Pharmacological targeting of SPAK kinase in disorders of impaired epithelial transport.

Zhang J, Karimy JK, Delpire E, Kahle KT
Expert Opin Ther Targets. 2017 21 (8): 795-804

PMID: 28679296 · PMCID: PMC6081737 · DOI:10.1080/14728222.2017.1351949

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.

MeSH Terms (12)

Animals Colitis Cystic Fibrosis Drug Design Epithelial Cells Essential Hypertension Humans Hypertension Ion Transport Molecular Targeted Therapy Protein-Serine-Threonine Kinases Signal Transduction

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