doi: 10.1161/01.RES.0000087333.88497.AE
© 2003 American Heart Association, Inc.
Editorials |
Fill a Gab(1) in Cardiac Hypertrophy Signaling
Search a Missing Link Between gp130 and ERK5 in Hypertrophic Remodeling in Heart
From the Division of Molecular Medicine, Department of Anesthesiology and Medicine, University of California, David Geffen School of Medicine, Los Angles, Calif.
Correspondence to Yibin Wang, Division of Molecular Medicine, Department of Anesthesiology and Medicine, University of California, David Geffen School of Medicine, Los Angles, CA 90095. E-mail ywangibi{at}ucla.edu
Key Words: cardiac hypertrophy • Gab-1 • scaffold protein • cytokine signaling • extracellular signal-regulated kinase 5
Cardiac hypertrophy represents one of the most central issues in heart failure, involving many aspects of changes in cardiac myocyte from cellular morphology to gene expression and contractile function.1,2 Although the process is at the beginning compensatory in response to hemodynamic load or myocardial injury, cardiac hypertrophy is often followed by pathological remodeling in myocardium and a transition to overt heart failure.3 A large number of extracellular ligands, their cognate receptors and corresponding intracellular signal transduction pathways have been implicated in the hypertrophic process from both in vitro and in vivo studies.4–13 Among them, cardiotrophin-1 (CT-1) was discovered as a potent activator of cardiac hypertrophy14 that shares extensive sequence and functional similarities with leukemia inhibitory factor (LIF) as members of interleukin-6 (IL-6)–related cytokine family.15 LIF/CT-1 bind to gp130/LIF cytokine receptor ß heterodimer and activate downstream signaling pathways, including members of signal transducer and activator of transcription (STATs), mitogen-activated protein (MAP) kinases such as extracellular signal–regulated kinases (ERK1/2), and phosphatidylinositol 3-kinase (PI3K)/Akt.15,16 Studies have demonstrated that both LIF and CT-1 promote myocyte hypertrophy, survival, and a unique pattern of embryonic/fetal gene induction.17–22 LIF and CT-1 expression and gp130 signaling also correlated with mechanical stress in myocytes in culture23 and human and experimental models of heart failure.24–30 More significantly, targeted inactivation of gp130 in ventricular myocytes via Cre-loxP–mediated tissue-specific knockout resulted in rapid chamber dilation and a significant increase in myocyte apoptosis upon pressure overload.31 All these findings underscore the potential function of gp130 signaling in myocyte remodeling and survival in response to mechanical stress.
In addition to marker gene activation and antiapoptotic effects, gp130-mediated hypertrophy has a distinctive pattern of sarcomere organization. Unlike phenylephrine or endothelin-1 that induce hypertrophy response in cultured myocytes with enlarged cell size in all dimensions, LIF or CT-1 increases cell length by adding sarcomere units in a serial rather than parallel fashion.19 Such observation has prompted speculation that gp130 signaling may have a specific role in eccentric hypertrophy, a remodeling process more specifically associated with volume overload, as to concentric hypertrophy induced by pressure overload.1 A recent report by Nicol et al32 suggests that MEK5, an activator of big MAP kinase (BMK/ERK5), is capable to elicit serial assembly of sarcomere in myocytes and induces eccentric hypertrophy in transgenic hearts. They further demonstrate that MEK5/ERK5 is essential to LIF-induced myocyte elongation. However, the molecular mechanism underlying LIF/CT-1–induced MEK5/ERK5 activation via gp130 signal complex remains unclear. In this issue of Circulation Research, Nakaoka et al33 provide some interesting new evidence to suggest that a missing puzzle linking gp130 to MEK5/ERK5 pathway may have been found.
