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Distinct pathways of ERK1/2 activation by hydroxy-carboxylic acid receptor-1

Mechanistic investigations have shown that, upon agonist activation, hydroxy-carboxylic acid receptor-1(HCA.sub.1) couples to a G.sub.i protein and inhibits adenylate cyclase activity, leading to inhibition of liberation of free fatty acid. However, the underlying molecular mechanisms for HCA.sub.1... Full description

Journal Title: PLoS ONE 01 January 2014, Vol.9(3), p.e93041
Main Author: Guo Li
Other Authors: Hui-Qian Wang , Li-Hui Wang , Ru-Ping Chen , Jun-Ping Liu
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0093041
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recordid: doaj_soai_doaj_org_article_42a9e9f6427748a2983488467b9b7e09
title: Distinct pathways of ERK1/2 activation by hydroxy-carboxylic acid receptor-1
format: Article
creator:
  • Guo Li
  • Hui-Qian Wang
  • Li-Hui Wang
  • Ru-Ping Chen
  • Jun-Ping Liu
subjects:
  • Sciences (General)
ispartof: PLoS ONE, 01 January 2014, Vol.9(3), p.e93041
description: Mechanistic investigations have shown that, upon agonist activation, hydroxy-carboxylic acid receptor-1(HCA.sub.1) couples to a G.sub.i protein and inhibits adenylate cyclase activity, leading to inhibition of liberation of free fatty acid. However, the underlying molecular mechanisms for HCA.sub.1 signaling remain largely unknown. Using CHO-K1 cells stably expressing HCA.sub.1, and L6 cells, which endogenously express rat HCA.sub.1 receptors, we found that activation of ERK1/2 by HCA.sub.1 was rapid, peaking at 5 min, and was significantly blocked by pertussis toxin. Furthermore, time course experiments with different kinase inhibitors demonstrated that HCA.sub.1 induced ERK1/2 activation via the extracellular Ca.sup.2+, PKC and IGF-I receptor transactivation-dependent pathways. In addition, we observed that pretreated the cells with M119K, an inhibitor of G.sub.[beta][gamma] subunit-dependent signaling, effectively attenuated the ERK1/2 activation triggered by HCA.sub.1, suggesting a critical role for [beta][gamma]-subunits in HCA.sub.1 -activated ERK1/2 phosphorylation. Furthermore, the present results also indicated that the arrestin2/3 were not required for ERK1/2 activation. In conclusion, our findings demonstrate that upon binding to agonist, HCA.sub.1 receptors initially activate G.sub.i, leading to dissociation of the G.sub.[beta][gamma] subunit from activated G.sub.i, and subsequently induce ERK1/2 activation via two distinct pathways: one PKC-dependent pathway and the other IGF-IR transactivation-dependent pathway. Our results provide the first in-depth evidence that defines the molecular mechanism of HCA.sub.1 -mediated ERK1/2 activation.
language: eng
source:
identifier: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0093041
fulltext: fulltext_linktorsrc
issn:
  • 1932-6203
  • 19326203
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descriptionMechanistic investigations have shown that, upon agonist activation, hydroxy-carboxylic acid receptor-1(HCA.sub.1) couples to a G.sub.i protein and inhibits adenylate cyclase activity, leading to inhibition of liberation of free fatty acid. However, the underlying molecular mechanisms for HCA.sub.1 signaling remain largely unknown. Using CHO-K1 cells stably expressing HCA.sub.1, and L6 cells, which endogenously express rat HCA.sub.1 receptors, we found that activation of ERK1/2 by HCA.sub.1 was rapid, peaking at 5 min, and was significantly blocked by pertussis toxin. Furthermore, time course experiments with different kinase inhibitors demonstrated that HCA.sub.1 induced ERK1/2 activation via the extracellular Ca.sup.2+, PKC and IGF-I receptor transactivation-dependent pathways. In addition, we observed that pretreated the cells with M119K, an inhibitor of G.sub.[beta][gamma] subunit-dependent signaling, effectively attenuated the ERK1/2 activation triggered by HCA.sub.1, suggesting a critical role for [beta][gamma]-subunits in HCA.sub.1 -activated ERK1/2 phosphorylation. Furthermore, the present results also indicated that the arrestin2/3 were not required for ERK1/2 activation. In conclusion, our findings demonstrate that upon binding to agonist, HCA.sub.1 receptors initially activate G.sub.i, leading to dissociation of the G.sub.[beta][gamma] subunit from activated G.sub.i, and subsequently induce ERK1/2 activation via two distinct pathways: one PKC-dependent pathway and the other IGF-IR transactivation-dependent pathway. Our results provide the first in-depth evidence that defines the molecular mechanism of HCA.sub.1 -mediated ERK1/2 activation.
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Mechanistic investigations have shown that, upon agonist activation, hydroxy-carboxylic acid receptor-1(HCA1) couples to a Gi protein and inhibits adenylate cyclase activity, leading to inhibition of liberation of free fatty acid. However, the underlying molecular mechanisms for HCA1 signaling remain largely unknown. Using CHO-K1 cells stably expressing HCA1, and L6 cells, which endogenously express rat HCA1 receptors, we found that activation of ERK1/2 by HCA1 was rapid, peaking at 5 min, and was significantly blocked by pertussis toxin. Furthermore, time course experiments with different kinase inhibitors demonstrated that HCA1 induced ERK1/2 activation via the extracellular Ca2+, PKC and IGF-I receptor transactivation-dependent pathways. In addition, we observed that pretreated the cells with M119K, an inhibitor of Gβγ subunit-dependent signaling, effectively attenuated the ERK1/2 activation triggered by HCA1, suggesting a critical role for βγ-subunits in HCA1-activated ERK1/2...

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Mechanistic investigations have shown that, upon agonist activation, hydroxy-carboxylic acid receptor-1(HCA1) couples to a Gi protein and inhibits adenylate cyclase activity, leading to inhibition of liberation of free fatty acid. However, the underlying molecular mechanisms for HCA1 signaling remain largely unknown. Using CHO-K1 cells stably expressing HCA1, and L6 cells, which endogenously express rat HCA1 receptors, we found that activation of ERK1/2 by HCA1 was rapid, peaking at 5 min, and was significantly blocked by pertussis toxin. Furthermore, time course experiments with different kinase inhibitors demonstrated that HCA1 induced ERK1/2 activation via the extracellular Ca2+, PKC and IGF-I receptor transactivation-dependent pathways. In addition, we observed that pretreated the cells with M119K, an inhibitor of Gβγ subunit-dependent signaling, effectively attenuated the ERK1/2 activation triggered by HCA1, suggesting a critical role for βγ-subunits in HCA1-activated ERK1/2...

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