SPAK, a STE20/SPS1-related kinase that activates the p38 pathway

We have cloned a member of the STE20/SPS1 protein kinase family from a tran sformed rat pancreatic beta cell line. SPAK (STE20/SPS1-related, proline al anine-rich kinase) belongs to the SPS1 subfamily of STE20 kinases and is hi ghly conserved between species. SPAK is expressed ubiquitously, although pr eferentially in brain and pancreas. Biochemical characterization of SPAK ca talytic activity demonstrates that is a serine/threonine kinase that can ph osphorylate itself and an exogenous substrate in vitro. SPAK is immunopreci pitated from transfected mammalian cells as a complex with another, as yet uncharacterized, serine/threonine kinase which is capable of phosphorylatin g catalytically-inactive SPAK and myelin basic protein in an in vitro kinas e assay. SPAK specifically activates the p38 pathway in cotransfection assa ys. Like MST1 and MST2, SPAK contains a putative caspase cleavage site at t he junction of the catalytic domain and the C-terminal region. Full-length SPAK is expressed in the cytoplasm in transfected cells, while a mutant cor responding to caspase-cleaved SPAK is expressed predominantly in the nucleu s. The similarity of SPAK to other SPS1 family members, its ability to acti vate the p38 pathway, in addition to its putative caspase cleavage site, pr ovide evidence that SPAK may act as a novel mediator of stress-activated si gnals.