title: GSK3beta modulates PACAP-induced neuritogenesis in PC12 cells by acting downstream of Rap1 in a caveolae-dependent manner.
abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neurotrophic peptide. Here, we show that PACAP recruits Rap1 into caveolin-enriched membrane subdomains in PC12 cells and activates Rap1, nuclear ERK1/2, Elk-1 and CREB in a caveolae-dependent manner. We reveal that GSK3beta is a novel modulator in PACAP signalling. PACAP induces phosphorylation of serine 9 in GSK3beta, which is inhibited by silencing Rap1. Lithium and valproate promote but wortmannin and LY294002 attenuate PACAP-induced phosphorylation of both GSK3beta and ERK1/2, whereas MEK inhibitor PD98059 inhibits nerve growth factor- but not PACAP-induced phosphorylation of GSK3beta, suggesting that GSK3beta operates downstream of Rapt 1 but upstream of ERK1/2 in PACAP signalling. Inhibition or stimulation of GSK3beta results in a 2-fold increase and 6-fold decrease in PACAP-induced neurite outgrowth, respectively. These results reveal an important role of caveolae in the signal transduction of PACAP and that GSK3beta is a critical regulator in PACAP-induced neuronal differentiation.
authors.affiliation: Department of Biochemistry, Yong Loo Lin of Medicine, The National University of Singapore, 8 Medical Drive, Singapore, 117597, Singapore.
authors.forename: Weishi
authors.initials: W
authors.lastname: Zhang
authors.forename: Adam
authors.initials: A
authors.lastname: Smith
authors.forename: Jun-ping
authors.initials: JP
authors.lastname: Liu
authors.forename: Nam Sang
authors.initials: NS
authors.lastname: Cheung
authors.forename: Shufeng
authors.initials: S
authors.lastname: Zhou
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.forename: Qiu-Tian
authors.initials: QT
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
mesh_terms: D000818:Animals; D021941:Caveolae / Q000187:drug effects / Q000378:metabolism*; D051242:Caveolin 1 / Q000276:immunology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008094:Lithium / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D034741:RNA, Small Interfering; D014635:Valproic Acid; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D020827:rap1 GTP-Binding Proteins