It should not be a surprise that Grb2-associated binder-1 (Gab-1) is a prime suspect in the search for a functional linker between gp130 and downstream MAP kinase activation. Gab-1 is a member of the Gab/DOS (daughter of sevenless) family of scaffolding/docking molecules and contains a pleckstrin homology (PH) domain and potential SH2/SH3 binding motifs.34,35 Tyrosine-phosphorylated Gab-1 can interact with a number of signaling molecules, including p85 PI3K, phospholipase C-
, and a src homology (SH) 2 domain–containing protein tyrosine phosphatase (SHP-2).36,37 Genetic inactivation Gab-1 leads to embryonic lethality and loss of ERK activation in response to growth factor stimulation, thus underscoring the importance of Gab-1 in MAP kinase activation via tyrosine kinase receptors and cytokine receptors.38 Since SHP-2 recruitment to gp130 is important to downstream MAP kinase activation,36 and SHP-2 is found to be a strong binding partner of Gab-1,35 it does not seem to be a far-fetched hunch that Gab-1 may also play a role in gp130-mediated MAP kinase activation in heart. In the present study,33 Nakaoka et al combined both biochemical and cellular studies to demonstrate that Gab-1 phosphorylation and SHP-2 binding were dependent on LIF stimulation and was required for ERK5 activation, selective marker gene regulation, and most interestingly sarcomere organization associated with myocyte elongation (Figure). In contrast, STAT3 activation was not affected by Gab-1/SHP-2 interaction, and activity of AKT and ERK1/2 was only partially affected, suggesting a rather specific role for Gab-1/SHP-2 interaction in gp130 dependent signaling in myocytes. This result is somewhat surprising because SHP-2 and JAK/STAT are shown to have reciprocal function downstream of gp130 and may reflect a unique signaling property in cardiomyocytes versus other cell types.39
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Although the findings of the present report are consistent with the hypothesis that Gab-1 serves as a scaffold protein to link SHP-2 and its downstream signaling partner(s) into a functional signaling complex, it will remain speculative until all of its molecular components can be identified. Indeed, identification of the interacting partners of Gab-1 in cardiomyocytes will help to address many related questions. For example, which upstream kinase is part of the signaling complex that is responsible for ERK5 activation, whether and how SHP-2 phosphatase activity mediates downstream kinase activation, whether and how Gab-1/SHP-2 interaction affects other tyrosine kinase receptor–mediated signaling pathways and other gp130-mediated signaling. Obviously, finding Gab-1 will lead to many more puzzle pieces involved in the signaling network of cardiac hypertrophy.
Perhaps an even more intriguing question from the present study is whether Gab-1/SHP-2 functions as a differential signaling switch that turns on eccentric hypertrophy. Since no effective therapy is available to treat this specific form of cardiomyopathy, the potential impact of identifying a responsible signaling pathway cannot be understated. A recent report from Yasukawa et al30 demonstrated that gp130-dependent signaling was highly induced by pressure overload along with a number of other signaling pathways, such as ERK1/2, p38, and AKT, but was negatively regulated by suppressor of cytokine signaling-3 (SOCS3), which was also induced by pressure overload and was capable of blocking almost all aspects of CT-1–induced myocyte hypertrophy. Furthermore, SOCS3 shares its preferred binding site on gp130 with the same docking site of SHP-2, suggesting that SOCS3 may compete and suppress Gab-1/SHP-2–mediated signaling from gp130 receptor.40 Therefore, in pressure-overloaded hearts, gp130-dependent signaling may have been suppressed by intrinsic inhibitor SOCS3 that channels the cardiac remodeling process toward a concentric form. By the same token, we can speculate that in volume-overloaded hearts, there might be a different balance between SOCS3 and Gab-1/SHP-2 signaling that favors ERK5 activation and leads to eccentric hypertrophy. Indeed, CT-1 has been found to be elevated in patients with valvular regurgitation but normal left ventricular systolic function.26 However, SOCS3 expression and the expression/phosphorylation/intracellular distribution of Gab-1 have not been fully characterized in an in vivo model of volume overload. Hopefully, the findings from Nakaoka et al33 will provide enough incentive and guidance to look into these questions in a relevant model system. Lastly, the study reported here represents only some preliminary investigation exclusively performed in cultured myocytes. Manipulation of Gab-1 expression and its interaction with SHP-2 in intact heart will be necessary to further establish its role in gp130-mediated cardiac remodeling. In that regard, sophisticated genetic approaches are already developed to achieve cardiac-specific and developmental stage–regulated manipulation to overcome embryonic lethality and to provide more concrete evidence for the physiological role of Gab-1 in cardiac hypertrophy.13 There is no doubt that future studies will lead us to more missing links in the complex signaling network of cardiac hypertrophy.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1. Lorell BH, Carabello BA. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation. 2000; 102: 470–479.
2. Houser SR, Piacentino V 3rd, Weisser J. Abnormalities of calcium cycling in the hypertrophied and failing heart. J Mol Cell Cardiol. 2000; 32: 1595–1607.[CrossRef][Medline] [Order article via Infotrieve]
3. Lorell BH. Transition from hypertrophy to failure. Circulation. 1997; 96: 3824–3827.[Medline] [Order article via Infotrieve]
4. Nicol RL, Frey N, Olson EN. From the sarcomere to the nucleus: role of genetics and signaling in structural heart disease. Annu Rev Genomics Hum Genet. 2000; 1: 179–223.[CrossRef][Medline] [Order article via Infotrieve]
5. Molkentin JD, Dorn IG 2nd. Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annu Rev Physiol. 2001; 63: 391–426.[CrossRef][Medline] [Order article via Infotrieve]
6. Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 2001; 81: 807–869.
