Kermorgant and Parker.
c-Met is the plasma membrane receptor for hepatocyte growth factor (HGF), and signals by phosphorylating the transcription factor STAT3. But it's a weak activator of STAT3, and STAT3 faces a gauntlet of inactivating phosphatases that stand between the plasma membrane and the nucleus. This suggested to the authors that c-Met may not rely on long-distance diffusion of STAT3 to get its message across.
Looking at live cells, the team found that HGF stimulation caused c-Met and STAT3 to colocalize on endosomes at the periphery, where STAT3 became phosphorylated. But blocking microtubule trafficking of endosomes prevented active STAT3 from accumulating in the nucleus, confirming that diffusion was insufficient to get it there, and that its transport within endosomes, along with c-Met, was needed to deliver the signal. Not surprisingly, endosome trafficking was not required if the gauntlet of phosphatases was inactivated.
“Information flow from receptors is not simply a switch thrown at the cell surface,” says PI Peter Parker. “The spatial distribution of signaling components is important, and a Western blot doesn't necessarily tell you much about what the pathway is doing in the cell.” Although strong signal activators may be able to rely on peripheral signaling alone to get their message across, Parker suggests, for weaker ones, where they signal from may determine whether they are heard at all. RR