SPAK and OSR1: STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells

Since the discovery of an interaction between membrane transport proteins and the mammalian STE20 (sterile 20)-like kinases SPAK (STE20/SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase-1), a significant body of work has been performed probing the molecular physiology of these two kinases. To date, the function of SPAK and OSR1 is probably the best known of all mammalian kinases of the STE20 family. As they regulate by direct phosphorylation key ion transport mechanisms involved in fluid and ion homoeostasis, SPAK and OSR1 constitute key end-of-pathway effectors. Their significance in such fundamental functions as ion homoeostasis and cell volume control is evidenced by the evolutionary pressure that resulted in the duplication of the OSR1 gene in higher vertebrates. This review examines the distribution of these two kinases in the animal kingdom and tissue expression within a single organism. It also describes the main molecular features of these two kinases with emphasis on the interacting domain located at their extreme C-terminus. A large portion of the present review is devoted to the extensive biochemical and physiological studies that have resulted in our current understanding of SPAK/OSR1 function. Finally, as our understanding is a work in progress, we also identify unresolved questions and controversies that warrant further investigation.