ERK5 Activation by Gq-Coupled Muscarinic Receptors Is Independent of Receptor Internalization and β-Arrestin Recruitment

被引:9
作者
Sanchez-Fernandez, Guzman [1 ,2 ,3 ]
Cabezudo, Sofia [1 ,2 ,3 ]
Garcia-Hoz, Carlota [1 ,2 ,3 ]
Tobin, Andrew B. [4 ]
Mayor, Federico, Jr. [1 ,2 ,3 ]
Ribas, Catalina [1 ,2 ,3 ]
机构
[1] Univ Autonoma Madrid, UAM CSIC, Dept Biol Mol, Madrid, Spain
[2] Univ Autonoma Madrid, UAM CSIC, Ctr Biol Mol Severo Ochoa, Madrid, Spain
[3] Inst Invest Sanitaria La Princesa, Madrid, Spain
[4] Univ Leicester, Med Res Council Toxicol Unit, Leicester, Leics, England
来源
PLOS ONE | 2013年 / 8卷 / 12期
关键词
GROWTH-FACTOR RECEPTOR; PROTEIN; TRAFFICKING; ENDOCYTOSIS; G-ALPHA(Q); PATHWAY; BETA-ARRESTIN-2; CELLS; GPCR;
D O I
10.1371/journal.pone.0084174
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
G-protein-coupled receptors (GPCRs) are known to activate both G protein- and beta-arrestin-dependent signalling cascades. The initiation of mitogen-activated protein kinase (MAPK) pathways is a key downstream event in the control of cellular functions including proliferation, differentiation, migration and apoptosis. Both G proteins and beta-arrestins have been reported to mediate context-specific activation of ERK1/2, p38 and JNK MAPKs. Recently, the activation of ERK5 MAPK by Gq-coupled receptors has been described to involve a direct interaction between Gaq and two novel effectors, PKC zeta and MEK5. However, the possible contribution of beta-arrestin towards this pathway has not yet been addressed. In the present work we sought to investigate the role of receptor internalization processes and beta-arrestin recruitment in the activation of ERK5 by Gq-coupled GPCRs. Our results show that ERK5 activation is independent of M1 or M3 muscarinic receptor internalization. Furthermore, we demonstrate that phosphorylation-deficient muscarinic M1 and M3 receptors are still able to fully activate the ERK5 pathway, despite their reported inability to recruit beta-arrestins. Indeed, the overexpression of Gaq, but not that of beta-arrestin1 or beta-arrestin2, was found to potently enhance ERK5 activation by GPCRs, whereas silencing of beta-arrestin2 expression did not affect the activation of this pathway. Finally, we show that a beta-arrestin-biased mutant form of angiotensin II (SII; Sar1-Ile4-Ile8 AngII) failed to promote ERK5 phosphorylation in primary cardiac fibroblasts, as compared to the natural ligand. Overall, this study shows that the activation of ERK5 MAPK by model Gq-coupled GPCRs does not depend on receptor internalization, beta-arrestin recruitment or receptor phosphorylation but rather is dependent on Gaq-signalling.
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页数:8
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