Pharmacological targeting of SPAK kinase in disorders of impaired epithelial transport

ABSTRACT

Introduction: The mammalian SPS1-related proline/alanine-rich serine-threonine kinase SPAK (STK39) modulates ion transport across and between epithelial cells in response to environmental stimuli such osmotic stress and inflammation. Research over the last decade has established a central role for SPAK in the regulation of ion and water transport in the distal nephron, colonic crypts, and pancreatic ducts, and has implicated deregulated SPAK signaling in NaCl-sensitive hypertension, ulcerative colitis and Crohn’s disease, and cystic fibrosis.

Areas covered: We review recent advances in our understanding of the role of SPAK kinase in the regulation of epithelial transport. We highlight how SPAK signaling – including its upstream Cl^– sensitive activators, the WNK kinases, and its downstream ion transport targets, the cation- Cl^– cotransporters contribute to human disease. We discuss prospects for the pharmacotherapeutic targeting of SPAK kinase in specific human disorders that feature impaired epithelial homeostasis.

Expert opinion: The development of novel drugs that antagonize the SPAK-WNK interaction, inhibit SPAK kinase activity, or disrupt SPAK kinase activation by interfering with its binding to MO25α/β could be useful adjuncts in essential hypertension, inflammatory colitis, and cystic fibrosis.

KEYWORDS:

• Blood pressure regulation
• cation-chloride cotransporters (CCCs)
• ion homeostasis
• kinase inhibitors
• signal transduction
• SPAK phosphorylation

Article highlights

• Discovery and characterization of the SPAK kinase

• SPAK as major regulator of CCCs

• Targeting SPAK in essential hypertension

• Targeting SPAK in secretory diarrhea/colitis

• Strategies of SPAK inhibition

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was supported in part by NIH grant R21GM118944 to E. Delpire; and the March of Dimes Basil O’Connor Award, Simons Foundation SFARI Awardand NIH award (NRCDP K12) to K. T. Kahle.