Protein Kinase A Rescues Microtubule Affinity-regulating Kinase 2-induced Microtubule Instability and Neurite Disruption by Phosphorylating Serine 409

doi:10.1074/jbc.M114.629873

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	Protein Kinase A Rescues Microtubule Affinity-regulating Kinase 2-induced Microtubule Instability and Neurite Disruption by Phosphorylating Serine 409
	Deng, Si-Si 1; Wu, Le-Yu 2; Wang, Ya-Chao 5; Cao, Peng-Rong 1; Xu, Lei 1; Li, Qian-Ru 1; Liu, Meng 1; Zhang, Lun 1; Jiang, Yue-Jing 1; Yang, Xiao-Yu 2
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2015-01-30
卷号	290 期号:5 页码:3149-3160
关键词	Microtubule Microtubule-associated Protein (MAP) Neurite Outgrowth Protein Kinase A (PKA) Tau Protein (Tau) MARK2
ISSN号	0021-9258
DOI	10.1074/jbc.M114.629873
文献子类	Article
英文摘要	Background: MARK2 and PKA are both involved in the regulation of microtubule stability. Results: PKA significantly inhibits MARK2 by phosphorylating serine 409 and rescues MARK2-induced microtubule instability and neurite disruption. Conclusion: PKA functions as an upstream inhibitor of MARK2 by directly interacting and phosphorylating it. Significance: The results identify a novel interaction between PKA and MARK2, providing new insight into the signal networks of both. Microtubule affinity-regulating kinase 2 (MARK2)/PAR-1b and protein kinase A (PKA) are both involved in the regulation of microtubule stability and neurite outgrowth, but whether a direct cross-talk exists between them remains unclear. Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409. PKA could not reverse the microtubule disruption effect induced by a serine 409 to alanine (Ala) mutant of MARK2 (MARK2 S409A). In contrast, mutation of MARK2 serine 409 to glutamic acid (Glu) (MARK2 S409E) did not affect microtubule stability and neurite outgrowth. We propose that PKA functions as an upstream inhibitor of MARK2 in regulating microtubule stability and neurite outgrowth by directly interacting and phosphorylating MARK2.
资助项目	National Science Fund for Distinguished Young Scholars[81125023] ; Program of Shanghai Subject Chief Scientist Grant[13XD1404300] ; National Natural Science Foundation of China[81173033] ; National Natural Science Foundation of China[81123004] ; Open Project Program of State Key Laboratory of Natural Medicines[00000000] ; China Pharmaceutical University[SKLN-MKF201407] ; Chinese Academy of Science "strategic leader in science and technology projects"[XDA01040303] ; Chinese Academy of Science "strategic leader in science and technology projects"[XDA01040304]
WOS关键词	UBIQUITIN-ASSOCIATED DOMAINS ; TAU-PHOSPHORYLATION ; ALZHEIMERS-DISEASE ; NEURONAL POLARITY ; MARK/PAR-1 ; FAMILY ; OUTGROWTH ; TOXICITY ; DIFFERENTIATION ; ESTABLISHMENT
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
WOS记录号	WOS:000349310700049
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276662]
专题	国家新药筛选中心中科院受体结构与功能重点实验室新药研究国家重点实验室药理学第二研究室
通讯作者	Zang, Yi
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Dept Neuropharmacol, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Chem Prote Ctr, Shanghai 201203, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 5.E China Normal Univ, Sch Life Sci, Shanghai 200062, Peoples R China
推荐引用方式 GB/T 7714	Deng, Si-Si,Wu, Le-Yu,Wang, Ya-Chao,et al. Protein Kinase A Rescues Microtubule Affinity-regulating Kinase 2-induced Microtubule Instability and Neurite Disruption by Phosphorylating Serine 409[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2015,290(5):3149-3160.
APA	Deng, Si-Si.,Wu, Le-Yu.,Wang, Ya-Chao.,Cao, Peng-Rong.,Xu, Lei.,...&Li, Jia.(2015).Protein Kinase A Rescues Microtubule Affinity-regulating Kinase 2-induced Microtubule Instability and Neurite Disruption by Phosphorylating Serine 409.JOURNAL OF BIOLOGICAL CHEMISTRY,290(5),3149-3160.
MLA	Deng, Si-Si,et al."Protein Kinase A Rescues Microtubule Affinity-regulating Kinase 2-induced Microtubule Instability and Neurite Disruption by Phosphorylating Serine 409".JOURNAL OF BIOLOGICAL CHEMISTRY 290.5(2015):3149-3160.