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Mol. Biol. Cell 14 (4): 1346-1354

Copyright © 2003 by The American Society for Cell Biology.

Vol. 14, Issue 4, 1346-1354, April 2003

Endosomal Dynamics of Met Determine Signaling Output

Dean E. Hammond,*dagger Stephanie Carter,*dagger John McCullough,dagger Sylvie Urbé,dagger George Vande Woude,Dagger and Michael J. Claguedagger §

 dagger Physiological Laboratory, University of Liverpool, Liverpool, L69 3BX, United Kingdom; and  Dagger Van Andel Institute, Grand Rapids, Michigan 49503

Proteasomal activity is required for Met receptor degradation after acute stimulation with hepatocyte growth factor (HGF). Inhibition of proteasomal activity with lactacystin leads to a block in the endocytic trafficking of Met such that the receptor fails to reach late endosomes/lysosomes, where degradation by acid-dependent proteases takes place (Hammond et al., 2001). In this article, we have biochemically determined Met internalization rates from the cell surface and shown that lactacystin does not inhibit the initial HGF-dependent internalization step of Met. Instead, it promotes the recycling pathway from early endosomes at the expense of sorting to late endosomes, thereby ensuring rapid return of internalized Met to the cell surface. We have used this perturbation of Met endosomal sorting by lactacystin to examine the consequences for HGF-dependent signaling outputs. In control cells HGF-dependent receptor autophosphorylation reaches a maximal level over 5-10 min but then attenuates over the ensuing 50 min. Furthermore, Met dephosphorylation can be kinetically dissociated from Met degradation. In lactacystin-treated cells, we observe a failure of Met dephosphorylation as well as Met degradation. Elements of the mitogen-activated protein kinase cascade, downstream of receptor activation, show a normal kinetic profile of phosphorylation, indicating that the mitogen-activated protein kinase pathway can attenuate in the face of sustained receptor activation. The HGF-dependent phosphorylation of a receptor substrate that is localized to clathrin-coated regions of sorting endosomes, Hrs, is dramatically reduced by lactacystin treatment. Reduction of cellular Hrs levels by short interfering RNA modestly retards Met degradation and markedly prevents the attenuation of Met phosphorylation. HGF-dependent Hrs phosphorylation and Met dephosphorylation may provide signatures for retention of the receptor in coated regions of the endosome implicated in sorting to lysosomes.


* These authors contributed equally to this work.

§ Corresponding author. E-mail address: clague{at}liv.ac.uk.


Molecular Biology of the Cell
Vol. 14, 1346-1354, April 2003
Copyright © 2003 by The American Society for Cell Biology


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