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GSK3β modulates PACAP-induced neuritogenesis in PC12 cells by acting downstream of Rap1 in a caveolae-dependent manner

journal contribution
posted on 2009-02-01, 00:00 authored by W Zhang, Adam Smith, J P Liu, Steve Cheung, S Zhou, K Liu, Q T Li, Wei DuanWei Duan
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 GSK3β is a novel modulator in PACAP signalling. PACAP induces phosphorylation of serine 9 in GSK3β, which is inhibited by silencing Rap1. Lithium and valproate promote but wortmannin and LY294002 attenuate PACAP-induced phosphorylation of both GSK3β and ERK1/2, whereas MEK inhibitor PD98059 inhibits nerve growth factor- but not PACAP-induced phosphorylation of GSK3β, suggesting that GSK3β operates downstream of Rapt 1 but upstream of ERK1/2 in PACAP signalling. Inhibition or stimulation of GSK3β 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 GSK3β is a critical regulator in PACAP-induced neuronal differentiation.

History

Journal

Cellular signalling

Volume

21

Issue

2

Pagination

237 - 245

Publisher

Elsevier Inc.

Location

Amsterdam, The Netherlands

ISSN

0898-6568

eISSN

1873-3913

Language

eng

Publication classification

C1 Refereed article in a scholarly journal; C Journal article

Copyright notice

2008, Elsevier Inc