The MAPK kinase Pek1 acts as a phosphorylation-dependent molecular switch

The mitogen-activated protein kinase (MAPK) pathway is a highly conserved e ukaryotic signalling: cascade that converts extracellular signals into vari ous outputs, such as cell growth and differentiation(1-3), MAPK is phosphor ylated and activated by a specific MAPK kinase (MAPKK)(4): MAPKK is therefo re considered to be an activating regulator of MAPK. Pmk1 is a MAPK that re gulates cell integrity(5) and which, with calcineurin phosphatase, antagoni zes chloride homeostasis(6) in fission yeast. We have now identified Pek1, a MAPKK for Pmk1 MAPK. We show here that Pek1, in its unphosphorylated form , acts as a potent negative regulator of Pmk1 MAPK sig-nailing. Mkh1(7), an upstream MAPKK kinase (MAPKKK), converts Pek1 from being an inhibitor to a n activator. Our results indicate that Pek1 has a dual stimulatory and inhi bitory function which depends on its phosphorylation state. This switch-lik e mechanism could contribute to the all-or-none physiological response medi ated by the MAPK signalling pathway.