CASK

Last update 23 Jan 2025

Basic Info

Synonyms

CAGH39, calcium/calmodulin dependent serine protein kinase, Calcium/calmodulin-dependent serine protein kinase

+ [9]

Introduction

Multidomain scaffolding Mg(2+)-independent protein kinase that catalyzes the phosphotransfer from ATP to proteins such as NRXN1, and plays a role in synaptic transmembrane protein anchoring and ion channel trafficking (PubMed:18423203). Contributes to neural development and regulation of gene expression via interaction with the transcription factor TBR1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1. Component of the LIN-10-LIN-2-LIN-7 complex, which associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules (By similarity).

100 Clinical Results associated with CASK

100 Translational Medicine associated with CASK

0 Patents (Medical) associated with CASK

894

Literatures (Medical) associated with CASK

01 Feb 2025·Neuropharmacology

Neuroprotection by 4R-cembranoid against Gulf War Illness-related Chemicals is mediated by ERK, PI3K, and CaMKII pathways

Article

Author: Marrero Valentín, José L ; Tosado-Rodríguez, Eduardo L ; Ferchmin, Pedro A ; Roche Lima, Abiel ; Sabeva, Nadezhda ; Ferchmin, Pedro A. ; Rivera-Moctezuma, Félix G. ; Marrero Valentín, José L. ; Vázquez Alicia, Sorangely ; Tosado-Rodríguez, Eduardo L. ; Pérez, Dinely ; Alicia, Sorangely Vázquez ; Rivera-Moctezuma, Félix G

Gulf War Illness (GWI) has been consistently linked to exposure to pyridostigmine (PB), N,N-Diethyl-meta-toluamide (DEET), permethrin (PER), and traces of sarin. In this study, diisopropylfluorophosphate (DFP, sarin surrogate) and the GWI-related chemicals were found to reduce the number of functionally active neurons in rat hippocampal slices. These findings confirm a link between GWI neurotoxicants and N-Methyl-D-Aspartate (NMDA)-mediated excitotoxicity, which was successfully reversed by Edelfosine (a phospholipase Cβ (PLCβ3) inhibitor) and Flupirtine (a Kv7 channel agonist). To test whether 4R-cembranoid (4R), a nicotinic α7 acetylcholinesterase receptor (α7AChR) modulator known for its neuroprotective properties, can restore hippocampal neurons from glutamate-induced neurotoxicity, we exposed rat hippocampal slices with DFP for 10 min followed by 60 min treatment with 4R. We investigated the 4R mechanisms of neuroprotection after preincubation with LY294002, PD98059, and KN-62. The inhibition of the phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MEK1/2), and calcium/calmodulin-dependent protein kinase (CaMKII) abrogated the protective effect of 4R against DFP-induced neurotoxicity. In separate experiments, after incubation with DFP, followed by 4R for 1 h, cellular extracts were prepared for Western blotting of phospho-Akt, phospho-GSK3β, phosphorylated extracellular signal-regulated kinase (ERK)1/2, CaMKII and cAMP response element-binding protein (CREB). Our results show that DFP induces neuronal dysfunction by dephosphorylation, while 4R restores the phosphorylation of Akt, GSK3, ERK1/2, CREB, and CaMKII. Moreover, our proteomics analysis supported the notion that 4R activates additional signaling pathways related to enhancing neuronal signaling, synaptic plasticity, and apoptotic inhibition to promote cell survival against DFP, offering biomarkers for developing treatment against GWI.

01 Jan 2025·International Immunopharmacology

Isoferulic acid regulates CXCL12/CXCR4-mediated apoptosis and autophagy in podocyte and mice with STZ-induced diabetic nephropathy

Article

Author: Ni, Boran ; Chang, Aqian ; Qu, Changhai ; Hu, Panxiang ; Yao, Aina ; Dong, Xiaoxv ; Peng, Hulinyue ; Yin, Xingbin ; Liu, Jing ; Ni, Jian ; Huang, Huating

Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus and a major cause of end-stage renal disease. Isoferulic acid (IFA) is a phenolic compound that has strong antioxidant, anti-inflammatory, and hypoglycemic effects. Researches and our previous study showed the potential anti-diabetic capacity and anti- oxidative stress damage targeting podocytes of IFA. The purpose of this study was to investigate whether IFA protects MPC5 podocytes from high glucose damage and alleviates DN symptoms in STZ-induced mice, as well as to explore the mechanism. The findings revealed that IFA (10, 25, 50 μM) significantly reduced high glucose-mediated toxicity, abnormal motility and morphology, ROS release, Ca²⁺ elevation with MPTP opening, apoptotic alterations with Caspase-3/7 activity increase and CXCL12 chemotaxis and interaction with CXCR4 in MPC5 podocytes. Furthermore, IFA increased Podocalyxin and LC3 II/I ratio. Meanwhile, IFA suppressed p53, mTOR, CASK, and p62. Furthermore, IFA has the ability to directly influence downstream mTOR, p53, and CASK apoptotic and podocyte motility regulatory targets when inhibiting the CXCL12/CXCR4 signaling pathway. In the sequent in vivo experiment, the results showed STZ-induced DN mice had higher kidney index, urination, UACR, lipid metabolism abnormalities and renal dysfunction, raised blood glucose, and podocyte damage than normal C57BL/6 mice. However, IFA treatment (50 mg/kg, 25 mg/kg, and 12.5 mg/kg) for 10 weeks restored the DN symptoms in the mice. IFA treatment elevated LC3B and LC3 II/I ratios and decreased p62 via suppressing chemokine axis CXCL12/CXCR4 with PI3K/Akt/mTOR, MMP9, and NF-κB p65 and activating podocyte markers WT1, nephrin, and Podocalyxin, thereby inducing autophagy and mitigating apoptosis in the DN mice kidneys. These findings suggest that IFA protective mechanism on kidney and podocytes simulating DN symptoms is primarily mediated by the CXCL12/CXCR4 pathways with the inactivation of apoptotic pathways and activation of autophagy.

01 Dec 2024·Alzheimer's & Dementia

Dissecting the mechanisms of CASK deficiency on the clearance of Aβ in microglia

Article

Author: Chang, Jacky ; Cho, Yen Ting ; Lin, Yu Yi ; Cheng, Irene Han‐Juo

AbstractBackgroundAmyloid‐beta (Aβ) deposition is a key pathological characteristic of Alzheimer’s disease (AD). Microglia serves as a crucial system responsible for clearing Aβ. Activated microglia migrate towards Aβ deposits, engulf them, and breakdown Aβ through cathepsins within the lysosome. Calcium/calmodulin‐dependent serine protein kinase (CASK) regulates microglia’s migration and phagocytic activity. Notably, our findings revealed a reduction in the expression of microglial CASK upon Aβ treatment. Nevertheless, the specific function of CASK in activated microglia remains undiscovered.MethodThe chemotaxis and migration of CASK KO BV2 microglia were examined via transwell and wound healing assays with Aβ presence variations. Focal adhesion kinase (FAK) protein levels were assessed through western blotting. Phagocytic capacity will be tested by using fluorescence‐labeled Aβ and microbeads after activated by LPS and Aβ. Vinculin, CD68 or lysosome associated membrane (LAMP1) were visualized using immunostaining. Actin was stained with phalloidin. The colocalization was measured by ImageJ. Expression of cathepsin B, D, and S, and Aβ‐degrading enzymes in CASK KO microglia were measured via qPCR. Lysosome morphology was tracked using lysotracker.ResultThe expression of microglial CASK was reduced upon Aβ treatment. The chemotaxis and migration capabilities of CASK KO microglia are notably inferior to WT microglia. After Aβ treatment, FAK protein levels were significantly higher in WT but not CASK KO microglia. Moreover, CASK KO microglia had lower vinculin‐lamellipodia colocalization and lamellipodia area than WT microglia. Conversely, CASK deficiency in microglia increased Aβ engulfment and the number of lysosomes. In addition, LAMP1‐Aβ colocalization was diminished in CASK KO microglia. CASK KO microglia had higher levels of cathepsin B, D, and S, as well as and Aβ‐degrading enzymes than WT microglia.ConclusionOur investigation revealed the critical roles of CASK in regulating microglial migration and phagocytic functions, particularly in the context of Aβ treatment. These findings necessitate further exploration into the nuanced functions of CASK in activated microglia, potentially offering insights into novel therapeutic avenues for AD.

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