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A New Gq-Initiated MAPK Signaling Pathway in the Heart

2009; Elsevier BV; Volume: 16; Issue: 2 Linguagem: Inglês

10.1016/j.devcel.2009.01.021

1878-1551

J. Silvio Gutkind, Stefan Offermanns,

Viral Infectious Diseases and Gene Expression in Insects

Pathological cardiac hypertrophy involves auto/paracrine mediators acting through Gq/11-coupled receptors. A novel signaling route stimulated by βγ-subunits of Gq/11 results in the autophosphorylation of ERK1/2 on a new site and the nuclear retention of ERK1/2, thereby activating hypertrophic gene programs. Pathological cardiac hypertrophy involves auto/paracrine mediators acting through Gq/11-coupled receptors. A novel signaling route stimulated by βγ-subunits of Gq/11 results in the autophosphorylation of ERK1/2 on a new site and the nuclear retention of ERK1/2, thereby activating hypertrophic gene programs. Myocardial hypertrophy is an adaptational response of the heart to increased work load that involves enhanced protein synthesis and an increase in size of individual cardiomyocytes. However, under pathological conditions such as hypertension or after myocardial infarction maladaptive cardiac hypertrophy can result in tissue fibrosis and is associated with a high risk of mortality due to heart failure and arrhythmia (Hill and Olson, 2008Hill J.A. Olson E.N. N. Engl. J. Med. 2008; 358: 1370-1380Crossref PubMed Scopus (802) Google Scholar). Multiple growth factor receptors and their downstream signaling pathways—including the activation of Ras and Rho GTPases, various mitogen-activated protein kinase (MAPK) cascades, and a multitude of calcium-dependent regulators such as calcineurin, CaM-kinases, and the transcription factor NFAT—have been all implicated in cardiac hypertrophy (Clerk and Sugden, 2000Clerk A. Sugden P.H. Circ. Res. 2000; 86: 1019-1023Crossref PubMed Scopus (129) Google Scholar, Heineke and Molkentin, 2006Heineke J. Molkentin J.D. Nat. Rev. Mol. Cell Biol. 2006; 7: 589-600Crossref PubMed Scopus (1401) Google Scholar, Hill and Olson, 2008Hill J.A. Olson E.N. N. Engl. J. Med. 2008; 358: 1370-1380Crossref PubMed Scopus (802) Google Scholar). Accumulating evidence indicates that the initial phase in the development of maladaptive myocardial hypertrophy involves the production of cardiac para- and/or autocrine factors like endothelin-1, norepinephrine, and angiotensin II, all of which act on cognate receptors expressed in the myocardium (Clerk and Sugden, 2000Clerk A. Sugden P.H. Circ. Res. 2000; 86: 1019-1023Crossref PubMed Scopus (129) Google Scholar, Heineke and Molkentin, 2006Heineke J. Molkentin J.D. Nat. Rev. Mol. Cell Biol. 2006; 7: 589-600Crossref PubMed Scopus (1401) Google Scholar, Hill and Olson, 2008Hill J.A. Olson E.N. N. Engl. J. Med. 2008; 358: 1370-1380Crossref PubMed Scopus (802) Google Scholar). These receptors belong to the large family of cell surface molecules that initiate signal transmission by stimulating heterotrimeric G proteins of the Gq/11, G12/13, and Gi/o families. Aligned with these observations, the cardiomyocyte-specific transgenic overexpression of some of these G protein-coupled receptors (GPCRs), such as α1-adrenergic and angiotensin (AT1) receptors, or activated mutants of their coupled G protein α-subunits, Gαq, results in myocardial hypertrophy (Dorn and Brown, 1999Dorn G.W. Brown J.H. Trends Cardiovasc. Med. 1999; 9: 26-34Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). Furthermore, mice lacking both Gαq and Gα11 in cardiomyocytes are protected from cardiac hypertrophy