Interaction Mapping of the Atypical Protein Kinase WNK3




Self, Jon Tate

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The story of the protein kinase "with no lysine 3" (WNK3) represents a unique chapter in the larger story of protein kinases, the so-called 'molecular switches' of the cell that serve the vital function of phosphorylating myriad proteins. In doing so, these enzymes furnish the cell with one of the primary means by which signals from the external environment are transduced into cellular consequences. At the time our lab reported discovery of the first WNK, it was thought that all protein kinases contained an invariant catalytic lysine necessary for phosphoryl transfer in ß strand 3 (protein kinase subdomain II) of the highly conserved catalytic domain. Analysis of WNK1 uncovered a cysteine in the place of the so-called canonical catalytic lysine--hence the name WNK for "with no lysine". Subsequently, other WNKs came to light, and together with WNK1, they comprise an atypical branch of the kinome--the functions and significance of which are still being elucidated. Of clinical significance, WNKs 1 and 4 have been implicated in a heritable form of hypertension (pseudohypoaldosteronism type II). WNK3 has been reported to regulate certain members of the SLC12A family of cation/Cl- cotransporters (KCC1/2; NKCC1; NCC), and also to localize to various Cl- transporting epithelia and certain brain neurons with GABA-A ionotropic receptors. My goal with these interaction mapping efforts has been to build a collection of putative WNK3 interactors to serve as a source of information and project leads for the ongoing research program of the Cobb laboratory. The yeast two-hybrid screens described here have yielded hundreds of putative interactors. While this written work deals only with a small number of the most interesting putative interactors, together they point toward a number of unexpected roles for WNK3, including putative interactions with RNA-binding proteins, transcriptional regulators and proteins implicated in developmental disorders and neurodegenerative disease. The story of the WNK kinases will go on. With a connection to ion flux diseases well-established, the WNK family will surely continue to attract attention for many years, particularly given their potential as drug targets.

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