Editors' ChoiceReceptor signaling

Receptor Trafficking Controls Signaling Strength

Science Signaling  16 Sep 2008:
Vol. 1, Issue 37, pp. ec326
DOI: 10.1126/scisignal.137ec326

Stimulation of the receptors for oncostatin M and hepatocyte growth factor (HGF) results in activation of signal transducer and activator of transcription 3 (STAT3) through a process involving phosphorylation and nuclear accumulation of STAT3, which allows STAT3 to regulate gene expression. Kermorgant and Parker show that, in HeLa cells, activation of STAT3 by HGF requires the endocytosis and trafficking to a perinuclear region of the HGF receptor c-Met, whereas activation of STAT3 by oncostatin M through its receptor does not rely on this internalization process. The authors found that STAT3 and phosphorylated STAT3 colocalized with c-Met at endosomes. If endocytosis was blocked through various means, or if delivery of c-Met to the perinuclear region was blocked by disrupting either microtubule motor function or microtubules, then STAT3 activation and nuclear translocation was inhibited. Activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) was inhibited if c-Met endocytosis was blocked but was not impaired if microtubules were disrupted so that c-Met trafficking to the perinuclear compartment was blocked, suggesting differential signaling requirements for these two downstream components of c-Met signaling. If c-Met activity was inhibited pharmacologically with a cell-permeable inhibitor after the cells were exposed to HGF (to allow time for receptor endocytosis), then STAT3 and ERK1/2 phosphorylation was inhibited. However, application of an antibody that neutralizes HGF did not inhibit STAT3 and ERK1/2 activation, suggesting that receptor recycling to the membrane was not required. The differential requirements for receptor trafficking appear to control the kinetics of downstream signaling: ERK1/2 activation in response to HGF was rapid and occurred within 15 minutes of HGF addition, whereas STAT3 activation required longer exposure to HGF. Activation of STAT3 by oncostatin M was also rapid, occurring within 15 minutes of ligand addition, and the total phosphorylated STAT3 was greater than when the cells were exposed to HGF. Thus, receptor trafficking appears to control both the kinetics and strength of the STAT3 response.

S. Kermorgant, P. J. Parker, Receptor trafficking controls weak signal delivery: A strategy used by c-Met for STAT3 nuclear accumulation. J. Cell Biol. 182, 855-863 (2008). [Abstract] [Full Text]