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Oncology Research 2024年第2期32卷 421-432页

作者： SEUNG-HEE GWAK JUHYUN LEE EUNJI OH DOHYUN LEE WONSHIK HAN JONGMIN KIM KYONG-TAI KIM Department of Life Sciences Pohang University of Science and TechnologyPohang37673Korea R&D Center NovMetaPharma Co.Ltd.Pohang37668Korea Department of Surgery and Cancer Research Institute Seoul National University College of MedicineSeoul03080Korea Generative Genomics Research Center Global Green Research&Development CenterHandong Global UniversityPohang37554Korea

Genetic information is transcribed from genomic DNA to mRNA,which is then translated into threedimensional proteins.mRNAs can undergo various post-transcriptional modifications,including RNA editing that alters mRNA sequences,ultimately affecting protein function.In this study,RNA editing was identified at the 499th base(c.499)of human vaccinia-related kinase 2(VRK2).This RNA editing changes the amino acid in the catalytic domain of VRK2 from isoleucine(with adenine base)to valine(with guanine base).Isoleucine-containing VRK2 has higher kinase activity than the valine-containing VRK2,which leads to an increase in tumor cell proliferation.Earlier we reported that VRK2 directly interacts with dystrobrevin-binding protein(dysbindin)and results in reducing its stability.Herein,we demonstrate that isoleucine-containing VRK2 decreases the level of dysbindin than valinecontaining VRK2.Dysbindin interacts with cyclin D and thereby regulates its expression and function.The reduction in the level of dysbindin by isoleucine-containing VRK2 further enhances the cyclin D expression,resulting in increased tumor growth and reduction in survival rates.It has also been observed that in patient samples,VRK2 level was elevated in breast cancer tissue compared to normal breast tissue.Additionally,the isoleucine form of VRK2 exhibited a greater increase in breast cancer tissue.Therefore,it is concluded that VRK2,especially dependent on the 167th variant amino acid,can be one of the indexes of tumor progression and proliferation.

关键词： VRK2 kinase activity Breast cancer Tumor RNA editing Cell proliferation Cell growth

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Neddylation controls basal MKK7 kinase activity in breast cancer cells

Neddylation controls basal MKK7 kinase activity in breast ca...

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第十届全国免疫学学术大会

作者： Jing Wang Yujun Pei Ting Zhu Qingyang Wang Ye Wu Guihua Qiu Dalin Zhang Beifen Shen Jiyan Zhang Beijing Institute of Basic Medical Sciences

The JNK pathway has been implicated in mammary tumor development.However,the molecular mechanisms regulating JNK activity in breast cancer cells remain unclear.Here,we report that MKK7,a JNK-specific MAP2K,is covalently conjugated with the ubiquitin-like modifier NEDD8 in human breast cancer cells.Knockdown of NEDD8 or UBA3,a component of the E1 heterodimer,results in enhanced basal JNK phosphorylation.Since augmented basal JNK phosphorylation via ectopic MKK7 expression leads to reduced anchorage-independent growth and more apoptosis in response to TRAIL,the neddylation system might contribute to mammary tumor development partially through limiting basal JNK phosphorylation.Further exploration suggests that the neddylation system inhibits the basal kinase activity of MKK7.MKK7 co-precipitated with a fragment of Ran-binding protein 2(Ran BP2),a large multimodular and pleiotropicprotein which has been recognized as a SUMO E3 ligase.Knockdown of Ran BP2 attenuates MKK7 neddylation and augments basal JNK phosphorylation without affecting the neddylation of Cullins,whereas ectopic expression of a Ran BP2 fragment possessing SUMO E3 activity(Ran BP2DFG)manifests the opposite effects.In vitro neddylation assays confirm that Ran BP2DFG works as the neddylation E3 ligase for MKK7.The basal kinase activity of endogenous MKK7 increases upon Ran BP2 knockdown but decreases upon the ectopic expression of Ran BP2DFG.Furthermore,purified MKK7 shows reduced basal kinase activity after in vitro neddylation.Taken together,our data suggest that MKK7undergoes neddylation in human breast cancer cells,which limits its basal kinase activity.

关键词： MKK7 kinase activity breast cancer neddylation oncogenic growth

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Structural and biochemical basis of Arabidopsis FERONIA receptor kinase-mediated early signaling initiation

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Plant Communications 2023年第4期4卷 132-145页

作者： Yanqiong Kong Jia Chen Lingli Jiang Hong Chen Yanan Shen Lifeng Wang Yujie Yan Huan Zhou Heping Zheng Feng Yu Zhenhua Ming State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources College of Life Science and TechnologyGuangxi Key Laboratory for Sugarcane BiologyGuangxi UniversityNanning 530004P.R.China State Key Laboratory of Chemo/Biosensing and Chemometrics College of BiologyHunan Key Laboratory of Plant Functional Genomics and Developmental RegulationHunan UniversityChangsha 410082P.R.China State Key Laboratory of Hybrid Rice Hunan Hybrid Rice Research CenterChangsha 410125P.R.China Shanghai Synchrotron Radiation Facility Shanghai Advanced Research InstituteChinese Academy of SciencesShanghaiP.R.China

