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 GSK3ß is a novel modulator in PACAP signalling. PACAP induces phosphorylation of serine 9 in GSK3ß, which is inhibited by silencing Rap1. Lithium and valproate promote but wortmannin and LY294002 attenuate PACAP-induced phosphorylation of both GSK3ß and ERK1/2, whereas MEK inhibitor PD98059 inhibits nerve growth factor- but not PACAPinduced phosphorylation of GSK3ß, suggesting that GSK3ß operates downstream of Rapt 1 but upstream of ERK1/2 in PACAP signalling. Inhibition or stimulation of GSK3ß 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 GSK3ß is a critical regulator in PACAP-induced neuronal differentiation.

Item Type:	Refereed Article
Keywords:	PACAP, GSK3ß, Rap1, Caveolae, PC12, Neurite outgrowth
Research Division:	Biomedical and Clinical Sciences
Research Group:	Neurosciences
Research Field:	Cellular nervous system
Objective Division:	Health
Objective Group:	Clinical health
Objective Field:	Clinical health not elsewhere classified
UTAS Author:	Cheung, NS (Dr Nam Cheung)
ID Code:	59003
Year Published:	2009
Web of Science® Times Cited:	18
Deposited By:	Menzies Institute for Medical Research
Deposited On:	2009-11-12
Last Modified:	2011-07-28
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