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This version published online on December 11, 2003
Endocrinology, doi:10.1210/en.2003-1023
A more recent version of this article appeared on April 1, 2004
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Submitted on August 8, 2003
Accepted on December 5, 2003

Specificity and regulation of ERK1/2 phosphorylation through CRF receptors 1 and 2{beta} by the CRF/Ucn family of peptides

Bhawanjit K. Brar1, Alon Chen1, Marilyn H. Perrin1, and Wylie Vale1*

1 The Clayton Laboratories for Peptide Biology, The Salk Institute For Biological Studies, La Jolla, CA, 92037

* To whom correspondence should be addressed. E-mail: vale{at}salk.edu.

Corticotropin releasing factor (CRF) receptor mediated activation of the extracellular receptor kinases (ERK1/2-p42, 44) has been reported for CRF, urocortin (Ucn-I) and sauvagine. Recently, two new members of the CRF/urocortin family of peptides have been identified, urocortin II(Ucn-II)/stresscopin related peptide and urocortin III(Ucn-III)/stresscopin. Using Chinese hamster ovary cells (CHO) stably expressing CRFR1 and CRFR2{beta}, we show that Ucn-I, Ucn-II and Ucn-III activate ERK1/2-p42, 44 via CRFR2{beta}. CRF and Ucn-I, but not Ucn-II or Ucn-III activates ERK1/2-p42, 44 in CHO cells stably expressing CRFR1. The selectivity of the ligands for CRFR1 and CRFR2{beta} is shown in a time and dose dependent manner. The regulatory mechanisms for ERK1/2-p42, 44 activation by both receptor types are dependent upon phosphatidylinositol (PI)-3 OH kinase, mitogen activated protein kinase kinase (MEK1), 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 CRFR2{beta}. 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 Gi and Go protein inhibitor pertussis toxin showed that ERK1/2-p42, 44 activation by Ucn-I via CRFR1 and CRFR2{beta} are both Gi and/or Go 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 CRF receptors.
Key words: CRF • Ucn-I • Ucn-II • Ucn-III and CRF receptors




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