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GSK3 modulates PACAP-induced neuritogenesis in PC12 cells by acting downstream of Rap1 in a caveolae-dependent manner

Citation

Zhang, W and Smith, A and Liu, J and Cheung, NS and Zhou, S and Liu, K and Li, QT and Duan, W, GSK3s modulates PACAP-induced neuritogenesis in PC12 cells by acting downstream of Rap1 in a caveolae-dependent manner, Cellular Signalling, 21, (2) pp. 237-245. ISSN 0898-6568 (2009) [Refereed Article]

DOI: doi:10.1016/j.cellsig.2008.10.008

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 GSK3 is a novel modulator in PACAP signalling. PACAP induces phosphorylation of serine 9 in GSK3, which is inhibited by silencing Rap1. Lithium and valproate promote but wortmannin and LY294002 attenuate PACAP-induced phosphorylation of both GSK3 and ERK1/2, whereas MEK inhibitor PD98059 inhibits nerve growth factor- but not PACAPinduced phosphorylation of GSK3, suggesting that GSK3 operates downstream of Rapt 1 but upstream of ERK1/2 in PACAP signalling. Inhibition or stimulation of GSK3 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 GSK3 is a critical regulator in PACAP-induced neuronal differentiation.

Item Details

Item Type:Refereed Article
Keywords:PACAP, GSK3, Rap1, Caveolae, PC12, Neurite outgrowth
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Cellular Nervous System
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Cheung, NS (Dr Nam Cheung)
ID Code:59003
Year Published:2009
Web of Science® Times Cited:13
Deposited By:Menzies Institute for Medical Research
Deposited On:2009-11-12
Last Modified:2011-07-28
Downloads:0

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