for Michael J. Claque: clague{at}liv.ac.uk. E-mail for Sylvie Urbé: urbe{at}liv.ac.uk.

Molecular and Cellular Biology, October 2000, p. 7685-7692, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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