The Ste20p family of protein kinases are pleiotropic in action, influencing intracellular signaling networks through actions on multiple signal transduction pathways. We will focus our continuing studies of mammalian Ste20p-related kinases on two groups of these enzymes that we previously identified, WNKs (with no lysine (K)) and TAOs (thousand-and-one residues), which have important biological functions. The urgency of a mechanistic examination of WNKs is heightened by the discovery that they are mutated in pseudohypoaldosteronism type II, PHA II, a Mendelian form of hypertension. Lifton et al. found that mutations in either WNK1 or WNK4 causes pseudohypoaldosteronism type II, a heritable form of hypertension. Our investigation of mechanisms linking WNK1 to sodium reabsorption may reveal strategies to develop anti-hypertensive therapies. We will define the biochemical mechanisms that control WNK1 activity, and we will examine the ligands and cellular events that stimulate WNK1 activity in distal convoluted tubule cells. We have identified two targets of WNKI. We will define the biochemical mechanisms regulating the target proteins and determine functional changes associated with their phosphorylation. TAOs are the only MAP3Ks currently known to be required for activation of the p38 MAPK pathway by heterotrimeric G proteins. TAOs are highly expressed in brain, activated during myoblast differentiation, and overexpressed in some tumors, suggesting several key sites of action. We will define the biochemical mechanisms by which heterotrimeric G proteins signal to TAO2 and p38. We also found that TAO2 phosphorylates G protein alpha subunits and alters their GTP binding. Therefore, we will investigate the functional effects of phosphorylation of G proteins by TAO2, and we will determine the events in mammalian cells for which TAOs are required.
| Gallolu Kankanamalage, Sachith; Lee, A-Young; Wichaidit, Chonlarat et al. (2016) Multistep regulation of autophagy by WNK1. Proc Natl Acad Sci U S A 113:14342-14347 |
| Dbouk, Hashem A (2015) PI3King the right partner: unique interactions and signaling by p110?. Postdoc J 3:71-87 |
| Taylor 4th, Clinton A; Juang, Yu-Chi; Earnest, Svetlana et al. (2015) Domain-Swapping Switch Point in Ste20 Protein Kinase SPAK. Biochemistry 54:5063-71 |
| Dbouk, Hashem A; Weil, Lauren M; Perera, G K Sachith et al. (2014) Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK. Proc Natl Acad Sci U S A 111:15999-6004 |
| Piala, Alexander T; Moon, Thomas M; Akella, Radha et al. (2014) Chloride sensing by WNK1 involves inhibition of autophosphorylation. Sci Signal 7:ra41 |
| Sengupta, Samarpita; Lorente-Rodríguez, Andrés; Earnest, Svetlana et al. (2013) Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals. Proc Natl Acad Sci U S A 110:18826-31 |
| Lee, A-Young; Chen, Wei; Stippec, Steve et al. (2012) Protein kinase WNK3 regulates the neuronal splicing factor Fox-1. Proc Natl Acad Sci U S A 109:16841-6 |
| Sengupta, Samarpita; Tu, Szu-Wei; Wedin, Kyle et al. (2012) Interactions with WNK (with no lysine) family members regulate oxidative stress response 1 and ion co-transporter activity. J Biol Chem 287:37868-79 |
| Tu, Szu-wei; Bugde, Abhijit; Luby-Phelps, Katherine et al. (2011) WNK1 is required for mitosis and abscission. Proc Natl Acad Sci U S A 108:1385-90 |
| Heise, Charles J; Xu, Bing-e; Deaton, Staci L et al. (2010) Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members. J Biol Chem 285:25161-7 |
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