This Article Full Text Full Text (PDF) All Versions of this Article: 20/12/3179    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Punn, A. Articles by Grammatopoulos, D. K. Search for Related Content PubMed PubMed Citation Articles by Punn, A. Articles by Grammatopoulos, D. K.

Identification of Signaling Molecules Mediating Corticotropin-Releasing Hormone-R1-Mitogen-Activated Protein Kinase (MAPK) Interactions: The Critical Role of Phosphatidylinositol 3-Kinase in Regulating ERK1/2 But Not p38 MAPK Activation

Endocrinology and Metabolism (A.P., D.K.G.), Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom; and Division of Pediatrics (M.A.L.), The Children’s Hospital of The Cleveland Clinic Foundation, Cleveland, Ohio 44195

Address all correspondence and requests for reprints to: Dr. D. Grammatopoulos, Sir Quinton Hazell Molecular Medicine Research Centre, Department of Biological Sciences, The University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, United Kingdom. E-mail: d.grammatopoulos{at}warwick.ac.uk.

In most target cells, activation of the type 1 CRH receptor (CRH-R1) by CRH or urocortin (UCN I) leads to stimulation of the Gs-protein/adenylyl cyclase/protein kinase A cascade. Signal transduction of CRH-R1 also involves alternative pathways such as phosphorylation of ERK1/2 and p38 MAPK, two members of the MAPK family that mediate important pathophysiological responses. The intracellular pathways by which CRH-R1 activates these MAPK are only partially understood; here we characterized further signaling mechanisms and molecules involved in CRH-R1-mediated ERK1/2 and p38 MAPK activation. In human embryonic kidney 293 cells overexpressing recombinant CRH-R1, UCN I induced ERK1/2 and p38 MAPK activation was dependent on signaling molecules involved in agonist-induced CRH-R1 trafficking and endocytosis. Furthermore, time course studies and use of selective inhibitors demonstrated that ERK1/2 activation occured within 5 min, was sustained for at least 60 min, and was dependent on both phosphatidylinositol 3-kinase (PI3-K)/Akt activation and epidermoid growth factor receptor transactivation involving matrix metelloproteinases. UCN I effect on p38 MAPK phosphorylation was more transient, returned to basal within 40 min and was dependent on epidermoid growth factor receptor transactivation, but not PI3-K/Akt activation. Overexpression of G_-transducin, showed that G_ß-subunit activation is only partially required for ERK1/2 phosphorylation and does not play a role in p38 MAPK phosphorylation, whereas overexpression of a dominant-negative Ras (Ras N17) attenuated both ERK and p38 MAPK activation. In conclusion, a complex signaling network appears to mediate CRH-R1-MAPK interactions; PI3-K might play a critical role in the regulation of CRH-R1 signaling selectivity and cellular responses.

This article has been cited by other articles:

				D. Markovic, A. Punn, H. Lehnert, and D. K. Grammatopoulos Intracellular Mechanisms Regulating Corticotropin-Releasing Hormone Receptor-2{beta} Endocytosis and Interaction with Extracellularly Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase Signaling Cascades Mol. Endocrinol., March 1, 2008; 22(3): 689 - 706. [Abstract] [Full Text] [PDF]