7. Saito Y, Berk BC. Angiotensin II-mediated signal transduction pathways. Curr Hypertens Rep. 2002; 4: 167–171.[Medline] [Order article via Infotrieve]
8. Bueno OF, van Rooij E, Molkentin JD, Doevendans PA, De Windt LJ. Calcineurin and hypertrophic heart disease: novel insights and remaining questions. Cardiovasc Res. 2002; 53: 806–821.
9. Port JD, Bristow MR. Altered ß-adrenergic receptor gene regulation and signaling in chronic heart failure. J Mol Cell Cardiol. 2001; 33: 887–905.[CrossRef][Medline] [Order article via Infotrieve]
10. Zolk O, Kouchi I, Schnabel P, Bohm M. Heterotrimeric G proteins in heart disease. Can J Physiol Pharmacol. 2000; 78: 187–198.[CrossRef][Medline] [Order article via Infotrieve]
11. Yamauchi-Takihara K, Kishimoto T. A novel role for STAT3 in cardiac remodeling. Trends Cardiovasc Med. 2000; 10: 298–303.[CrossRef][Medline] [Order article via Infotrieve]
12. Wollert KC, Chien KR. Cardiotrophin-1 and the role of gp130-dependent signaling pathways in cardiac growth and development. J Mol Med. 1997; 75: 492–501.[CrossRef][Medline] [Order article via Infotrieve]
13. Wang Y. Signal transduction in cardiac hypertrophy: dissecting compensatory versus pathological pathways utilizing a transgenic approach. Curr Opin Pharmacol. 2001; 1: 134–140.[CrossRef][Medline] [Order article via Infotrieve]
14. Pennica D, King KL, Shaw KJ, Luis E, Rullamas J, Luoh SM, Darbonne WC, Knutzon DS, Yen R, Chien KR, et al. Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc Natl Acad Sci U S A. 1995; 92: 1142–1146.
15. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of IL-6-type cytokine signalling and its regulation. Biochem J. May 29, 2003; 10.1042/BJ20030407. Available at: http://www.biochemj.org. Accessed July 15, 2003.
16. Kamimura D, Ishihara K, Hirano T. IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev Physiol Biochem Pharmacol. In press.
17. Pennica D, Shaw KJ, Swanson TA, Moore MW, Shelton DL, Zioncheck KA, Rosenthal A, Taga T, Paoni NF, Wood WI. Cardiotrophin-1: biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex. J Biol Chem. 1995; 270: 10915–10922.
18. Jin H, Yang R, Keller GA, Ryan A, Ko A, Finkle D, Swanson TA, Li W, Pennica D, Wood WI, Paoni NF. In vivo effects of cardiotrophin-1. Cytokine. 1996; 8: 920–926.[CrossRef][Medline] [Order article via Infotrieve]
19. Wollert KC, Taga T, Saito M, Narazaki M, Kishimoto T, Glembotski CC, Vernallis AB, Heath JK, Pennica D, Wood WI, Chien KR. Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy: assembly of sarcomeric units in series VIA gp130/leukemia inhibitory factor receptor-dependent pathways. J Biol Chem. 1996; 271: 9535–9545.
20. Sheng Z, Knowlton K, Chen J, Hoshijima M, Brown JH, Chien KR. Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway: divergence from downstream CT-1 signals for myocardial cell hypertrophy. J Biol Chem. 1997; 272: 5783–5791.
21. Kuwahara K, Saito Y, Ogawa Y, Tamura N, Ishikawa M, Harada M, Ogawa E, Miyamoto Y, Hamanaka I, Kamitani S, Kajiyama N, Takahashi N, Nakagawa O, Masuda I, Nakao K. Endothelin-1 and cardiotrophin-1 induce brain natriuretic peptide gene expression by distinct transcriptional mechanisms. J Cardiovasc Pharmacol. 1998; 31 (suppl 1): S354–S356.[CrossRef][Medline] [Order article via Infotrieve]
22. Hirota H, Yoshida K, Kishimoto T, Taga T. Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci U S A. 1995; 92: 4862–4866.
23. Pan J, Fukuda K, Saito M, Matsuzaki J, Kodama H, Sano M, Takahashi T, Kato T, Ogawa S. Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. Circ Res. 1999; 84: 1127–1136.
24. Aoyama T, Takimoto Y, Pennica D, Inoue R, Shinoda E, Hattori R, Yui Y, Sasayama S. Augmented expression of cardiotrophin-1 and its receptor component, gp130, in both left and right ventricles after myocardial infarction in the rat. J Mol Cell Cardiol. 2000; 32: 1821–1830.[CrossRef][Medline] [Order article via Infotrieve]
25. Jougasaki M, Tachibana I, Luchner A, Leskinen H, Redfield MM, Burnett JC Jr. Augmented cardiac cardiotrophin-1 in experimental congestive heart failure. Circulation. 2000; 101: 14–17.
