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Specificity and Regulation of Extracellularly Regulated Kinase1/2 Phosphorylation through Corticotropin-Releasing Factor (CRF) Receptors 1 and 2ß by the CRF/Urocortin Family of Peptides

The Clayton Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California 92037

Address all correspondence and requests for reprints to: Wylie Vale, The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037. E-mail: address: vale{at}salk.edu.

Corticotropin-releasing factor (CRF) receptor (CRFR)-mediated activation of the ERKs 1/2-p42 and -44) has been reported for CRF, urocortin (Ucn)-I, and sauvagine. Recently two new members of the CRF/Ucn family of peptides have been identified, Ucn-II/stresscopin-related peptide and Ucn-III/stresscopin. Using Chinese hamster ovary cells stably expressing CRFR1 and CRFR2ß, we show that Ucn-I, Ucn-II and Ucn-III activate ERK1/2-p42, 44 via CRFR2ß. CRF and Ucn-I but not Ucn-II or Ucn-III activates ERK1/2-p42, 44 in Chinese hamster ovary cells stably expressing CRFR1. The selectivity of the ligands for CRFR1 and CRFR2ß is shown in a time- and dose-dependent manner. The regulatory mechanisms for ERK1/2-p42, 44 activation by both receptor types are dependent on phosphatidylinositol-3 OH kinase, MAPK kinase 1, and phospholipase C. Raf-1 kinase, tyrosine kinases, and possibly intracellular Ca²⁺ provide regulatory roles for Ucn-I activation of ERK1/2-p42, 44 by CRFR1 and CRFR2ß. Studies of the regulation of ERK1/2-p42, 44 by Ucn-I were extended to cell lines that endogenously express CRFR1 (AtT-20 and CATHa cells) and CRFR2 (A7r5 and CATHa cells). Use of the G_i and G_o protein inhibitor pertussis toxin showed that ERK1/2-p42, 44 activation by Ucn-I via CRFR1 and CRFR2ß are both G_i and/or G_o protein dependent. Based on the data in this study, we present putative signaling pathways by which the CRF/Ucn family of peptides activate ERK1/2-p42, 44 by CRFRs.

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