Receptor trafficking controls weak signal delivery: a strategy used by c-Met for STAT3 nuclear accumulation.
C-Met, the receptor of hepatocyte growth factor (HGF), through overexpression or mutation, is a major protooncogene that provides an attractive molecular target for cancer therapy. HGF/c-Met-induced tumorigenesis is dependent, in part, on the transcription factor and oncogene signal transducer and activator of transcription 3 (STAT3), which is believed to be activated by the receptor at the plasma membrane and then to travel to the nucleus where it acts. We demonstrate that although the robust signal to STAT3 elicited from the cytokine oncostatin-M does indeed support this mechanism of STAT3 action, for the weaker STAT3 signal emanating from c-Met, the activated receptor itself needs to be delivered to a perinuclear endosomal compartment to sustain phosphorylated STAT3 in the nucleus. This is signal specific because c-Met-induced extracellular signal-regulated kinase nuclear accumulation does not require receptor trafficking to the perinuclear compartment. This response is triggered from peripheral endosomes. Thus, control of growth factor receptor traffic determines the nature of the signal output, providing novel opportunities for intervention.
Kermorgant
Stéphanie
S
Department of Tumour Biology, Cancer Research UK Clinical Centre, Bart's and the London Queen Mary's School of Medicine and Dentistry, London EC1M 6BQ, England, UK.
Parker
Peter J
PJ
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D021381:Protein Transport; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000378:metabolism*; D015398:Signal Transduction
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
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