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MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 protein kinases

Filippi, Beatrice M., de los Heros, Paola, Mehellou, Youcef, Navratilova, Iva, Gourlay, Robert, Deak, Maria, Plater, Lorna, Toth, Rachel, Zeqiraj, Elton and Alessi, Dario R. 2011. MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 protein kinases. EMBO Journal 30 (9) , pp. 1730-1741. 10.1038/emboj.2011.78

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Mouse protein‐25 (MO25) isoforms bind to the STRAD pseudokinase and stabilise it in a conformation that can activate the LKB1 tumour suppressor kinase. We demonstrate that by binding to several STE20 family kinases, MO25 has roles beyond controlling LKB1. These new MO25 targets are SPAK/OSR1 kinases, regulators of ion homeostasis and blood pressure, and MST3/MST4/YSK1, involved in controlling development and morphogenesis. Our analyses suggest that MO25α and MO25β associate with these STE20 kinases in a similar manner to STRAD. MO25 isoforms induce approximately 100‐fold activation of SPAK/OSR1 dramatically enhancing their ability to phosphorylate the ion cotransporters NKCC1, NKCC2 and NCC, leading to the identification of several new phosphorylation sites. siRNA‐mediated reduction of expression of MO25 isoforms in mammalian cells inhibited phosphorylation of endogenous NKCC1 at residues phosphorylated by SPAK/OSR1, which is rescued by re‐expression of MO25α. MO25α/β binding to MST3/MST4/YSK1 also stimulated kinase activity three‐ to four‐fold. MO25 has evolved as a key regulator of a group of STE20 kinases and may represent an ancestral mechanism of regulating conformation of pseudokinases and activating catalytically competent protein kinases.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: kinase activation; STE20 kinases; WNK1; WNK4
Publisher: European Molecular Biology Organization; Nature Publishing Group
ISSN: 0261-4189
Last Modified: 04 Jun 2017 09:35

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