title: Protein kinase A rescues microtubule affinity-regulating kinase 2-induced microtubule instability and neurite disruption by phosphorylating serine 409.
abstract: 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.
authors.affiliation: From the National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Road, Shanghai 201203, China.
authors.forename: Si-Si
authors.initials: SS
authors.lastname: Deng
authors.affiliation: Department of Neuropharmacology, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Le-Yu
authors.initials: LY
authors.lastname: Wu
authors.affiliation: School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
authors.forename: Ya-Chao
authors.initials: YC
authors.lastname: Wang
authors.affiliation: From the National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Road, Shanghai 201203, China.
authors.forename: Peng-Rong
authors.initials: PR
authors.lastname: Cao
authors.affiliation: From the National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Road, Shanghai 201203, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: From the National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Road, Shanghai 201203, China.
authors.forename: Qian-Ru
authors.initials: QR
authors.lastname: Li
authors.affiliation: From the National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Road, Shanghai 201203, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.affiliation: From the National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Road, Shanghai 201203, China.
authors.forename: Lun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: From the National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Road, Shanghai 201203, China.
authors.forename: Yue-Jing
authors.initials: YJ
authors.lastname: Jiang
authors.affiliation: Department of Neuropharmacology, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Yang
authors.affiliation: The Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China, and.
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Sun
authors.affiliation: The Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China, and.
authors.forename: Min-jia
authors.initials: MJ
authors.lastname: Tan
authors.affiliation: School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
authors.forename: Min
authors.initials: M
authors.lastname: Qian
authors.affiliation: From the National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Road, Shanghai 201203, China, yzang@simm.ac.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zang
authors.affiliation: Department of Neuropharmacology, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China, lyfeng@simm.ac.cn.
authors.forename: Linyin
authors.initials: L
authors.lastname: Feng
authors.affiliation: From the National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Road, Shanghai 201203, China, School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China jli@simm.ac.cn.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D012694:Serine / Q000378:metabolism*
chemical_list: D012694:Serine; C094670:MARK2 protein, human; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: MARK2; Microtubule; Microtubule-associated Protein (MAP); Neurite Outgrowth; Protein Kinase A (PKA); Tau Protein (Tau)