更新于：2024-09-19

MARK1

更新于：2024-09-19

基本信息

别名

KIAA1477、MAP/microtubule affinity-regulating kinase 1、MARK

+ [6]

简介

Serine/threonine-protein kinase (PubMed:23666762). Involved in cell polarity and microtubule dynamics regulation. Phosphorylates DCX, MAP2 and MAP4. Phosphorylates the microtubule-associated protein MAPT/TAU (PubMed:23666762). Involved in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3).

关联

100 项与 MARK1 相关的临床结果

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100 项与 MARK1 相关的转化医学

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0 项与 MARK1 相关的专利（医药）

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208

项与 MARK1 相关的文献（医药）

2024-07-01·British Journal of Pharmacology

A novel role for microtubule affinity‐regulating kinases in neuropathic pain

Article

作者: Xu, Yang ; Yu, Lin-Yao ; Su, Chun-Yu ; Tian, Jing-Wei ; Wang, Zhe-Zhe ; Sun, Zhi-Hong ; Li, Chun-Mei ; Shi, Yao-Qin ; Gao, Yong-Lin ; Zhang, Wei ; Wang, Hong-Bo

AbstractBackground and PurposeNeuropathic pain affects millions of patients, but there are currently few viable therapeutic options available. Microtubule affinity‐regulating kinases (MARKs) regulate the dynamics of microtubules and participate in synaptic remodelling. It is unclear whether these changes are involved in the central sensitization of neuropathic pain. This study examined the role of MARK1 or MARK2 in regulating neurosynaptic plasticity induced by neuropathic pain.Experimental ApproachA rat spinal nerve ligation (SNL) model was established to induce neuropathic pain. The role of MARKs in nociceptive regulation was assessed by genetically knocking down MARK1 or MARK2 in amygdala and systemic administration of PCC0105003, a novel small molecule MARK inhibitor. Cognitive function, anxiety‐like behaviours and motor coordination capability were also examined in SNL rats. Synaptic remodelling‐associated signalling changes were detected with electrophysiological recording, Golgi‐Cox staining, western blotting and qRT‐PCR.Key ResultsMARK1 and MARK2 expression levels in amygdala and spinal dorsal horn were elevated in SNL rats. MARK1 or MARK2 knockdown in amygdala and PCC0105003 treatment partially attenuated pain‐like behaviours along with improving cognitive deficit, anxiogenic‐like behaviours and motor coordination in SNL rats. Inhibition of MARKs signalling reversed synaptic plasticity at the functional and structural levels by suppressing NR2B/GluR1 and EB3/Drebrin signalling pathways both in amygdala and spinal dorsal horn.Conclusion and ImplicationsThese results suggest that MARKs‐mediated synaptic remodelling plays a key role in the pathogenesis of neuropathic pain and that pharmacological inhibitors of MARKs such as PCC0105003 could represent a novel therapeutic strategy for the management of neuropathic pain.

2024-06-01·Genome Research

DEAD box RNA helicases are pervasive protein kinase interactors and activators

Article

作者: Švorinić, Andrea ; Karaulanov, Emil ; Sinning, Irmgard ; Krijgsveld, Jeroen ; Papageorgiou, Dimitris ; Cruciat, Cristina-Maria ; Kohlbacher, Oliver ; Acebron, Sergio P ; Hirth, Alexander ; Fatti, Edoardo ; Netz, Eugen ; Zhu, Tianheng ; Niehrs, Christof ; Gopanenko, Alexandr

DEAD box (DDX) RNA helicases are a large family of ATPases, many of which have unknown functions. There is emerging evidence that besides their role in RNA biology, DDX proteins may stimulate protein kinases. To investigate if protein kinase–DDX interaction is a more widespread phenomenon, we conducted three orthogonal large-scale screens, including proteomics analysis with 32 RNA helicases, protein array profiling, and kinome-wide in vitro kinase assays. We retrieved Ser/Thr protein kinases as prominent interactors of RNA helicases and report hundreds of binary interactions. We identified members of ten protein kinase families, which bind to, and are stimulated by, DDX proteins, including CDK, CK1, CK2, DYRK, MARK, NEK, PRKC, SRPK, STE7/MAP2K, and STE20/PAK family members. We identified MARK1 in all screens and validated that DDX proteins accelerate the MARK1 catalytic rate. These findings indicate pervasive interactions between protein kinases and DEAD box RNA helicases, and provide a rich resource to explore their regulatory relationships.

