Kinases in Diabetes and Hypertension

Abstract

WNKs (with‐no‐lysine [K]) 1–4 are unique protein‐serine/threonine kinases conserved in multicellular organisms. The ATP‐binding lysine present in all protein kinases is in an atypical position in WNKs. Two of the four WNKs were identified as genes mutated in pseudohypoaldosteronism type II, a genetic syndrome characterized by hypertension and hyperkalemia. All four WNKs contain very large noncatalytic regions with no currently known domain organization that appear to function as scaffolds. WNKs have been implicated not only in regulation of ion balance, but also in cell survival and proliferation, membrane trafficking and embryonic organ development. Mitogen‐activated protein kinases MAPKs transduce signals in a multitude of cellular pathways in response to many ligands and cell stimuli. MAPKs have been implicated in diseases including cancer, inflammatory disease, obesity, and diabetes. The MAPKs ERK1/2 are required for glucose‐regulated insulin gene transcription in pancreatic beta cells. Nutrients and hormones that stimulate or reduce insulin secretion have a parallel effect on ERK1/2 activity in beta cells. ERK1/2 control the function of several transcription factors that mediate glucose‐regulated insulin gene transcription, including at least two factors that are encoded by maturity‐onset diabetes (MODY) genes.Research supported by grants from the National Institutes of Health, R01‐GM53032, R37‐DK034128, R01‐DK055310 and the Robert A. Welch Foundation I‐1243 and the American Diabetes Association Mentor‐based Postdoctoral Fellowship award.