PKC controls HGF-dependent c-Met traffic, signalling and cell migration.
The growth factor/receptor pair HGF/c-Met exerts control on proliferation, morphogenesis and motility, and through overexpression and mutation is implicated in cancer. Here we have investigated the relationship between receptor signalling and traffic, and its control by specific PKC isotypes. It is shown that c-Met signalling to the ERK cascade occurs within endosomal compartments and that it is in this compartment that PKCepsilon specifically exerts its control on the pathway with the consequent accumulation of ERK in focal complexes. These events are clearly separated from the subsequent microtubule-dependent sorting of c-Met to its perinuclear destination, which is shown to be under the control of PKCalpha. Thus while it is shown that traffic to endosomes is essential for HGF/c-Met to trigger an ERK response, the subsequent traffic and signalling of c-Met controlled by these two PKC isotypes are unconnected events. The dynamic properties conferred by the PKCepsilon control are shown to be essential for a normal HGF-dependent migratory response. Thus PKCs are shown to control both receptor traffic and signal traffic to relay HGF/c-Met responses.
Kermorgant
Stéphanie
S
Protein Phosphorylation Laboratory, Cancer Research UK London Research Institute, London, UK.
Zicha
Daniel
D
Parker
Peter J
PJ
D002465:Cell Movement; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D021381:Protein Transport; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction
D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C496628:PRKCA protein, human; C497255:PRKCE protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D020928:Mitogen-Activated Protein Kinases