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Vol. 93, Issue 19, 10078-10083, September 17, 1996

Biochemistry
 Ultrasensitivity in the mitogen-activated protein kinase cascade

Chi-Ying F. Huang and James E. Ferrell Jr.dagger

Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, CA 94305-5332

Communicated by Daniel E. Koshland, Jr., University of California, Berkeley, CA, May 16, 1996 (received for review January 22, 1996)

The mitogen-activated protein kinase (MAPK) cascade is a highly conserved series of three protein kinases implicated in diverse biological processes. Here we demonstrate that the cascade arrangement has unexpected consequences for the dynamics of MAPK signaling. We solved the rate equations for the cascade numerically and found that MAPK is predicted to behave like a highly cooperative enzyme, even though it was not assumed that any of the enzymes in the cascade were regulated cooperatively. Measurements of MAPK activation in Xenopus oocyte extracts confirmed this prediction. The stimulus/response curve of the MAPK was found to be as steep as that of a cooperative enzyme with a Hill coefficient of 4-5, well in excess of that of the classical allosteric protein hemoglobin. The shape of the MAPK stimulus/response curve may make the cascade particularly appropriate for mediating processes like mitogenesis, cell fate induction, and oocyte maturation, where a cell switches from one discrete state to another.

dagger    To whom reprint requests should be addressed.

0027-8424/96/9310078-6/0
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