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Aging and disease    2018, Vol. 9 Issue (3) : 537-552     DOI: 10.14336/AD.2017.0702
Review Article |
Mammalian Sterile20-like Kinases: Signalings and Roles in Central Nervous System
Chen Sheng1,*, Fang Yuanjian1, Xu Shenbin1, Reis Cesar2,3, Zhang Jianmin1,4,*
1Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
2Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, California, USA.
3Brain Research Institute, Zhejiang University, Hangzhou, Zhejiang, China.
4Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, Zhejiang, China.
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Mammalian Sterile20-like (MST) kinases are located upstream in the mitogen-activated protein kinase pathway, and play an important role in cell proliferation, differentiation, renewal, polarization and migration. Generally, five MST kinases exist in mammalian signal transduction pathways, including MST1, MST2, MST3, MST4 and YSK1. The central nervous system (CNS) is a sophisticated entity that takes charge of information reception, integration and response. Recently, accumulating evidence proposes that MST kinases are critical in the development of disease in different systems involving the CNS. In this review, we summarized the signal transduction pathways and interacting proteins of MST kinases. The potential biological function of each MST kinase and the commonly reported MST-related diseases in the neural system are also reviewed. Further investigation of MST kinases and their interaction with CNS diseases would provide the medical community with new therapeutic targets for human diseases.

Keywords Mammalian Sterile20-like kinases      central nervous system disorders      mitogen-activated protein kinase     
Corresponding Authors: Chen Sheng,Zhang Jianmin   
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These authors contributed equally to this work.

Issue Date: 05 June 2018
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Chen Sheng
Fang Yuanjian
Xu Shenbin
Reis Cesar
Zhang Jianmin
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Chen Sheng,Fang Yuanjian,Xu Shenbin, et al. Mammalian Sterile20-like Kinases: Signalings and Roles in Central Nervous System[J]. Aging and disease, 2018, 9(3): 537-552.
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Figure 1.  Signaling network of MST1 and MST2 kinase. The signaling pathways of MST1/2 mainly include MST1/2-YAP/TAZ signaling pathway and MST1/2-FOXO signaling pathway. MST1/2 phosphorylates the downstream Lats1/2 and subsequently inhibits the transcriptional function of intranuclear YAP/TAZ, avoiding the excessive cell proliferation and organ overgrowth. The MST1/2 can also mediate this signaling pathway by suppressing GABA function. The MST1/2-FOXO signaling pathway mainly regulates the apoptosis process. MST1/2 phosphorylates AKT and subsequently disrupts its function of interaction between FOXO3 with 14-3-3 proteins. This indirectly promotes apoptosis process. In addition, Mst1 promotes the proapoptotic mediator NOXA transcription via the assistance of FOXO1. The MST1-induced JNK activation can also promote apoptosis. Several interacting partners such as RASSF members, DAP4, acinus and Raf-1 also combine with the MST1/2 and perform different biological functions.
Figure 2.  Signaling network of MST3, MST4 and YSK1 kinase. MST3, MST4 and YSK1 located on the Golgi apparatus with the assistance of GM130 and Striatin proteins. Unlike MST3 and MST4, YSK1 acts a positive role when localized to the Golgi via interaction with 14-3-3. This link potentially mediates the protein transport, cell polarity and cell adhesion. CCM3 or Mo25 induces the movement of MST3 and MST4 from the Golgi apparatus to the plasma membrane. Activated MST3/4 can promote co-localization of the actomyosin with help of Ezrin. Besides, MST3 inhibit PTP-PEST and prevent PTP-PEST dependent paxillin phosphorylation which consequently attenuates the cell migration. MST3 also can activate the NDR protein kinases to regulate the apoptosis process.
Figure 3.  Regulators of MST1 and MST2. Several regulators are involved in the MST1/2 signaling pathway. AMOT2 protein may potentially activate the Hippo-YAP pathway by sensing the mechanical alteration from the cell-cell junction. With the assistance GPCR, biological activation mediate Lats1/2 function in different circumstances. In addition, the SAV1/WW45 and RASSF can activate the MST1/2 through the interaction with SARAH domain. Caspase proteins from apoptotic processes can cleave the MST1/2 and promote human Hippo pathway. While PP2A, STRIPAK complex and TAO may own the potential effect on this pathway.