2024-06-01·Experimental Neurology

MARK1 regulates dendritic spine morphogenesis and cognitive functions in vivo

Article

作者: Bhagwat, Maitreyee ; Dindigal, Ankitha H ; Shear, Rebecca ; Kelly-Castro, Emily C ; Zhang, Huaye

Dendritic spines play a pivotal role in synaptic communication and are crucial for learning and memory processes. Abnormalities in spine morphology and plasticity are observed in neurodevelopmental and neuropsychiatric disorders, yet the underlying signaling mechanisms remain poorly understood. The microtubule affinity regulating kinase 1 (MARK1) has been implicated in neurodevelopmental disorders, and the MARK1 gene shows accelerated evolution in the human lineage suggesting a role in cognition. However, the in vivo role of MARK1 in synaptogenesis and cognitive functions remains unknown. Here we show that forebrain-specific conditional knockout (cKO) of Mark1 in mice causes defects in dendritic spine morphogenesis in hippocampal CA1 pyramidal neurons with a significant reduction in spine density. In addition, we found loss of MARK1 causes synaptic accumulation of GKAP and GluA2. Furthermore, we found that MARK1 cKO mice show defects in spatial learning in the Morris water maze and reduced anxiety-like behaviors in the elevated plus maze. Taken together, our data show a novel role for MARK1 in regulating dendritic spine morphogenesis and cognitive functions in vivo.

项与 MARK1 相关的新闻（医药）

2023-05-06

·生物谷

Pharmacol Res：科学家找到了与肝癌患者生存率显著相关的靶点

LKB1（肝激酶B1）信号通路已被证明在调节能量稳态、极性和代谢等关键细胞过程中发挥着不可或缺的作用。 LKB1（肝激酶B1）信号通路已被证明在调节能量稳态、极性和代谢等关键细胞过程中发挥着不可或缺的作用。早期研究将LKB1从人类胎肝中分离出来，发现它具有抑癌作用，其突变与遗传性癌症障碍Peutz-Jeghers综合征有关。进一步的研究确定LKB1是一种主激酶，它通过与CAB39和STRAD支架作用来磷酸化16种下游激酶（AMPK1/2、MARK1/2/3/4、NUAK1/2、SIK1/2/3、BRSK1/2和SNRK），从而对细胞生物学产生影响。尽管LKB1信号轴的部分，如AMPK途径，已经得到了很好的研究和报道，但LKB1直接下游的许多激酶仍然没有得到充分的表征。图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1016/j.phrs.2023.106757 近日，来自杜兰大学的研究者们在Pharmacol Res.杂志上发表了题为“LKB1 Signaling and Patient Survival Outcomes in Hepatocellular Carcinoma”的文章，该研究表明LKB1下游的许多激酶对肝癌患者生存率有统计学显著影响。 LKB1、STRAD和CAB39形成一种复合物，其功能是磷酸化和激活下游信号通路。有趣的是，所有复杂成员的mRNA水平都与患者生存率呈正相关，但只有STRADß和CAB39L具有统计学意义。这可以通过LKB1在恶性细胞细胞谢改变中的作用来解释。除了支架蛋白外，具有统计学正生存相关性的下游LKB1激酶是SIK1、SIK2和SNRK。 GEPIA的其他生物信息学分析还发现，与正常肝组织相比，癌症中SIK1的表达减少了2倍。通过蛋白质印迹进行的蛋白质表达分析未能产生任何SIK1条带，进一步支持SIK1在肝细胞癌中的肿瘤抑制作用。此外，SIK3的患者生存风险比范围为0.52-1.03。该值被加权为正相关，但在统计上不显著。尽管如此，似乎与正生存率有着趋势性的相关性。肝细胞癌细胞系的蛋白质印迹分析显示高表达水平（Huh7和Hep3B）和无表达水平（HepG2和PLC/PRF/5）之间存在明显的二分法，表明存在肝细胞癌亚型的可能性。相反，AMPKα2、MARK2、BRSK1和BRSK2与肝细胞癌的不良生存结果具有统计学显著相关性。GEPIA分析表明，AMPKα2、BRSK1和BRSK2在正常肝组织中低表达。与正常组织相比，肝脏肿瘤中的AMPKα2和BRSK1分别扩增了5倍和2倍。免疫印迹分析显示癌症细胞中AMPKα2和MARK2的高水平表达。此外，AMPKα2、MARK2和BRSK2已被证明分别在肝细胞癌、非小细胞肺癌和胰腺癌的营养缺乏条件下通过Warburg效应促进肿瘤活性和生长。影响肝癌患者生存率的下游激酶。图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1016/j.phrs.2023.106757 综上所述，STRADß、CAB39L、AMPKα、MARK2、SIK1、SIK2、BRSK1、BRSK2和SNRK的表达对肝癌患者生存率有统计学显著影响。该综述旨在解决下游LKB1激酶在知识方面的差距，并为他们在肝细胞癌发生中的潜在作用奠定基础。（生物谷 Bioon.com）参考文献 Khoa Nguyen et al. LKB1 Signaling and Patient Survival Outcomes in Hepatocellular Carcinoma. Pharmacol Res. 2023 Apr 4;106757. doi: 10.1016/j.phrs.2023.106757.