Punn, Anu, Levine, Michael A. and Grammatopoulos, Dimitris K.. (2006) Identification of signaling molecules mediating corticotropin-releasing hormone-R1 alpha-mitogen-activated protein kinase (MAPK) interactions: The critical role of phosphatidylinositol 3-kinase in regulating ERK1/2 but not p38 MAPK activation. MOLECULAR ENDOCRINOLOGY, 20 (12). pp. 3179-3195. ISSN 0888-8809

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Abstract

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 CRHR1 alpha, UCN I induced ERK1/2 and p38 MAPK activation was dependent on signaling molecules involved in agonist-induced CRH-R1 alpha 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 alpha-transducin, showed that G beta gamma-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 alpha-MAPK interactions; PI3-K might play a critical role in the regulation of CRH-R1 alpha signaling selectivity and cellular responses.

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine
Journal or Publication Title:	MOLECULAR ENDOCRINOLOGY
Publisher:	ENDOCRINE SOC
ISSN:	0888-8809
Date:	December 2006
Volume:	20
Number:	12
Number of Pages:	17
Page Range:	pp. 3179-3195
Identification Number:	10.1210/me.2006-0255
Publication Status:	Published
URI:	http://wrap.warwick.ac.uk/id/eprint/32749

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