in response to pressure overload (Wettschureck et al., 2001Wettschureck N. Rutten H. Zywietz A. Gehring D. Wilkie T.M. Chen J. Chien K.R. Offermanns S. Nat. Med. 2001; 7: 1236-1240Crossref PubMed Scopus (301) Google Scholar). Taken together, these findings suggest that chronic activation of Gq and G11 and their downstream signaling pathways is necessary and sufficient for myocardial hypertrophy. However, the nature of the molecular mechanisms deployed by these heterotrimeric G proteins and their coupled receptors to initiate a hypertrophic response in the myocardium are still not fully understood (Figure 1). In this regard, a recent study by Lorenz et al., 2009Lorenz K. Schmitt J.P. Schmitteckert E.M. Lohse M.J. Nat. Med. 2009; 15: 75-83Crossref PubMed Scopus (153) Google Scholar, provided evidence that this process involves a novel signaling route initiated by Gq/11. Here, ERK1/2 autophosphorylation on a previously undescribed site, threonine 188 (Thr188), results in the translocation of ERK1/2 to the nucleus and the persistent activation of ERK1/2-dependent nuclear events that contribute to cardiac hypertrophy. At the molecular level, Lorenz et al., 2009Lorenz K. Schmitt J.P. Schmitteckert E.M. Lohse M.J. Nat. Med. 2009; 15: 75-83Crossref PubMed Scopus (153) Google Scholar showed that GPCRs coupled to Gq/11 cause the activation and Thr188 phosphorylation of ERK1/2 by a two-pronged mechanism. Upon agonist activation of Gq-coupled receptors, the Gαq subunit stimulates the Raf1/MEK/ERK1/2 pathway, reflected by the accumulation of ERK1/2 phosphorylated in the ThrGluTyr (TEY) motif within its activation loop (Turjanski et al., 2007Turjanski A.G. Vaque J.P. Gutkind J.S. Oncogene. 2007; 26: 3240-3253Crossref PubMed Scopus (316) Google Scholar and references therein). Concomitantly, the βγ subunits released from Gq/11 associate with the Raf1/MEK/ERK1/2 complex, enhancing the efficiency of ERK1/2 activation and favoring the intermolecular autophosphorylation of ERK1/2 on its Thr188 (Lorenz et al., 2009Lorenz K. Schmitt J.P. Schmitteckert E.M. Lohse M.J. Nat. Med. 2009; 15: 75-83Crossref PubMed Scopus (153) Google Scholar). The presence of Thr188 phosphorylated ERK1/2 was detected in experimental animal models of cardiac hypertrophy, and readily observed in failing, hypertrophic human hearts, supporting the clinical relevance of these findings. In contrast to the phosphorylation of the TEY motif, phosphorylation of Thr188 was not required for ERK1/2 activation but led to prolonged nuclear retention, thus enhancing its ability to phosphorylate its nuclear targets involved in the initiation of a hypertrophic gene program. Indeed, elegant studies involving the transgenic expression of mutant forms of ERK2 showed that mice expressing a "phosphorylation mimic" Thr188Asp mutant are more sensitive to the development of cardiac hypertrophy and fibrosis in response to pressure overload caused by transverse aortic constriction (Lorenz et al., 2009Lorenz K. Schmitt J.P. Schmitteckert E.M. Lohse M.J. Nat. Med. 2009; 15: 75-83Crossref PubMed Scopus (153) Google Scholar). In contrast, mice expressing a nonphosphorylatable Thr188Ala mutant were partially protected from pressure-induced cardiac hypertrophy. Surprisingly, substitution of Thr188 for Ser had a similar mild protective effect, suggesting that Thr and Ser are not interchangeable and that perhaps Ser may not represent an effective substrate for intermolecular phosphorylation on ERK1/2. Overall, these studies provide additional mechanistic insight and support the relevance of the