Nuts and bolts of the salt-inducible kinases (SIKs)

Darling, Nicola J.; Cohen, Philip

doi:10.1042/bcj20200502

Cited by 74 publications

(117 citation statements)

References 136 publications

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“…SIKs from different species share a general structure with a catalytic domain, an ubiquitin-associated domain and a C terminal domain [35][36][37] . There are multiple sites of phosphorylation in a SIK protein, among which targets for PKA have been well studied: PKA usually negatively regulates SIK activities 28,[38][39][40][41][42] .…”

Section: Specific Recognition Of Phosphorylated T221 In Sik3 By a Monoclonal Antibody In Vitro And In Vivomentioning

confidence: 99%

Sleep Need, the Key Regulator of Sleep Homeostasis, Is Indicated and Controlled by Phosphorylation of Threonine 221 in Salt Inducible Kinase 3

Zhou

Liu

et al. 2021

Preprint

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Sleep need drives sleep and plays a key role in homeostatic regulation of sleep. So far sleep need can only be inferred by animal behaviors and indicated by electroencephalography (EEG). Here we report that threonine 221 (T221) of the salt inducible kinase 3 (SIK3) was important for the catalytic activity and stability of SIK3. T221 phosphorylation in the mouse brain indicates sleep need: more sleep resulting in less phosphorylation and less sleep more phosphorylation during daily sleep/wake cycle and after sleep deprivation (SD). Sleep need was reduced in SIK3 loss of function (LOF) mutants and by T221 mutation to alanine (T221A). Sleep rebound after SD was also decreased in SIK3 LOF and T221A mutant mice. Other kinases such as SIK1 and SIK2 or other sites in SIK3 do not fulfil criteria to be both an indicator and a controller of sleep need. Our results reveal SIK3 T221 phosphorylation as the first and only chemical modification which indicates and controls sleep need.

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Section: Specific Recognition Of Phosphorylated T221 In Sik3 By a Monoclonal Antibody In Vitro And In Vivomentioning

confidence: 99%

Sleep Need, the Key Regulator of Sleep Homeostasis, Is Indicated and Controlled by Phosphorylation of Threonine 221 in Salt Inducible Kinase 3

Zhou

Liu

et al. 2021

Preprint

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“…CREB has a wide tissue distribution and plays a pivotal role in depression, metabolic homeostasis and tumorigenesis [ 7 , 21 – 23 ]. The effects of SIK2 inactivation were likely due to heightened CRTC2-mediated signaling at CREB.…”

Section: Discussionmentioning

confidence: 99%

“…Salt-inducible kinase 2 (SIK2), a member of the AMP-activated protein kinases (AMPKs) family, is a serine/threonine kinase that phosphorylates the cAMP response element binding protein (CREB)-regulated transcription co-activators (CRTCs) [ 6 , 7 ]. Phosphorylation by SIK2 promotes the cytoplasm translocation of CRTCs, preventing them from activating the transcription factors CREB [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…Within the nucleus, CRTCs interact with CREB and promote CREB-dependent gene transcription [ 6 , 8 , 9 ]. SIK2 is widely expressed in many tissues and regulates many physiological processes, including innate immunity, bone formation, depression and metabolism [ 7 ]. So far, the function of SIK2 under pulmonary fibrosis conditions remains undefined.…”

Section: Introductionmentioning

confidence: 99%

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Salt-inducible kinase 2 (SIK2) inhibitor ARN-3236 attenuates bleomycin-induced pulmonary fibrosis in mice

