A WNK and a Nudge towards Kinase Biology




Sengupta, Samarpita

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A family of four atypical protein kinases; WNKs are characterized by a non-canonical position of the catalytic lysine. The significance of WNKs was first realized when they were found to be causatively linked to a rare form of genetic hypertensive disease known as PHAII. WNKs are an ancient family of kinases and are known to have roles in regulating salt homeostasis in the body in response to osmotic stress, regulating vesicular transport and regulating circadian rhythm in plants. All four WNKs can activate their downstream substrate, OSR1 which in turn can activate ion cotransporters downstream such as NCC and NKCC which results in regulation of ion balance in the cell. WNKs can bind to each other and can potentially form an autoactivable complex. Thus, regulation by WNKs is a complex affair. Further, OSR1 binds to its upstream regulators and substrates via RFxV motifs. WNK1, depending on the splice form, possesses at least five RFxV motifs. I have defined a minimal region on WNK1 required for interaction with OSR1. I have shown that expression of this minimal binding region in cells is sufficient to inhibit OSR1 activation by WNKs. I have also determined that the WNK-OSR1 pathway can cross-talk with the mTORC2 pathway. mTORC2 can directly phosphorylate OSR1 and regulate its activity. Finally, to understand why WNKs possess a slow substrate turnover rate and whether a crucial cofactor is missing, I have determined that WNKs can bind to lipids in vitro. Lipids can alter kinase activity of WNK1 towards OSR1. Future studies will be aimed at understanding the mechanism of action of mTORC2 in regulating the WNK-OSR1 pathway and to determine whether WNKs can bind to lipids in cells and the importance of the lipid binding activity of WNKs. Understanding the intricacies of WNKs would give us important tools to determine its roles in human diseases.