ULTRASENSITIVITY IN THE MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE

The mitogen-activated protein kinase (MAPK) cascade is a highly conser ved series of three protein kinases implicated in diverse biological p rocesses. Here we demonstrate that the cascade arrangement has unexpec ted consequences for the dynamics of MAPK signaling. We solved the rat e equations for the cascade numerically and found that MAPK is predict ed to behave like a highly cooperative enzyme, even though it was not assumed that any of the enzymes in the cascade were regulated cooperat ively. Measurements of MAPK activation in Xenopus oocyte extracts conf irmed this prediction. The stimulus/response curve of the MAPK was fou nd to be as steep as that of a cooperative enzyme with a Hill coeffici ent of 4-5, well in excess of that of the classical allosteric protein hemoglobin. The shape of the MAPK stimulus/response curve may make th e cascade particularly appropriate for mediating processes like mitoge nesis, cell fate induction, and oocyte maturation, where a cell switch es from one discrete state to another.