Time encoding by ERKs

There are many more biological processes than there are signaling pathways. How, then, do multiple signals converge on one pathway and yet elicit diverse responses? Satoru Sasagawa, Shinya Kuroda (University of Tokyo, Japan), and colleagues find that rapid increases in epidermal and nerve growth factors (EGF and NGF) trigger transient ERK activation, whereas it is the final concentration of NGF that determines whether a sustained ERK activation occurs. The differences probably explain why EGF prompts PC12 cell proliferation whereas NGF makes the same cells differentiate.The Tokyo group used in vivo measurement and in silico simulations to show that changes in growth factor concentration prompted fast SOS recruitment and thus Ras activation. Slower Ras-GAP recruitment was effective in turning off the Ras and thus made the response transient.

By contrast, the sustained response was dominated by the levels of Rap1 activation. Rap1-GAP activity was constitutive rather than inducible, so the overall response depended only on how much activator was supplied by the growth factor receptor. High constant levels of NGF (and a lack of the degradation seen with the EGF receptor) gave sustained ERK activation necessary for PC12 differentiation.

Thus, Ras and Rap1 capture transient and sustained receptor activation, respectively. This is translated into either transient or sustained ERK activation. Kuroda and colleagues are now looking at how this difference in the persistence of ERK activity is converted into distinct cellular behaviors.

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