MAPK Signaling

Multiple Inputs

Science's STKE  27 Jan 2004:
Vol. 2004, Issue 217, pp. tw34-TW34
DOI: 10.1126/stke.2172004TW34

Mitogen-activated protein kinase (MAPK) cascades are described as linear processes whereby a stimulus leads to activation of the MAPK kinase kinase (MAPKKK), which in turn phosphorylates and activates a MAPK kinase, which then phosphorylates and activates the MAPK. Harrison et al. used activated versions of two upstream components of the Saccharomyces cerevisiae cell integrity MAPK pathway to investigate the activation of this pathway in response to different stimuli. Their results suggest that activation at individual steps in the pathway seems to be insufficient to reproduce full activation, suggesting that more complicated regulatory interactions result in permissive rather than self-sufficient signals at various steps in the pathway. The cell integrity pathway involves activation by guanosine triphosphate (GTP) loading of Rho1p, activation of protein kinase C (Pkc1p), followed by the activation of Bck1p (a MAPKKK), Mkk1p and Mkk2p (MAPKKs), and finally Mpk1p (a MAPK). However, Harrison et al. show that low-level expression of a GTP-locked form of Rho1p did not promote increased phosphorylation of Mpk1p. The cell integrity pathway is activated by several stresses, including disruption of the actin cytoskeleton, hypoosmotic shock, and heat shock. Yeast strains expressing constitutively active Bck1p (BCK1-20 allele) were unable to activate Mpk1p in response to hypoosmotic shock. Furthermore, in the absence of Pkc1p, the activated Bkp1p mutant did not promote Mpk1p phosphorylation in response to actin depolymerization. Responsiveness was restored by expression of Pkc1p; thus, the constitutively active form of Bkp1p was still regulated by Pkc1p despite the activating mutations and the response to actin disruption required this Pkc1p-mediated regulation. Yeast strains expressing constitutively active Mkk1p (MKK1DD, with two phosphorylatable serines replaced with aspartic acid) were unable to stimulate Mpk1p in response to hypoosmotic shock or actin depolymerization in the presence or absence of wild-type Bck1p. In contrast, heat shock stimulated Mpk1p phosphorylation in the presence of the active Mkk1p mutant. The authors propose that the kinases provide a permissive environment upon which stress input can regulate activity at different points in the pathway.

J. C. Harrison, T. R. Zyla, E. S. G. Bardes, D. J. Lew, Stress-specific activation mechanisms for the "cell integrity" MAPK pathway. J. Biol. Chem. 279, 2616-2622 (2004). [Abstract] [Full Text]