A novel non-canonical mechanism of regulation of MST3 (mammalian Sterile20-related kinase 3)

Fuller, Stephen J.; McGuffin, Liam J.; Marshall, Andrew K.; Giraldo, Alejandro; Pikkarainen, Sampsa; Clerk, Angela; Sugden, Peter H.

doi:10.1042/bj20112000

Cited by 33 publications

(55 citation statements)

References 75 publications

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“…95 GCK-III kinases may target the Golgi apparatus through binding with GM130 ( Figure 3). 53,96 Despite forming a stable complex, PDCD10 and Striatin may differentially regulate GCK-III. For example, PDCD10 knockdown promotes Golgi localization of MST4 in HeLa cells.…”

Section: Gcks In Immune Regulationmentioning

confidence: 99%

Germinal center kinases in immune regulation

Yin

Shi

et al. 2012

Cell Mol Immunol

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Section: Gcks In Immune Regulationmentioning

confidence: 99%

Germinal center kinases in immune regulation

Yin

Shi

et al. 2012

Cell Mol Immunol

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“…Recently it has been reported that in addition to autophosphorylating on Thr178 of its activation loop, MST3 also autophosphorylates on Thr328 which is located just after the WIF motif (sequence WIF T I) [24]. Clearly these sequence motifs have a strong resemblance to each other, being of the form Φx (1−2) Φ T Φ where Φ is a hydrophobic residue.…”

Section: Resultsmentioning

confidence: 99%

Structural insights into the activation of MST3 by MO25

Mehellou

Alessi

Macartney

et al. 2013

Biochemical and Biophysical Research Communications

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“…It might also be involved in stabilizing the protein. Another Ste20 kinase was recently shown to autophosphorylate on a comparable C-terminal site (45). The phosphorylation itself was not thought to directly change activity, but was proposed to be involved in docking CAB39 (44).…”

Section: Discussionmentioning

confidence: 99%

Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals

Sengupta¹,

Lorente-Rodríguez²,

Earnest³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The Ste20 family protein kinases oxidative stress-responsive 1 (OSR1) and the STE20/SPS1-related proline-, alanine-rich kinase directly regulate the solute carrier 12 family of cation-chloride cotransporters and thereby modulate a range of processes including cell volume homeostasis, blood pressure, hearing, and kidney function. OSR1 and STE20/SPS1-related proline-, alanine-rich kinase are activated by with no lysine [K] protein kinases that phosphorylate the essential activation loop regulatory site on these kinases. We found that inhibition of phosphoinositide 3-kinase (PI3K) reduced OSR1 activation by osmotic stress. Inhibition of the PI3K target pathway, the mammalian target of rapamycin complex 2 (mTORC2), by depletion of Sin1, one of its components, decreased activation of OSR1 by sorbitol and reduced activity of the OSR1 substrate, the sodium, potassium, two chloride cotransporter, in HeLa cells. OSR1 activity was also reduced with a pharmacological inhibitor of mTOR. mTORC2 phosphorylated OSR1 on S339 in vitro, and mutation of this residue eliminated OSR1 phosphorylation by mTORC2. Thus, we identify a previously unrecognized connection of the PI3K pathway through mTORC2 to a Ste20 protein kinase and ion homeostasis.T he protein kinases oxidative stress-responsive 1 (OSR1) and its homolog the STE20/SPS1-related proline-, alanine-rich kinase (SPAK or PASK) are the mammalian members of the germ-cell kinase VI subgroup of the large Ste20 branch of the mammalian kinome. OSR1 and SPAK directly regulate the solute carrier 12 family of cation-chloride cotransporters which modulate ion homeostasis throughout the body (1, 2). OSR1/ SPAK kinase domains lie close to their N-termini and they contain two additional conserved regions named "PF1" and "PF2" [PASK and Fray (Drosophila homolog)] (3). PF1 is a C-terminal extension to the kinase domain and is required for enzyme activity (4). PF2 binds the consensus motif [(R/K)FX(V/I)] (5) in substrates including ion cotransporters and in regulators. OSR1 and SPAK are activated by with no lysine [K] (WNK) protein kinases, which phosphorylate the essential activation loop regulatory site as well as a second site in the PF1 region with an undefined function (6-9).The four WNK protein kinases are large enzymes notable for the alternative placement of the essential ATP-binding lysine residue in their catalytic domains, distinguishing them from other members of the protein kinase superfamily (10, 11). Initial attention was focused on these enzymes because certain mutations in two family members cause pseudohypoaldosteronism type II, a heritable form of hypertension (12). WNKs are activated by changes in tonicity. Cellular reconstitution studies and mouse genetics demonstrated the importance of WNK function in cell volume regulation and maintenance of blood pressure (13-19). Control of cation-chloride cotransporters through OSR1 and SPAK is among the best-documented actions of WNKs in diverse tissues (5,(20)(21)(22).WNKs also regulate serum-and glucocorticoid-inducible protein k...

show abstract

A novel non-canonical mechanism of regulation of MST3 (mammalian Sterile20-related kinase 3)

Cited by 33 publications

References 75 publications

Germinal center kinases in immune regulation

Germinal center kinases in immune regulation

Structural insights into the activation of MST3 by MO25

Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals

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