Zou

Hong

Li³

et al. 2022

BMC Pulm Med

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Background Pulmonary fibrosis is a fatal lung disease with complex pathogenesis and limited effective therapies. Salt-inducible kinase 2 (SIK2) is a kinase that phosphorylates CRTCs and regulates many physiological processes. However, the role of SIK2 on pulmonary fibrosis remains unclear, and whether SIK2 inhibitor can attenuate pulmonary fibrosis is unknown. Method We subjected human fetal lung fibroblasts (HFLs) to transforming growth factor-β1 (5 ng/mL) for 12 h, and examined the expression of SIK2, CRTCs and pCRTCs in fibroblasts by western-blot. To address the roles of SIK2 and CRTCs involved in the progression of pulmonary fibrosis, HFLs were treated with a small-molecule inhibitor ARN-3236 or by siRNA-mediated knockdown of SIK2 expression. Pulmonary fibrosis model was established with mice by exposing to bleomycin, and assessed by H&E and Masson’s trichrome staining. COL1A and α-SMA distributions were detected in lung tissues by immunohistochemical staining. Results We discovered that SIK2 and phosphorylated-CRTC2 were expressed at a low basal level in normal lung tissues and quiescent fibroblasts, but increased in fibrotic lung tissues and activated fibroblasts. Inhibition of SIK2 by ARN-3236 prevented the fibroblasts differentiation and extracellular matrix expression in HFLs and attenuated bleomycin-induced pulmonary fibrosis in mice. Mechanistically, inactivation of SIK2 resulted in the dephosphorylation and nuclear translocation of CRTC2. Within the nucleus, CRTC2 binds to CREB, promoting CREB-dependent anti-fibrotic actions. Conclusion In conclusion, our results elucidated a previously unexplored role of SIK2 in pulmonary fibrosis, and identified SIK2 as a new target for anti-fibrosis medicines.

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“…T cell development is a tightly regulated process that requires the precise temporal control of genes needed for the differentiation of T cells 1 – 3 . Salt Inducible Kinases (SIK) are a group of three protein kinases that have been linked to the transcriptional regulation of a number of genes involved in multiple processes including metabolism and innate immunity 4 – 6 , but their role in T cell development has not been addressed. SIK1 was first identified in the adrenocortical tissues of rats fed on a high salt diet 7 and, together with the closely related SIK2 and SIK3 isoforms, they form a sub-group of the AMPK-related family of protein kinases (reviewed in 8 ).…”

Section: Introductionmentioning

confidence: 99%

Salt inducible kinases 2 and 3 are required for thymic T cell development

Nefla

Darling

Gijsel-Bonnello

et al. 2021

Sci Rep

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Salt Inducible Kinases (SIKs), of which there are 3 isoforms, are established to play roles in innate immunity, metabolic control and neuronal function, but their role in adaptive immunity is unknown. To address this gap, we used a combination of SIK knockout and kinase-inactive knock-in mice. The combined loss of SIK1 and SIK2 activity did not block T cell development. Conditional knockout of SIK3 in haemopoietic cells, driven by a Vav-iCre transgene, resulted in a moderate reduction in the numbers of peripheral T cells, but normal B cell numbers. Constitutive knockout of SIK2 combined with conditional knockout of SIK3 in the haemopoietic cells resulted in a severe reduction in peripheral T cells without reducing B cell number. A similar effect was seen when SIK3 deletion was driven via CD4-Cre transgene to delete at the DP stage of T cell development. Analysis of the SIK2/3 Vav-iCre mice showed that thymocyte number was greatly reduced, but development was not blocked completely as indicated by the presence of low numbers CD4 and CD8 single positive cells. SIK2 and SIK3 were not required for rearrangement of the TCRβ locus, or for low level cell surface expression of the TCR complex on the surface of CD4/CD8 double positive thymocytes. In the absence of both SIK2 and SIK3, progression to mature single positive cells was greatly reduced, suggesting a defect in negative and/or positive selection in the thymus. In agreement with an effect on negative selection, increased apoptosis was seen in thymic TCRbeta high/CD5 positive cells from SIK2/3 knockout mice. Together, these results show an important role for SIK2 and SIK3 in thymic T cell development.

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Nuts and bolts of the salt-inducible kinases (SIKs)

Cited by 74 publications

References 136 publications

Sleep Need, the Key Regulator of Sleep Homeostasis, Is Indicated and Controlled by Phosphorylation of Threonine 221 in Salt Inducible Kinase 3

Sleep Need, the Key Regulator of Sleep Homeostasis, Is Indicated and Controlled by Phosphorylation of Threonine 221 in Salt Inducible Kinase 3

Salt-inducible kinase 2 (SIK2) inhibitor ARN-3236 attenuates bleomycin-induced pulmonary fibrosis in mice

Salt inducible kinases 2 and 3 are required for thymic T cell development

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