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Receptor-Extracellularly Regulated Kinase Signal Transduction Pathway: The Critical Role of Ser301 for Signaling Switch and Selectivity
Sir Quinton Hazell Molecular Medicine Research Centre (N.P., J.C., H.S.R., D.K.G.), Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom; Division of Pediatrics (M.A.L.), The Children’s Hospital of The Cleveland Clinic Foundation, Cleveland, Ohio 44195; and The Medical School (E.W.H.), University of Leeds, Leeds LS2 9NL, United Kingdom
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.
Activation of CRH receptors type 1 (CRH-R1) by CRH or urocortin (UCN) leads to stimulation of multiple G proteins with consequent effects on diverse signaling cascades in a tissue-specific manner. In human myometrium and human embryonic kidney (HEK)293 cells, binding of UCN to CRH-R1
receptors activates both the Gs and Gq, leading to activation of the adenylyl cyclase/protein kinase A (PKA) and the phospholipase C/protein kinase C and ERK1/2 signaling pathways, respectively. The overall result of these signals is often unpredictable, as these two signaling pathways can interact in many cellular systems, with either potentiation or inhibition of ERK1/2 activity. In the present studies we investigated potential signaling interactions after stimulation of CRH-R1 receptors in human cultured pregnant myometrial cells or HEK293 cells overexpressing recombinant CRH-R1 receptors. We found that the adenylyl cyclase/PKA pathway has the capacity to markedly decrease UCN-induced ERK1/2 activation, and that these effects were due in part to the ability of PKA to phosphorylate the CRH-R1 at position Ser301 in the third intracellular loop. Mutant CRH-R1 receptors with substitutions at position Ser301, which is the only potential PKA phosphorylation site, were resistant to PKA-dependent phosphorylation and showed altered signaling characteristics, which were dependent upon the amino acid substitution at this position.
We conclude that Ser301, which is located in the third intracellular loop of CRH-R1, is critical for efficient coupling of the receptor to G proteins and to second messenger generation. Phosphorylation by PKA prevents maximal coupling of the CRH-R1 to Gq-protein, and thereby reduces activation of ERK 1/2.
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