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Cellular Biology |
From the Departments of Molecular Medicine (Y.N., M.I., K.T., Y.O., S.S., K.Y.-T., I.K., H.H.) and Molecular Oncology (T.H.), Osaka University Graduate School of Medicine, Osaka, Japan; Laboratory for Cytokine Signaling (K.N., T.H.), RIKEN Research Center for Allergy and Immunology, Kanagawa, Japan; Department of Clinical Evaluation of Medicines and Therapeutics (Y.F.), Osaka University Graduate School of Pharmaceutical Sciences, Osaka, Japan; Department of Microbiology and Immunology (S.M., S.K.), Keio University School of Medicine, Tokyo, Japan; Core Research for Evolutional Science and Technology (CREST) (S.M., S.K.), Japan Science and Technology Corporation, Saitama, Japan; and Laboratory for Developmental Immunology (T.H.), Osaka University Graduate School of Frontier Bioscience, Osaka, Japan.
Correspondence to Hisao Hirota, MD, PhD, Assistant Professor, Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita City, Osaka, 565-0871, Japan. E-mail hirota{at}imed3.med.osaka-u.ac.jp
| Abstract |
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-actin mRNA expression through interaction with SHP2. Furthermore, activation of extracellular signalregulated kinase 5 (ERK5) was enhanced in cardiomyocytes infected with AdGab1WT compared with cardiomyocytes infected with Adß-gal but repressed in cardiomyocytes infected with AdGab1F627/659. Coinfection of AdGab1WT with adenovirus vector carrying dominant-negative ERK5 abrogated longitudinal elongation of cardiomyocytes induced by LIF. Taken together, these findings indicate that Gab1-SHP2 interaction plays a crucial role in gp130-dependent longitudinal elongation of cardiomyoctes through activation of ERK5.
Key Words: hypertrophy Gab1 SHP2 gp130 ERK5
| Introduction |
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Gab1 interacts with multiple signaling molecules, such as protein tyrosine phosphatase SHP2, p85 phosphatidylinositol 3-kinase, phospholipase C-
, and Grb2.36 Among these, the major binding partner of Gab1 in cells stimulated with growth factors and cytokines is SHP2, a ubiquitously expressed protein tyrosine phosphatase with two SH2 domains.8 Two tyrosine residues located in the most C-terminal ends of the Gab family proteins have been reported to fall within consensus binding motifs (YXXV/I/L) for SHP2 on tyrosine phosphorylation.912 The functional significance of Gab1-SHP2 interaction has been extensively studied using mutants of Gab1 unable to bind SHP2 in vitro and in vivo. The Gab1 mutant unable to bind SHP2 is defective in delivering signals for Met-dependent morphogenesis and for epidermal growth factor (EGF)-dependent epidermal proliferation and also blocks extracellular signal-regulated kinase 1/2 (ERK1/2) activation by EGF and lysophosphatidic acid.914 These findings underscore the importance of Gab1-SHP2 interaction and strongly suggest that the primary role of Gab1 might be to recruit SHP2.
To reveal the functional role of Gab1 in vivo, we and others generated mice lacking Gab1 by gene targeting.15,16 Gab1-deficient mice died in utero and displayed developmental defects in the heart, placenta, liver, and skin. Gab1 was highly expressed in embryonic heart from E10.5 to E13.5. The ventricular chamber displayed dilatation, and the ventricular wall was extremely thin in all of the Gab1-/- embryos that survived past E13.5.15 These findings indicate that Gab1 is necessary for development of the heart.
Leukemia inhibitory factor (LIF) and cardiotrophin-1 (CT-1) are interleukin-6 (IL-6)-related cytokines and bind to a heterodimer of gp130 and LIF receptor ß.17,18 LIF and CT-1 are potent inducers of cardiomyocyte hypertrophy and also serve as myocyte survival factors in vitro and in vivo.1924 The hypertrophic response in cardiomyocytes induced by LIF and CT-1 is distinct from the hypertrophic response observed after GPCR stimulation.20 Adrenergic agonists, endothelin-1 (ET-1), and angiotensin II (Ang II) binding to GPCR induce a rather uniform increase in cardiomyocyte size, resulting from the addition of myofibrils in parallel.2527 In contrast, LIF and CT-1 induce a predominant increase in cell length with the addition of new sarcomeric units in series.20 Interestingly, recent reports have shown that the mitogen-activated protein kinase (MAPK) kinase 5 (MEK5)-MAPK extracellular signal-regulated kinase 5 (ERK5) pathway plays a critical role in gp130-mediated eccentric cardiac hypertrophy in vitro and in vivo.28
In this study, we found that Gab1 was tyrosine phosphorylated and associated with SHP2 after stimulation with LIF in cardiomyocytes. It was also revealed that Gab1 plays a critical role in elongation of cardiomyocytes induced by LIF through interaction with SHP2, using adenovirus vectors expressing wild-type Gab1 and mutated Gab1, which could not bind SHP2. In addition, we found that the interaction of Gab1 with SHP2 is involved not only in the regulation of brain natriuretic polypeptide (BNP) and skeletal
-actin (SKA) gene expression but also in the activation of ERK5 after stimulation with LIF in cardiomyocytes. Furthermore, dual infection of adenovirus vectors carrying wild-type Gab1 and dominant-negative ERK5 abrogated elongation of cardiomyocytes induced by LIF, suggesting that ERK5 may be an essential component of gp130-dependent cardiomyocyte hypertrophy through Gab1-SHP2 interaction.
