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J. Cell Biol. 182 (5): 855-863

Copyright © 2008 by the Rockefeller University Press.


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Receptor trafficking controls weak signal delivery: a strategy used by c-Met for STAT3 nuclear accumulation

Stéphanie Kermorgant1, and Peter J. Parker2

1 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
2 Protein Phosphorylation Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, England, UK, and Division of Cancer Studies, King's College School of Medicine, Guy's Hospital, London SE1 9RT, England, UK

Correspondence to Peter J. Parker: peter.parker{at}cancer.org.uk

Abstract: 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.

Abbreviations used in this paper: CHC, clathrin heavy chain; EEA1, early endosome autoantigen 1; ERK, extracellular signal-regulated kinase; HGF, hepatocyte growth factor; STAT3, signal transducer and activator of transcription 3.

© 2008 Kermorgant and Parker This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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