Microtubule affinity regulating kinase 4: A promising target in the pathogenesis of atherosclerosis

Qin, Yusheng; Li, Heng; Wang, Shuzhi; Wang, Zongbao; Tang, Chao-Ke

doi:10.1002/jcp.30530

Cited by 8 publications

(3 citation statements)

References 125 publications

(207 reference statements)

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“…Additionally, MARK4 has been reported to promote inflammation and mitochondrial oxidative stress via activating IκB kinase-α (IKKα), promoting NF-κB signaling [ 124 , 125 ]. Other proatherogenic effects exerted by MARK4 have been elaborately reviewed by Qin et al, and one effect they mentioned is the upregulation of the expression of the transcription factor sterol regulatory element-binding protein-1c (SREBP-1c), which promotes the expression of genes involved in lipogenesis in adipocytes [ 123 , 126 , 127 ]. Collectively, there is evidence pointing to a proatherogenic role for MARK4 ( Figure 4 ), rendering this kinase a potential therapeutic target in atherosclerosis.…”

Section: Camk-like Familymentioning

confidence: 99%

Navigating the Maze of Kinases: CaMK-like Family Protein Kinases and Their Role in Atherosclerosis

Teuwen,

van der Vorst,

Maas

2024

IJMS

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Circulating low-density lipoprotein (LDL) levels are a major risk factor for cardiovascular diseases (CVD), and even though current treatment strategies focusing on lowering lipid levels are effective, CVD remains the primary cause of death worldwide. Atherosclerosis is the major cause of CVD and is a chronic inflammatory condition in which various cell types and protein kinases play a crucial role. However, the underlying mechanisms of atherosclerosis are not entirely understood yet. Notably, protein kinases are highly druggable targets and represent, therefore, a novel way to target atherosclerosis. In this review, the potential role of the calcium/calmodulin-dependent protein kinase-like (CaMKL) family and its role in atherosclerosis will be discussed. This family consists of 12 subfamilies, among which are the well-described and conserved liver kinase B1 (LKB1) and 5′ adenosine monophosphate-activated protein kinase (AMPK) subfamilies. Interestingly, LKB1 plays a key role and is considered a master kinase within the CaMKL family. It has been shown that LKB1 signaling leads to atheroprotective effects, while, for example, members of the microtubule affinity-regulating kinase (MARK) subfamily have been described to aggravate atherosclerosis development. These observations highlight the importance of studying kinases and their signaling pathways in atherosclerosis, bringing us a step closer to unraveling the underlying mechanisms of atherosclerosis.

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Section: Camk-like Familymentioning

confidence: 99%

Navigating the Maze of Kinases: CaMK-like Family Protein Kinases and Their Role in Atherosclerosis

Teuwen,

van der Vorst,

Maas

2024

IJMS

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“…92 The overexpression of MARK2 caused hyperphosphorylation of MAPs, leading to the disruption of the MTN, morphological changes, and cell death. 92 MARK4 is an emerging target of interest in the pathogenesis of atherosclerosis, 93 given its demonstrated roles in the regulation of proteins related to lipid metabolism, 94 oxidative stress, 95 glucose homeostasis, 96 inflammation, 38,97 proliferation, 98 and white adipocyte browning. 99 In the cardiomyocyte, MARK4 can phosphorylate MAP4, which is bound to the polymerized microtubules, and phosphorylated MAP4 can detach from microtubules to form oligomerized MAP4 aggregates in the cytosol.…”

Section: Microtubule-associated Proteinsmentioning

confidence: 99%

Targeting Microtubules for the Treatment of Heart Disease

Warner

2022

Circulation Research

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Heart disease remains the leading cause of morbidity and mortality worldwide. With the advancement of modern technology, the role(s) of microtubules in the pathogenesis of heart disease has become increasingly apparent, though currently there are limited treatments targeting microtubule-relevant mechanisms. Here, we review the functions of microtubules in the cardiovascular system and their specific adaptive and pathological phenotypes in cardiac disorders. We further explore the use of microtubule-targeting drugs and highlight promising druggable therapeutic targets for the future treatment of heart diseases.

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“…Microtubule‐affinity regulation kinases (MARKs) are a family of novel mammalian serine/threonine kinases in mammals including four isoform members: MARK1, MARK2, MARK3 and MARK4. The four isoforms share a similar structural organization: one N‐terminal header, a kinase domain, a ubiquitin‐associated domain, a spacer region and a kinase‐associated domain (Kemphues et al, 1988; Qin et al, 2022). MARKs were originally discovered based on their ability to phosphorylate tau protein and related microtubule‐associated proteins (MAPs) such as MAP2 (Alexander, Kelly, et al, 2021), thereby regulating microtubule dynamics in neurons (Drewes et al, 1997; Tabassum et al, 2022; Trinczek et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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

Shi,

Sun,

Wang

et al. 2024

British J Pharmacology

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Background 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 remodeling. 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 MARKs inhibitor. The cognitive function, anxiety‐like behaviors and motor coordination capability were also examined in SNL rats. Synaptic remodeling‐associated signaling 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 behaviors along with improved cognitive deficit, anxiogenic‐like behaviors and motor coordination in SNL rats. Inhibition of MARKs signaling reversed synaptic plasticity at the functional and structural levels by suppressing NR2B/GluR1 and EB3/Drebrin signaling pathways both in amygdala and spinal dorsal horn.Conclusion and ImplicationsThese results suggest that MARKs‐mediated synaptic remodeling 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.

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Microtubule affinity regulating kinase 4: A promising target in the pathogenesis of atherosclerosis

Cited by 8 publications

References 125 publications

Navigating the Maze of Kinases: CaMK-like Family Protein Kinases and Their Role in Atherosclerosis

Navigating the Maze of Kinases: CaMK-like Family Protein Kinases and Their Role in Atherosclerosis

Targeting Microtubules for the Treatment of Heart Disease

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

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