Accumulating evidence indicates that early and essential events for receptor-like kinase(RLK)function involve both autophosphorylation and substrate phosphorylation.However,the structural and biochemical basis for these events is largely unclear.Here,we used RLK FERONIA(FER)as a model and crystallized its core kinase domain(FER-KD)and two FER-KD mutants(K565R,S525A)in complexes with ATP/ADP and Mg^(2+) in the unphosphorylated state.Unphosphorylated FER-KD was found to adopt an unexpected active conformation in its crystal structure.Moreover,unphosphorylated FER-KD mutants with reduced(S525A)or no catalytic activity(K565R)also adopt similar active conformations.Biochemical studies revealed that FER-KD is a dual-specificity kinase,and its autophosphorylation is accomplished via an intermolecular mechanism.Further investigations confirmed that initiating substrate phosphorylation requires autophosphorylation of the activation segment on T696,S701,and Y704.This study reveals the structural and biochemical basis for the activation and regulatory mechanism of FER,providing a paradigm for the early steps in RLK signaling initiation.

关键词： FERONIA active conformation kinase activity autophosphorylation activation

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SKAP interacts with Aurora B to guide end-on capture of spindle microtubules via phase separation

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Journal of Molecular Cell Biology 2021年第12期13卷 841-852页

作者： Manjuan Zhang Fengrui Yang Wenwen Wang Najdat Zohbi Xiwei Wang Dongmei Wang Xiaoxuan Zhuang Zhen Dou Dan Liu Xiaoyu Song Hadiyah-Nicole Green Xing Liu Xuebiao Yao MOE Key Laboratory for Cellular Dynamics and Hefei National Laboratory for Physical Sciences at the Microscale University of Science and Technology of ChinaHefei 230027China Anhui Key Laboratory for Cellular Dynamics and Chemical Biology and CAS Center for Excellence in Molecular Cell Science Hefei 230027China Keck Center for Organoids Plasticity Control Morehouse School of MedicineAtlantaGA 30310USA

Chromosome segregation in mitosis is orchestrated by the dynamic interactions between the kinetochore and spindle microtubules.Our recent studies show that mitotic motor CENP-E cooperates with SKAP and forms a link between kinetochore core MIS13 complexand spindle microtubule plus-ends to achieve accurate chromosome alignment in mitosis. However, it remains elusive how SKAP regulates kinetochore attachment from lateral association to end-on attachment during metaphase alignment. Here, we identify a novel interaction between Aurora B and SKAP that orchestrates accurate interaction between the kinetochore and dynamic spindle microtubules. Interestingly, SKAP spontaneously phase-separates in vitro via weak, multivalent interactions into droplets with fast internaldynamics. SKAP and Aurora B form heterogeneous coacervates in vitro, which recapitulate the dynamics and behavior of SKAP cometsin vivo. Importantly, SKAP interaction with Aurora B via phase separation is essential for accurate chromosome segregation and alignment. Based on those findings, we reason that SKAP–Aurora B interaction via phase separation constitutes a dynamic pool of Aurora Bactivity during the lateral to end-on conversion of kinetochore–microtubule attachments to achieve faithful cell division.

关键词： Aurora B SKAP kinase activity mitosis phase separation

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FERONIA cytoplasmic domain:node of varied signal outputs

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aBIOTECH 2020年第2期1卷 135-146页

作者： Jia Chen Sirui Zhu Zhenhua Ming Xuanming Liu Feng Yu State Key Laboratory of Chemo/Biosensing and Chemometrics College of BiologyHunan Key Laboratory of Plant Functional Genomics and Developmental RegulationHunan UniversityChangsha 410082P.R.China State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources College of Life Science and TechnologyGuangxi UniversityNanning 530004P.R.China

The receptor-like kinase(RLK)FERONIA(FER),located on the plasma membrane,belongs to the Catharanthus roseus RLK1-like kinase family(CrRLK1L)and participates in widespread biological processes in plants in a context-dependent fashion.Genetic studies in Arabidopsis illustrated the versatile roles that FER plays in fertilization,vegetative growth,defense and stress responses,cell-wall homeostasis,as well as protein synthesis.These studies also helped to identify genes and signal pathways involved in FER signal transduction.Despite increasingly larger numbers of studies discussing how FER senses its ligand,Rapid alkalinization factor(RALF)peptides,and further regulates downstream factors,few have shown the mechanisms of how FER mediates the specific regulation of downstream signals in context of the phosphorylation of its cytoplasmic domain.As understanding this would help in better understanding the diversity and complexity of FER function,this paper aims to review the roles of FER in regulating different signal outputs from the view of the role of its cytoplasmic domain.

