Dual role for membrane localization in XXXX MAP kinase cascade activation and its contribution to signaling fidelity.

@entity6771 @entity6770 @entity5678 @entity375 @entity5681
Distinct MAP kinase pathways in @entity375 share several signaling components , including the PAK Ste20 and the MAPKKK @entity6770 , yet signaling is specific. Mating pheromones trigger an initial step in which Ste20 activates @entity6770 , and this requires plasma membrane recruitment of the MAP kinase cascade scaffold protein, @entity5678 . Here, we demonstrate an additional role for @entity5678 membrane localization. Once @entity6770 is activated, signaling through the mating pathway remains minimal but is substantially amplified when @entity5678 is recruited to the membrane either by the Gbetagamma dimer or by direct membrane targeting, even to internal membranes. @entity6770 signaling is also amplified by @entity5678 oligomerization and by a hyperactivating mutation in the @entity6771 binding region of @entity5678 . We suggest a model in which membrane recruitment of @entity5678 concentrates its binding partners and thereby amplifies signaling through the kinase cascade. We find similar behavior in the osmotically responsive HOG pathway. Remarkably, while both @entity5681 and hyperosmotic stimuli amplify signaling from constitutively active @entity6770 , the resulting signaling output remains pathway specific. These findings suggest a common mode of regulation in which pathway stimuli both initiate and amplify MAP kinase cascade signaling. The regulation of rate-limiting steps that lie after a branchpoint from shared components helps ensure signaling specificity.
