title: Protein phosphatase 2A (PP2A) activation promotes axonal growth and recovery in the CNS.
abstract: Current treatments to restore neurological deficits caused by axonal disconnection following central nervous system (CNS) injury are extremely limited. Protein phosphatase 2A (PP2A), one of the main serine-threonine phosphatases in mammalian cells, dephosphorylates collapsin response mediator protein-2 (CRMP2) in the developing CNS. In our study, we found that the major CNS inhibiting substrates, including chondroitin sulfate proteoglycans (CSPGs) and myelin associated glycoproteins (MAG), activated epidermal growth factor receptor (EGFR), but inactivated PP2A and downstream CRMP2. Both EGFR inactivation and PP2A activation promoted axon elongation in vitro in the presence of inhibitory substrates. EGFR blockage by AG1478 selectively attenuated the inactive form of PP2A in pY307 phosphorylation, thus increasing PP2A activity. EGFR activation by EGF attenuated PP2A activity, whereas mutation of Y307 to phenylalanine abolished the effect. Furthermore, PP2A activity was down-regulated immediately after spinal cord injury (SCI) in rats. Chronic application of d-erythro-sphingosine (DES), the PP2A agonist, to spinal cord-lesioned rats enhanced the activity of this phosphatase and dephosphorylated CRMP2 around the lesion. PP2A activation induced significant axon sprouting in the lesioned spinal cord and promoted function recovery after SCI. These findings suggest that PP2A works downstream of EGFR and dephosphorylates CRMP2 after CNS injury. Therefore, therapies targeting PP2A may be effective following SCI.
authors.affiliation: Department of Orthopedics, Biological Engineering and Regenerative Medicine Center, Tongji Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Cheng
authors.affiliation: Department of Orthopedics, Biological Engineering and Regenerative Medicine Center, Tongji Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, Biological Engineering and Regenerative Medicine Center, Tongji Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Orthopedics, Biological Engineering and Regenerative Medicine Center, Tongji Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Shutao
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Pathology, Hubei Maternity and Child Health Hospital, Wuhan, China.
authors.forename: Shunze
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Orthopedics, Biological Engineering and Regenerative Medicine Center, Tongji Hospital, Tongii Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Hankou, Wuhan 430030, China. Electronic address: sunxuying1984@hotmail.com.
authors.forename: Xuying
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Orthopedics, Tongji Hospital, Tongii Medical College, Huazhong University of Science and Technology, No. 1095 Jie Fang Avenue, Hankou, Wuhan 430030, China. Electronic address: hhflying@hotmail.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans; D003911:Dextrans / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics / Q000276:immunology; D004676:Myelin Basic Protein / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013119:Spinal Cord Injuries / Q000188:drug therapy; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D003911:Dextrans; D004791:Enzyme Inhibitors; D004676:Myelin Basic Protein; D011799:Quinazolines; D020032:Tyrphostins; C076397:biotinylated dextran amine; C481931:erythro-(2R,3S)-sphingosine; C101044:RTKI cpd; D001710:Biotin; C483803:Egfr protein, rat; D066246:ErbB Receptors; D054648:Protein Phosphatase 2; D013110:Sphingosine
keywords: Axon growth; CRMP2; EGFR; PP2A; Spinal cord injury; Y307 phosphorylation