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PMID: 21423148 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The EMBO journal ·Vol. 30 ·No. 9 ·2011-05-04 ·Pages 1730-41

Filippi BM, de los Heros P, Mehellou Y, Navratilova I, Gourlay R, Deak M, Plater L, Toth R, Zeqiraj E, Alessi DR

Abstract

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.

MeSH Terms
Animals Calcium-Binding Proteins/metabolism Enzyme Activation/physiology Escherichia coli HEK293 Cells Homeostasis/physiology Humans Immunoblotting Insecta Intracellular Signaling Peptides and Proteins/metabolism Morphogenesis/physiology Phosphorylation Protein Isoforms/metabolism Protein Serine-Threonine Kinases/metabolism RNA, Small Interfering/genetics
Chemicals
CAB39 protein, human Calcium-Binding Proteins Intracellular Signaling Peptides and Proteins Protein Isoforms RNA, Small Interfering OXSR1 protein, human STK26 protein, human Protein Serine-Threonine Kinases STK25 protein, human STK39 protein, human
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Filippi Beatrice M
MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee, UK. [email protected]
de los Heros Paola
Mehellou Youcef
Navratilova Iva
Gourlay Robert
Deak Maria
Plater Lorna
Toth Rachel
Zeqiraj Elton
Alessi Dario R
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2011.78
Email
[email protected]
Published
2011-05-04
Epub
2011-00-18
Pages
1730-41
Language
English
Region
England
NLM ID
8208664
PMCID
PMC3101989
Subset
IM
Grants
Medical Research Council · MC_U127070193 · United Kingdom
External Links
PubMed source DOI: 10.1038/emboj.2011.78 PMC Full Text View journal details
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