26. Talwar S, Squire IB, Davies JE, Ng LL. The effect of valvular regurgitation on plasma cardiotrophin-1 in patients with normal left ventricular systolic function. Eur J Heart Fail. 2000; 2: 387–391.
27. Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M, Tsutsui T, Ohnishi M, Fujii M, Matsumoto T, Yamamoto T, Wang X, Asai S, Tsuji T, Tanaka H, Saito Y, Kuwahara K, Nakao K, Kinoshita M. Relationship between plasma level of cardiotrophin-1 and left ventricular mass index in patients with dilated cardiomyopathy. J Am Coll Cardiol. 2001; 38: 1485–1490.
28. Ancey C, Corbi P, Froger J, Delwail A, Wijdenes J, Gascan H, Potreau D, Lecron JC. Secretion of IL-6, IL-11 and LIF by human cardiomyocytes in primary culture. Cytokine. 2002; 18: 199–205.[CrossRef][Medline] [Order article via Infotrieve]
29. Takimoto Y, Aoyama T, Iwanaga Y, Izumi T, Kihara Y, Pennica D, Sasayama S. Increased expression of cardiotrophin-1 during ventricular remodeling in hypertensive rats. Am J Physiol Heart Circ Physiol. 2002; 282: H896–H901.
30. Yasukawa H, Hoshijima M, Gu Y, Nakamura T, Pradervand S, Hanada T, Hanakawa Y, Yoshimura A, Ross J Jr, Chien KR. Suppressor of cytokine signaling-3 is a biomechanical stress-inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways. J Clin Invest. 2001; 108: 1459–1467.[CrossRef][Medline] [Order article via Infotrieve]
31. Hirota H, Chen J, Betz UA, Rajewsky K, Gu Y, Ross J Jr, Muller W, Chien KR. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell. 1999; 97: 189–198.[CrossRef][Medline] [Order article via Infotrieve]
32. Nicol RL, Frey N, Pearson G, Cobb M, Richardson J, Olson EN. Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy. EMBO J. 2001; 20: 2757–2767.[CrossRef][Medline] [Order article via Infotrieve]
33. Nakaoka Y, Nishida K, Fujio Y, Izumi M, Terai K, Oshima Y, Sugiyama S, Matsuda S, Koyasu S, Yamauchi-Takihara K, Hirano T, Kawase I, Hirota H. Activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes. Circ Res. 2003; 93: 221–229.
34. Liu Y, Rohrschneider LR. The gift of Gab. FEBS Lett. 2002; 515: 1–7.[CrossRef][Medline] [Order article via Infotrieve]
35. Hibi M, Hirano T. Gab-family adapter molecules in signal transduction of cytokine and growth factor receptors, and T and B cell antigen receptors. Leuk Lymphoma. 2000; 37: 299–307.[Medline] [Order article via Infotrieve]
36. Qu CK. The SHP-2 tyrosine phosphatase: signaling mechanisms and biological functions. Cell Res. 2000; 10: 279–288.[CrossRef][Medline] [Order article via Infotrieve]
37. Nishida K, Yoshida Y, Itoh M, Fukada T, Ohtani T, Shirogane T, Atsumi T, Takahashi-Tezuka M, Ishihara K, Hibi M, Hirano T. Gab-family adapter proteins act downstream of cytokine and growth factor receptors and T- and B-cell antigen receptors. Blood. 1999; 93: 1809–1816.
38. Itoh M, Yoshida Y, Nishida K, Narimatsu M, Hibi M, Hirano T. Role of Gab1 in heart, placenta, and skin development and growth factor- and cytokine-induced extracellular signal-regulated kinase mitogen-activated protein kinase activation. Mol Cell Biol. 2000; 20: 3695–3704.
39. Ohtani T, Ishihara K, Atsumi T, Nishida K, Kaneko Y, Miyata T, Itoh S, Narimatsu M, Maeda H, Fukada T, Itoh M, Okano H, Hibi M, Hirano T. Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3- and SHP2-mediated signals in immune responses. Immunity. 2000; 12: 95–105.[CrossRef][Medline] [Order article via Infotrieve]
40. Nicholson SE, De Souza D, Fabri LJ, Corbin J, Willson TA, Zhang JG, Silva A, Asimakis M, Farley A, Nash AD, Metcalf D, Hilton DJ, Nicola NA, Baca M. Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. Proc Natl Acad Sci U S A. 2000; 97: 6493–6498.
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