novel Gq/11-ERK1/2 pathway in pressure-overload-induced myocardial hypertrophy in vivo. With respect to the signal specificity of these events, Lorenz et al. observed that Gβγ dimers released from Gq can cause ERK Thr188 phosphorylation, while Gβγ dimers released from Gi could not, in spite of stimulating ERK1/2 activation effectively. It is conceivable that different Gβγ dimers may exert distinct functions or that pathways mediated by different G-proteins are compartmentalized; however, it is also plausible that the activation of Gq/11 α-subunits and their diverse downstream targets may dictate the specificity of Gβγ function. For example, Gαq/11-initiated pathways may control the access of Gβγ to the Raf1/MEK/ERK1/2 complex, or regulate the subcellular distribution and function of the multitude of scaffolding molecules, kinases, and phosphatases that regulate the ERK1/2 MAPK cascade (Turjanski et al., 2007Turjanski A.G. Vaque J.P. Gutkind J.S. Oncogene. 2007; 26: 3240-3253Crossref PubMed Scopus (316) Google Scholar). Indeed, other Gq/11 targets, such as RhoA, phospholipase C-β, phospholipase C-ɛ, and the JNK, p38, and ERK5 MAPK cascades can all regulate gene expression in cardiomyocytes and contribute to cardiac hypertrophy (Clerk and Sugden, 2000Clerk A. Sugden P.H. Circ. Res. 2000; 86: 1019-1023Crossref PubMed Scopus (129) Google Scholar, Frey and Olson, 2003Frey N. Olson E.N. Annu. Rev. Physiol. 2003; 65: 45-79Crossref PubMed Scopus (1108) Google Scholar, Heineke and Molkentin, 2006Heineke J. Molkentin J.D. Nat. Rev. Mol. Cell Biol. 2006; 7: 589-600Crossref PubMed Scopus (1401) Google Scholar, Hill and Olson, 2008Hill J.A. Olson E.N. N. Engl. J. Med. 2008; 358: 1370-1380Crossref PubMed Scopus (802) Google Scholar). These changes in gene expression may serve as a prerequisite for Gβγ-dependent ERK1/2 Thr188 phosphorylation. They may also function in parallel to it. Although the Raf1/MEK/ERK1/2 cascade plays a prominent role in cardiac hypertrophy, its activation may not always be strictly required (Heineke and Molkentin, 2006Heineke J. Molkentin J.D. Nat. Rev. Mol. Cell Biol. 2006; 7: 589-600Crossref PubMed Scopus (1401) Google Scholar, Lorenz et al., 2009Lorenz K. Schmitt J.P. Schmitteckert E.M. Lohse M.J. Nat. Med. 2009; 15: 75-83Crossref PubMed Scopus (153) Google Scholar, and references therein). Thus, in addition to enabling ERK1/2 Thr188 phosphorylation, the aberrant activation of Gq/11-regulated pathways, if persistent, may circumvent the strict requirement of ERK1/2 stimulation to mount a cardiac hypertrophic response. It will therefore be interesting to explore whether manipulation of the complex interplay among these diverse signaling events downstream of Gq/11 will offer novel targets for pharmacological intervention to prevent heart failure, one of the leading causes of death in developed countries. It is worth noting that ERK1/2 phospho-Thr188 may also contribute to the activation of growth promoting and transforming pathways initiated by Gq/11 in other contexts (Dorsam and Gutkind, 2007Dorsam R.T. Gutkind J.S. Nat. Rev. Cancer. 2007; 7: 79-94Crossref PubMed Scopus (902) Google Scholar). In addition, polypeptide growth factors acting on tyrosine kinase receptors appear to stimulate this novel Gq/11-ERK1/2 pathway by a still incompletely understood mechanism (Lorenz et al., 2009Lorenz K. Schmitt J.P. Schmitteckert E.M. Lohse M.J. Nat. Med. 2009; 15: 75-83Crossref PubMed Scopus (153) Google Scholar). Further study of these intriguing possibilities will certainly represent an exciting area for future exploration.