Survival of the weakest: signaling aided by endosomes

Abstract

The tyrosine kinase receptor c-Met plays a key role in cell proliferation, morphogenesis, and motility in response to hepatocyte growth factor. C-Met is often altered in cancer and is a major target for therapeutic intervention. Despite knowing a great deal of the molecular machinery downstream of this receptor tyrosine kinase, the spatiotemporal regulation of c-Met signaling still remains elusive. In this issue of the Journal of Cell Biology, Kermorgant and Parker (Kermorgant, S. and P.J. Parker. 2008. J. Cell Biol. 182:855-863) provide evidence for a model in which the c-Met-activated STAT3 signal is mediated by endosomal trafficking. This study elegantly highlights how weak signals can be effectively transmitted to the nucleus by exploiting endosomal compartments, raising important mechanistic implications for the signaling research community.

Figure 1.

Survival of the weakest. Both ERK1/2 and STAT3 signaling require the endocytosis of the HGF-bound c-Met receptor. The signal strength differs between these two signaling proteins and this leads to disparate pathways to the nucleus. The strong ERK1/2 signal proceeds via cytosolic diffusion, whereas the weaker STAT3 signal requires a microtubule-dependent perinuclear localization of c-Met. In comparison, a strong STAT3 signal mediated by Oncostatin M proceeds similarly to ERK1/2. OSMR, Oncostatin M receptor.