Pharmacological targeting of SPAK kinase in disorders of impaired epithelial transport

Zhang, Jinwei; Karimy, Jason K.; Delpire, Eric; Kahle, Kristopher T.

doi:10.1080/14728222.2017.1351949

Cited by 15 publications

(14 citation statements)

References 105 publications

(169 reference statements)

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“…The Ste20-type Ser-Thr protein kinases SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stressresponsive kinase 1) are considered master regulators of the CCCs 35 . SPAK and OSR1 are activated by phosphorylation in the regulatory "T-loop" (SPAK Thr233 and OSR1 Thr185) by one of four WNK ["with no lysine" (K)] protein kinases 17,36 .…”

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confidence: 99%

Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a

et al. 2020

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The SLC12A cation-Cl − cotransporters (CCC), including NKCC1 and the KCCs, are important determinants of brain ionic homeostasis. SPAK kinase (STK39) is the CCC master regulator, which stimulates NKCC1 ionic influx and inhibits KCC-mediated efflux via phosphorylation at conserved, shared motifs. Upregulation of SPAK-dependent CCC phosphorylation has been implicated in several neurological diseases. Using a scaffold-hybrid strategy, we develop a novel potent and selective SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano) methyl)-2-methylphenyl)-2-hydroxybenzamide ("ZT-1a"). ZT-1a inhibits NKCC1 and stimulates KCCs by decreasing their SPAK-dependent phosphorylation. Intracerebroventricular delivery of ZT-1a decreases inflammation-induced CCC phosphorylation in the choroid plexus and reduces cerebrospinal fluid (CSF) hypersecretion in a model of post-hemorrhagic hydrocephalus. Systemically administered ZT-1a reduces ischemia-induced CCC phosphorylation, attenuates cerebral edema, protects against brain damage, and improves outcomes in a model of stroke. These results suggest ZT-1a or related compounds may be effective CCC modulators with therapeutic potential for brain disorders associated with impaired ionic homeostasis.

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Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a

et al. 2020

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“…In previous studies, STK39 was demonstrated to activate the p38 MAPK pathway, which indicates that STK39 is involved in cellular stress responses (26). In addition, STK39 has been revealed to play a critical role in the regulation of ionic and osmotic cellular homeostasis (36,37). Recent studies have demonstrated that STK39 has carcinogenic functions in several cancer types (27)(28)(29).…”

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confidence: 97%

MicroRNA‑299‑5p inhibits cell metastasis in breast cancer by directly targeting serine/threonine kinase 39

Wang

Chen

et al. 2020

Oncol Rep

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Numerous studies have demonstrated that microRNAs (miRNAs) play a key role in human carcinogenesis and metastasis. For example, miR-299-5p has previously been revealed to be dysregulated in several human cancers. However, the biological function of miR-299-5p in breast cancer remains unclear. The present study demonstrated that miR-299-5p was downregulated in breast cancer tissues and cell lines. The restoration of miR-299-5p expression suppressed cell migration and invasion, whereas inhibition of miR-299-5p promoted cell migration and invasion. In addition, in vivo studies demonstrated that miR-299-5p overexpression was able to inhibit tumour metastasis in nude mice. Mechanistically, through bioinformatics analysis and a dual-luciferase assay, it was confirmed that miR-299-5p directly targets serine/threonine kinase 39 (STK39). Silencing STK39 inhibited cell metastasis and suppressed epithelial-mesenchymal transition markers and matrix metalloproteinase expression, whereas restoration of STK39 expression was able to reverse miR-299-5p-inhibited cell migration and invasion. Collectively, the results of the present study demonstrated that miR-299-5p supresses breast cancer cell migration and invasion by targeting STK39. These findings may provide novel insights into miR-299-5p and its potential diagnostic and therapeutic benefits in breast cancer.

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“…The pharmacological targeting of SPAK includes antagonizing the SPAK-WNK interaction, inhibiting SPAK activity, or disrupting SPAK activation by interfering with its binding to Μ025α/β. These approaches could be useful for regulating the homeostasis of the renal epithelium and may have therapeutic potential for NaCl-sensitive hypertension [ 39 ]. In addition to the role in blood pressure regulation, abrogating SPAK activity may be a therapeutic strategy for other diseases.…”

Section: Discussionmentioning

confidence: 99%

SPAK-p38 MAPK signal pathway modulates claudin-18 and barrier function of alveolar epithelium after hyperoxic exposure

Shen

Lin

et al. 2021

BMC Pulm Med

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Background Hyperoxia downregulates the tight junction (TJ) proteins of the alveolar epithelium and leads to barrier dysfunction. Previous study has showed that STE20/SPS1-related proline/alanine-rich kinase (SPAK) interferes with the intestinal barrier function in mice. The aim of the present study is to explore the association between SPAK and barrier function in the alveolar epithelium after hyperoxic exposure. Methods Hyperoxic acute lung injury (HALI) was induced by exposing mice to > 99% oxygen for 64 h. The mice were randomly allotted into four groups comprising two control groups and two hyperoxic groups with and without SPAK knockout. Mouse alveolar MLE-12 cells were cultured in control and hyperoxic conditions with or without SPAK knockdown. Transepithelial electric resistance and transwell monolayer permeability were measured for each group. In-cell western assay was used to screen the possible mechanism of p-SPAK being induced by hyperoxia. Results Compared with the control group, SPAK knockout mice had a lower protein level in the bronchoalveolar lavage fluid in HALI, which was correlated with a lower extent of TJ disruption according to transmission electron microscopy. Hyperoxia down-regulated claudin-18 in the alveolar epithelium, which was alleviated in SPAK knockout mice. In MLE-12 cells, hyperoxia up-regulated phosphorylated-SPAK by reactive oxygen species (ROS), which was inhibited by indomethacin. Compared with the control group, SPAK knockdown MLE-12 cells had higher transepithelial electrical resistance and lower transwell monolayer permeability after hyperoxic exposure. The expression of claudin-18 was suppressed by hyperoxia, and down-regulation of SPAK restored the expression of claudin-18. The process of SPAK suppressing the expression of claudin-18 and impairing the barrier function was mediated by p38 mitogen-activated protein kinase (MAPK). Conclusions Hyperoxia up-regulates the SPAK-p38 MAPK signal pathway by ROS, which disrupts the TJ of the alveolar epithelium by suppressing the expression of claudin-18. The down-regulation of SPAK attenuates this process and protects the alveolar epithelium against the barrier dysfunction induced by hyperoxia.

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Pharmacological targeting of SPAK kinase in disorders of impaired epithelial transport

Cited by 15 publications

References 105 publications

Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a

Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a

MicroRNA‑299‑5p inhibits cell metastasis in breast cancer by directly targeting serine/threonine kinase 39

SPAK-p38 MAPK signal pathway modulates claudin-18 and barrier function of alveolar epithelium after hyperoxic exposure

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