Structural insights into the activation of MST3 by MO25

Mehellou, Youcef; Alessi, Dario R.; Macartney, Thomas; Szklarz, M.; Knapp, Stefan; Elkins, J.M.

doi:10.1016/j.bbrc.2012.12.113

Cited by 24 publications

(20 citation statements)

References 26 publications

(23 reference statements)

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“…When bound to SPAK and OSR1, MO25 isoforms induce their kinase activity, markedly enhancing their ability to phosphorylate the ion cotransporters NKCC1, NKCC2, and NCC (50). For other members of the STE20 family, such as MST3, MST4, and YSK1, which control development and morphogenesis, MO25 isoforms stimulate their kinase activity to a lesser degree than the stimulation observed in vitro for SPAK and OSR1 (50,88,89). The mechanism of MO25-mediated kinase activation is not fully understood.…”

Section: Inhibition Of Mo25 a Key Spak/osr1 Regulatormentioning

confidence: 98%

The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters

et al. 2014

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The WNK-SPAK/OSR1 kinase complex is composed of the kinases WNK (with no lysine) and SPAK (SPS1-related proline/alanine-rich kinase) or the SPAK homolog OSR1 (oxidative stress-responsive kinase 1). The WNK family senses changes in intracellular Cl(-) concentration, extracellular osmolarity, and cell volume and transduces this information to sodium (Na(+)), potassium (K(+)), and chloride (Cl(-)) cotransporters [collectively referred to as CCCs (cation-chloride cotransporters)] and ion channels to maintain cellular and organismal homeostasis and affect cellular morphology and behavior. Several genes encoding proteins in this pathway are mutated in human disease, and the cotransporters are targets of commonly used drugs. WNKs stimulate the kinases SPAK and OSR1, which directly phosphorylate and stimulate Cl(-)-importing, Na(+)-driven CCCs or inhibit the Cl(-)-extruding, K(+)-driven CCCs. These coordinated and reciprocal actions on the CCCs are triggered by an interaction between RFXV/I motifs within the WNKs and CCCs and a conserved carboxyl-terminal docking domain in SPAK and OSR1. This interaction site represents a potentially druggable node that could be more effective than targeting the cotransporters directly. In the kidney, WNK-SPAK/OSR1 inhibition decreases epithelial NaCl reabsorption and K(+) secretion to lower blood pressure while maintaining serum K(+). In neurons, WNK-SPAK/OSR1 inhibition could facilitate Cl(-) extrusion and promote γ-aminobutyric acidergic (GABAergic) inhibition. Such drugs could have efficacy as K(+)-sparing blood pressure-lowering agents in essential hypertension, nonaddictive analgesics in neuropathic pain, and promoters of GABAergic inhibition in diseases associated with neuronal hyperactivity, such as epilepsy, spasticity, neuropathic pain, schizophrenia, and autism.

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Section: Inhibition Of Mo25 a Key Spak/osr1 Regulatormentioning

confidence: 98%

The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters

et al. 2014

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“…MST and STRAD isoforms) [7, 104]. Therefore compounds that disrupt the activation of SPAK/OSR1 kinase activities by interfering with Μ025α/β binding could potentially represent a strategy for lowering blood pressure.…”

Section: Strategies Of Spak Inhibitionmentioning

confidence: 99%

Pharmacological targeting of SPAK kinase in disorders of impaired epithelial transport

Zhang

Karimy

Delpire

et al. 2017

Expert Opinion on Therapeutic Targets

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Introduction: The mammalian SPS1-related proline/alanine-rich serine-threonine kinase SPAK (STK39) modulates the transport across and between epithelial cells in response to environmental stimuli such osmotic stress and inflammation. Research over the last decade has established a central role for SPAK in the regulation of ion and water transport in the distal nephron, colonic crypts, and pancreatic ducts, and has implicated deregulated SPAK signaling in NaCl-sensitive hypertension, ulcerative colitis and Crohn’s disease, and cystic fibrosis. Areas covered: We review recent advances in our understanding of the role of SPAK kinase in the regulation of epithelial transport. We highlight how SPAK signaling - including its upstream Cl--sensitive activators, the WNK kinases, and its downstream ion transport targets, the cation- Cl--cotransporters contribute to human disease. We discuss prospects for the pharmacotherapeutic targeting of SPAK kinase in specific human disorders that feature impaired epithelial homeostasis. Expert opinion: The development of novel drugs that antagonize the SPAK-WNK interaction, inhibit SPAK kinase activity, or disrupt SPAK kinase activation by interfering with its binding to Μ025α/β could be useful adjuncts in essential hypertension, inflammatory colitis, and cystic fibrosis.

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“…Previously, we and others determined the crystal structures of MO25 in complex with different GCK members including MST3, MST4, STK25, as well as the pseudokinase STRAD␣ (25,28,31,33), which defined a unified structural mechanism featuring a MO25-stabilized active conformation of the ␣C helix and A-loop. The interfaces between MO25 and this group of GCKs are highly conserved within four major sites termed A-D.…”

Section: Mo25 Binds To Osr1 In a Conservedmentioning

confidence: 99%

Structural and Biochemical Insights into the Activation Mechanisms of Germinal Center Kinase OSR1

Mao

Shi

et al. 2014

Journal of Biological Chemistry

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Background: OSR1 modulates ion homeostasis and cell volume in mammal. Results: The CCT domain and ␣AL helix of OSR1 act together to suppress its basal activity, while WNKs and MO25 unlock such autoinhibition for full activation. Conclusion: OSR1 activity is regulated by autoinhibition, WNKs, and MO25. Significance: This work provides insights into the regulatory mechanisms of OSR1 activation to facilitate functional study.

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Structural insights into the activation of MST3 by MO25

Cited by 24 publications

References 26 publications

The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters

The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters

Pharmacological targeting of SPAK kinase in disorders of impaired epithelial transport

Structural and Biochemical Insights into the Activation Mechanisms of Germinal Center Kinase OSR1

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