Figure 4.  Regulators of MST3 and MST4 and YSK1. The biological function of MST3, MST4 and YSK1 kinases mainly depend on the interaction with GM130, Mo25 and CCM3 binding proteins. Caspase proteins from apoptosis, PP2A and STRIPAK complex also can regulate MST3 or MST4.
Author/YearMST kinaseSignaling pathwayMain function
Lehtinenet al.[36]/2006MST1MST1-FOXO3Mediates oxidative-stress-induced cell death
Yuan et al.[22]/2009MST1MST1-FOXO1Mediates survival factor deprivation-induced cell death
Xiao et al.[67]/2011MST1c-Abl-MST1-FOXO3Mediates oxidative-stress-induced cell death
Yun et al.[70]/2011MST1IFN-γ-Daxx-MST1Mediates proinflammatory-cytokine-induced cell death
Lee et al.[68]/2014MST1MT3-zin-c-Abl-MST1Mediates oxidative-stress-induced cell death
Liu et al.[25]/2012MST2c-Abl-MST2Mediates oxidative-stress-induced cell death
Tang et al.[71]/2014MST3Cdk-5-MST3-RhoAMediates RhoA-dependent actin dynamics and neuronal migration
Ultanir et al.[48]/2014MST3MST3-TAO1/2Promotes spine synapse development
Zhou et al.[24]/2000MST3bPKA-MST3bMediates MAPK pathways
Irwin et al.[72]/2006MST3bNeurotrophic-MST3bPromotes axon outgrowth
Lorber et al.[14]/2009MST3b/Promotes axon regeneration
Fidalgo et al.[74]/2012MST4MST4-ERMPrevents oxidative-stress-induced cell death
Matsuki et al.[77]/2010STK25LKB1-STK25-GM130Mediates Golgi dispersion, axon specification and dendrite growth
Zhang et al.[76]/2012STK25CCM3—STK25Promotes oxidative-stress-induced cell apoptosis
Matsuki et al.[79]/2013STK25/Acute inactivation of STK25 instead of constitutive STK25 deficiency disrupts the neuronal migration
Table 1  Main findings of MST kinases in CNS biological function.
Author/yearDiseaseMST kinaseMain finding
TumorCosta et al.[99]
MedulloblastomaSTK25STK25 prevents medulloblastoma cells death via attenuating TrkA—STK25 signaling pathway
Chao et al. [97]
GlioblastomaMST1Mst1 prevents glioblastoma growth via attenuating AKT—mTOR signaling pathway
Zhu et al.[91]
GlioblastomaMST1/2miR-130b promotes glioblastoma growth via attenuating MST1/2—Lats—YAP/TAZ signaling pathway
Zhang et al.[88]
GlioblastomaMST1/2YAP/TAZ—BIRC5 signaling pathway induced by Lats down-regulation promotes glioblastoma growth
Vascular diseasesVoss et al.[106]
CCMSTK25Interaction between CCM2, CCM3 and STK25 mediates vascular development and CCM pathogenesis
Zheng et al.[104]
CCMSTK24/25Interaction between CCMs and STKs mediates vascular development and CCM pathogenesis
Zhao et al.[108]
Cerebral ischemiaMST1MST1 promotes cerebral-ischemia-induced microglia activation via Src—MST1—IκBα signaling pathway
Weng et al.[112]
Cerebral ischemiaMST1Malibatol A prevents cerebral-ischemia-induced microglia activation via c-Abl—MST1 signaling pathway
Yang et al.[115]
VDMST1TSL protects neurons activity in VD via attenuating inflammatory reaction mediated by MST1—FOXO3 signaling pathway
Neurodegenerative diseasesMatsuki et al.[23]
ADSTK25Stk25 attenuating AD development via preventing Tau phosphorylation induced by Dab1 deficiency
Lee et al.[130]
ALSMST1MST1 mediates ALS development via interaction with SOD1
Pan et al.[138]/2014Prion diseasesMST1c-Abl—MST1 signaling pathway promotes prion-induced neuralapoptosisin Prion diseases
Other CNS diseasesZhang et al.[142]/2015Spine injuryMST3bMst3b promotes neural regeneration in injured spinal cord
Imitola et al.[13]/20152q37 microdeletion syndromeSTK25STK25 deletion was the most interacting gene in neural development disorder of 2q37 microdeletion syndrome
Table 2  The MST kinases in CNS diseases.
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