关键词： FER Cytoplasmic domain Phosphorylation sites kinase activity RALF peptides

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The alkaline tolerance in Arabidopsis requires stabilizing microfilament partially through inactivation of PKS5 kinase

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Journal of Genetics and Genomics 2011年第7期38卷 307-313页

作者： Juntao Liu Yan Guo State Key Laboratory of Plant Physiology and Biochemistry College of Biological Sciences China Agricultural University Beijing 100094 China National Institute of Biological Sciences Beijing No. 7 Science Park Road Zhongguancun Life Science Park Beijing 102206 China

High soil pH is harmful to plant growth and development. The organization and dynamics of microfilament （MF） cytoskeleton play important roles in the plant anti-alkaline process. In the previous study, we determined that alkaline stress induces a signal that triggers MF dynamicsdependent root growth. In this study we identified that PKS5 kinase involves in this regulatory process to facilitate the signal to reach the downstream target ME Under pH 8.3 treatment, the depolymerization of MF was faster in pks5-4 （PKS5 kinase constitutively activated） than that in wild-type plants. The inhibition of wild-type, pks5-1, and pks5-4 root growth by pH 8.3 was correlated to their MF depolymerization rate. When the plants were treated with phalloidin to stabilize MF, the high pH sensitive phenotype of pks5-4 can be partially rescued. When the plants were treated with a kinase inhibitor Staurosporine, the MF depolymerization rate in pks5-4 was similar as that in wild-type under pH 8.3 treatment and the sensitivity of root growth was also rescued. However, when the plants were treated with LaC13, a calcium channel blocker, the root growth sensitivity ofpks5-4 under pH 8.3 was rescued but MF depolymerization was even faster than that of plants without LaC13 treatment. These results suggest that the PKS5 involves in external high pH signal mediated MF depolymerization, and that may be independent of calcium signal.

关键词： Arabidopsis Alkaline stress Microfilament kinase activity

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Identification of Ser465 as a novel PINK1 autophosphorylation site

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Translational Neurodegeneration 2017年第1期6卷 338-346页

作者： Ji-feng Guo Ling-yan Yao Qi-ying Sun Yi-ting Cui Yang Yang Qian Xu Xin-xiang Yan Bei-sha Tang Department of Neurology Xiangya HospitalCentral South UniversityChangshaHunan 410008People’s Republic of China Laboratory of Medical Genetics Central South University ChangshaChangshaHunan 410078China National Clinical Research Center for Geriatric Disorders ChangshaHunan 410078China Key Laboratory of Hunan Province in Neurodegenerative Disorders Central South UniversityChangshaHunan 410008China Parkinson’s Disease Center of Beijing Institute for Brain Disorders Beijing 100069China Collaborative Innovation Center for Brain Science Shanghai 200032China Collaborative Innovation Center for Genetics and Development Shanghai 200433China

Background:PINK1(PTEN-induced putative kinase 1)gene is the causal gene for recessive familial type 6 of Parkinson’s disease(PARK6),which is an early-onset autosomal recessive inherited neurodegenerative disease.PINK1 has been reported to exert both autophosphorylation and phosphorylation activity,affecting cell damage under stress and other physiological responses.However,there has been no report on the identification of PINK1 autophosphorylation sites and their physiological functions.Methods:(1)We adopted mass spectrometry assay to identify the autophosphorylation site of PINK1,and autoradiography assay was further conducted to confirm this result.(2)kinase activity assay was used to compare the kinase activity of both Ser465 mutant PINK1 and disease-causing mutant PINK1.(3)We use Pulse-chase analysis to measure whether Ser465 may affect PINK1 degradation.(4)Immunocytochemistry staining was used to study the PINK1 subcellular localization and Parkin transition in subcellular level.Result:In our study,we identified the 465th serine residue(Ser465)as one of the autophosphorylation sites in PINK1 protein.The inactivation of Ser465 can decrease the kinase activity of PINK1.Either dissipated or excessive Ser465 site phosphorylation of PINK1 can slow down its degradation.PINK1 autophosphorylation contributes to the transit of Parkin to mitochondria,and has no effect on its subcellular localization.PARK6 causal mutations,T313 M and R492X,display the same characteristics as Ser465A mutation PINK1 protein,such as decreasing PINK1 kinase activity and affecting its interaction with Parkin.Conclusion:Ser465 was identified as one of the autophosphorylation sites of PINK1,which affected PINK1 kinase activity.In addition,Ser465 is involved in the degradation of PINK1 and the transit of Parkin to mitochondria.T313 M and R492X,two novel PARK6 mutations on Thr313 and Arg492,were similar to Ser465 mutation,including decreasing PINK1 phosphorylation activity and Parkin subcellular localization.

关键词： Parkinson’s disease PINK1 Autophosphorylation sites kinase activity

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