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Molecular and Cellular Biology, December 2006, p. 9136-9147, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.00332-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

A Novel Cyclic AMP-Dependent Epac-Rit Signaling Pathway Contributes to PACAP38-Mediated Neuronal Differentiation{triangledown}

Geng-Xian Shi,1 Holger Rehmann,2 and Douglas A. Andres1*

Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky 40536,1 Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands2

Received 23 February 2006/ Returned for modification 22 March 2006/ Accepted 6 September 2006

Pituitary adenylate cyclase-activating polypeptide (PACAP38) stimulation results in the activation of Gs{alpha} protein-coupled receptors to regulate neuronal differentiation in a cyclic AMP (cAMP)-dependent manner. These pathways involve protein kinase A (PKA)-dependent processes, but a growing body of evidence indicates that cAMP also regulates cellular functions through PKA-independent signaling cascades. Here we show that the Rit small GTPase is regulated by PACAP38 in a cAMP-dependent but PKA-independent fashion. Rit activation results from stimulation of the cAMP-activated guanine nucleotide exchange factor Epac but does not appear to rely upon the activation of Rap GTPases, the accepted cellular Epac substrates. Although RNA interference studies demonstrated that Epac is required for PACAP38-mediated Rit activation, neither Epac1 nor Epac2 activates Rit directly, indicating that Epac signals to Rit through a novel mechanism in which Rap signaling is not essential. Loss-of-function analysis demonstrated that Rit makes an important contribution to PACAP38-mediated neuronal differentiation. Surprisingly, although Rit is required for sustained extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase signaling following nerve growth factor stimulation of pheochromocytoma 6 (PC6) cells, Rit silencing selectively suppressed PACAP38-elicited activation of p38, without obvious effects on ERK signaling in the same cells. Moreover, the ability of PACAP38 to stimulate CREB-dependent transcription and to promote neurite outgrowth was inhibited by Rit knockdown. Together, these studies identify an unsuspected connection between cAMP and Rit signaling pathways and imply that Rit can function downstream of Gs{alpha}/cAMP/Epac in a novel signal transduction pathway necessary for PACAP38-mediated neuronal differentiation and CREB signaling.

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

{triangledown} Published ahead of print on 25 September 2006.

Molecular and Cellular Biology, December 2006, p. 9136-9147, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.00332-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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