Intrinsically active (MKK-independent) variants of SAPKs - How do they work?

The activity of Stress activated protein kinases (SAPKs) is critical for proper development, differentiation, and survival. Several SAPKs are expressed in each eukaryotic cell and are co-activated in response to stimulation. It is difficult therefore to reveal the specific functions of each SAPK. These functions could be accurately addressed by expression of SAPKs mutants that are spontaneously active in vivo. We have recently produced such mutants of the yeast Hog1 and of the four isoforms of mammalian p38. Here, we summarize the current understanding of their mechanism of action. Structural studies show that the mutations cause conformational changes at the L16 domain, primarily the disruption of a hydrophobic core. These changes confer an auto-phosphorylation capability to the enzyme and consequently activation. In addition, the mutants are spontaneously recruiting specific upstream components for increasing their activity. We suggest that this process emulates the natural mechanism of p38 activation, achieved via phosphorylation of Tyr323 (the "bypass" pathway). This notion suggests that the intrinsically active mutants are legitimate for biological studies.