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Endosomal Dynamics of Met Determine Signaling Output
Dean E.
Hammond,*
Stephanie
Carter,*
John
McCullough,
Sylvie
Urbé,
George
Vande Woude, and
Michael J.
Clague§
Physiological Laboratory, University of
Liverpool, Liverpool, L69 3BX, United Kingdom; and
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 ablock in the endocytic
trafficking of Met such that the receptorfails to reach late
endosomes/lysosomes, where degradation byacid-dependent proteases
takes place (Hammond et al., 2001). Inthis article, we
have biochemically determined Met internalizationrates from the cell
surface and shown that lactacystin does notinhibit the initial
HGF-dependent internalization step of Met.Instead, it promotes the
recycling pathway from early endosomesat the expense of sorting to
late endosomes, thereby ensuringrapid return of internalized Met to
the cell surface. We haveused this perturbation of Met endosomal
sorting by lactacystinto examine the consequences for HGF-dependent
signaling outputs.In control cells HGF-dependent receptor
autophosphorylation reachesa maximal level over 5-10 min but then
attenuates over the ensuing50 min. Furthermore, Met dephosphorylation
can be kineticallydissociated 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, downstreamof receptor
activation, show a normal kinetic profile of phosphorylation,indicating that the mitogen-activated protein kinase pathway canattenuate in the face of sustained receptor activation. The
HGF-dependentphosphorylation of a receptor substrate that is localized
to clathrin-coatedregions of sorting endosomes, Hrs, is dramatically
reduced bylactacystin treatment. Reduction of cellular Hrs levels by
shortinterfering RNA modestly retards Met degradation and markedlyprevents the attenuation of Met phosphorylation. HGF-dependentHrs
phosphorylation and Met dephosphorylation may provide signaturesfor
retention of the receptor in coated regions of the endosomeimplicated
in sorting tolysosomes.
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and
