Stressing out or stressing in: intracellular pathways for SAPK activation.

Stress-activated MAP kinases (SAPKs) respond to a wide variety of stressors. In most cases, the pathways through which specific stress signals are transmitted to the SAPKs are not known. Our recent findings have begun to address two important and related questions. First, do various stresses activate a SAPK through common pathways initiated at the cell surface, or through alternative, intracellular inputs? Second, how does an activated SAPK mount a specific response appropriate to the particular stress experienced? Our work has uncovered the mechanisms by which two stresses, arsenite treatment and DNA damage, stimulate the yeast SAPKs Hog1 and Mpk1, respectively. We found that these stresses activate the SAPKs through intracellular inputs that modulate their basal phosphorylation, rather than by activation of the protein kinase cascades known to stimulate them. Both stresses act through targeting, in different ways, the tyrosine-specific or dual-specificity protein phosphatases that normally maintain the SAPKs in a low-activity state. Previous work has demonstrated that basal signal flux through SAPK pathways is important for the sensitivity and dynamic response to external signals. Our work reveals that basal activity of SAPKs is additionally important to allow SAPK activation by intracellular inputs that modulate that activity. Additionally, because different stressors may activate SAPKs by modulation of basal signal through inputs at distinct nodes along the canonical activation pathway, stress-specific SAPK outputs may be controlled, in part, by the specific intracellular mechanisms of their activation. Thus, understanding the intracellular pathways through which various stressors activate SAPKs is likely to provide insight into how they elicit physiologically coherent responses to the specific stress experienced.