Molecular Physiology of SPAK and OSR1: Two Ste20-Related Protein Kinases Regulating Ion Transport

Abstract

SPAK (Ste20-related proline alanine rich kinase) and OSR1 (oxidative stress responsive kinase) are members of the germinal center kinase VI sub-family of the mammalian Ste20 (Sterile20)-related protein kinase family. Although there are 30 enzymes in this protein kinase family, their conservation across the fungi, plant and animal kingdom confirms their evolutionary importance. Already, a large volume of work has accumulated on the tissue distribution, binding partners, signaling cascades, and physiological roles of mammalian SPAK and OSR1 in multiple organ systems. After reviewing this basic information, we will examine newer studies that demonstrate the pathophysiological consequences to SPAK and/or OSR1 disruption, discuss the development and analysis of genetically-engineered mouse models, and address the possible role these serine/threonine kinases might have in cancer proliferation and migration.

Short Forms of Ste20-related Proline/Alanine-rich Kinase (SPAK) in the Kidney Are Created by Aspartyl Aminopeptidase (Dnpep)-mediated Proteolytic Cleavage

“…The proline/alanine-rich region of SPAK is of interest as it constitutes the differentiating feature from its ancestor kinase OSR1 (2). As demonstrated by our study, this unique region is primarily targeted by the protease, suggesting it may be involved in regulating the kinase.…”

“…In recent years a kinase cascade involving the Ste20p-like kinases, SPAK 2 (STK39) and OSR1 (OxSR1), has emerged as an important regulator of salt transport in the kidney (1,2). The kinases regulate two transport mechanisms involved in Na ϩ reabsorption: the Na-K-2Cl cotransporter, NKCC2, expressed in the thick ascending limb of Henle (TAL), and the Na-Cl cotransporter, NCC, expressed in the distal convoluted tubule.…”

“…1A). Examination of fully sequenced genomes revealed that SPAK originated from OSR1 gene duplication during vertebrate evolution (2,3). In heterologous expression systems, the two kinases behave similarly, anchoring themselves to the N-terminal tail of Na ϩ -dependent cotransporters in order to phosphorylate and stimulate their activities.…”

Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals

“…Cellular reconstitution studies and mouse genetics demonstrated the importance of WNK function in cell volume regulation and maintenance of blood pressure (13-19). Control of cation-chloride cotransporters through OSR1 and SPAK is among the best-documented actions of WNKs in diverse tissues (5,(20)(21)(22).WNKs also regulate serum-and glucocorticoid-inducible protein kinases (SGKs) through a noncatalytic mechanism leading to increased sodium influx through the epithelial sodium channel (ENaC) (23, 24). SGKs and the related Akt enzymes are activated by phosphorylation on multiple sites, most prominently a residue in the activation loop by the phosphoinositide-dependent protein kinase and on a second site in a C-terminal hydrophobic motif (25).…”

“…Cellular reconstitution studies and mouse genetics demonstrated the importance of WNK function in cell volume regulation and maintenance of blood pressure (13)(14)(15)(16)(17)(18)(19). Control of cation-chloride cotransporters through OSR1 and SPAK is among the best-documented actions of WNKs in diverse tissues (5,(20)(21)(22).…”