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Molecular and Cellular Biology, August 2008, p. 4940-4951, Vol. 28, No. 16
0270-7306/08/$08.00+0     doi:10.1128/MCB.02193-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Pituitary Adenylate Cyclase-Activating Polypeptide 38-Mediated Rin Activation Requires Src and Contributes to the Regulation of Hsp27 Signaling during Neuronal Differentiation{triangledown}

Geng-Xian Shi, Ling Jin, and Douglas A. Andres*

Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, 741 South Limestone Street, Lexington, Kentucky 40536-0509

Received 11 December 2007/ Returned for modification 28 January 2008/ Accepted 27 May 2008

Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) is a potent neuropeptide that acts through G-protein-coupled receptors. While it is well established that PACAP mediates both neurotrophic and neurodevelopmental effects, the signaling cascades that underlie these diverse actions remain incompletely characterized. Here we show that the Ras-related Rin GTP-binding protein, a GTPase that is expressed predominantly in neurons, is regulated by PACAP38 signaling, and loss-of-function analysis demonstrates that Rin makes an essential contribution to PACAP38-mediated pheochromocytoma cell differentiation. Rin is activated following stimulation of both Gs{alpha} and Gi{alpha} cascades but does not rely upon cyclic AMP (cAMP)-, Ca2+-, or Epac-dependent signaling pathways. Instead, Rin is activated in a Src kinase-dependent manner. Surprisingly, Rin knockdown significantly inhibits PACAP38-mediated neurite outgrowth, without affecting mitogen-activated protein kinase signaling cascades. Instead, Rin loss attenuates PACAP38-mediated HSP27 activation by disrupting a cAMP-protein kinase A cascade. RNA interference-mediated HSP27 silencing suppresses both PACAP38- and Rin-mediated neurite outgrowth, while expression of a constitutively active Rin mutant increases both HSP27 protein and phospho-HSP27 levels, supporting a role for Rin-HSP27 signaling in neuronal differentiation. Together, these observations identify an unsuspected role for Rin in neuronal PACAP signaling and establish a novel G{alpha}-Src-Rin-HSP27 signal transduction pathway as a critical element in PACAP38-mediated neuronal differentiation signaling.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, BBSRB Room B179, 741 South Limestone Street, Lexington, KY 40536-0509. Phone: (859) 257-6775. Fax: (859) 323-1037. E-mail: dandres{at}uky.edu

{triangledown} Published ahead of print on 9 June 2008.

Molecular and Cellular Biology, August 2008, p. 4940-4951, Vol. 28, No. 16
0270-7306/08/$08.00+0     doi:10.1128/MCB.02193-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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