| Materials and Methods |
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Cell Culture and Protocol for Adenovirus Infection
Primary cultures of neonatal rat cardiomyocytes were prepared from ventricles of 1-day-old Wistar rats (Kiwa Jikken Dobutsu) as described previously.31 At 16 hours after plating, cardiomyocytes were infected with adenovirus diluted in Medium-199 with 2% FBS at a multiplicity of infection (moi) of 20 and incubated for 8 hours. In the dual infection of adenovirus vectors, cardiomyocytes were infected with each virus at an moi of 10. After removal of viral suspension, cardiomyocytes were serum starved for 16 hours and stimulated with reagents. Infection efficiency, determined by lacZ gene expression in cultured cardiomyocytes, is consistently >90% with this method. Adenovirus vector expressing ß-galactosidase (Adß-gal) was used as a control.
Immunoprecipitation and Immunoblotting
The methods of immunoprecipitation were essentially as described previously.5 After stimulation, cells were immediately lysed in lysis buffer (20 mmol/L Tris-HCl [pH 7.4], 150 mmol/L NaCl, 1% Nonidet P-40, 500 µmol/L sodium vanadate, 1 mmol/L dithiothreitol, 5 µg/mL aprotinin, 5 µg/mL leupeptin, and 1 mmol/L phenylmethylsulfonyl fluoride). The cleared lysates were incubated with 2 µL of anti-Gab1 serum or 4 µL of anti-SHP2 antibody and 20 µL of protein A-Sepharose for 12 hours at 4°C. Collected immune complexes were eluted with 20 µL of 2xLaemmlis SDS loading buffer, separated on a 4% to 20% gradient polyacrylamide gel (Dai-ichi Kagaku), electrotransferred to a polyvinylidene difluoride membrane (Immobilon-P; Millipore), and processed for immunoblotting analysis essentially as described previously.5 The ECL system was used for detection.
Northern Blot Analysis
Northern blot analysis was performed as previously described.21 Total cellular RNA (8 µg) was loaded in each lane and size fractionated by 1% formaldehyde-agarose gel electrophoresis. The probes for BNP, SKA, and GAPDH were kindly donated by Dr K.R. Chien (University of California, San Diego, Calif).
Immunofluorescence
For immunofluorescence, cardiomyocytes were grown on glass coverslips coated with gelatin. Cells were incubated in the presence or absence of LIF 1x103 U/mL for 24 hours. Cells were fixed with 2% formaldehyde and permeabilized with 0.1% Triton X-100. Cells were incubated with monoclonal anti-sarcomeric
-actinin antibody, followed by incubation with fluorescein-conjugated goat anti-mouse secondary antibody. Cardiomyocytes stained against sarcomeric
-actinin were viewed by fluorescence microscopy. Cell size was estimated by measuring the area over which individual sarcomeric
-actininpositive cells had attached (planimetry), and cell length and cell width were determined as described previously.20
Statistics
Statistical analysis was performed with Students t test. Values of P<0.05 were considered significant.
An expanded Materials and Methods section can be found in the online data supplement available at http://www.circresaha.org.
| Results |
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Gab1 was tyrosine phosphorylated by LIF in a time-dependent and dose-dependent manner (Figures 2A and 2B). SHP2 was also tyrosine phosphorylated by LIF in a time-dependent and dose-dependent manner (Figures 2C and 2D). To elucidate the association of Gab1 with other SH2-containing molecules, cell lysates from cardiomyocytes treated with LIF were immunoprecipitated with anti-Gab1 serum and subjected to immunoblotting with anti-SHP2 and anti-p85 antibodies. SHP2 and p85 were coprecipitated with Gab1 in response to LIF (Figure 2E). Gab1 was also coprecipitated with SHP2 by the immunoprecipitation with anti-SHP2 antibody (Figure 2F). These results demonstrated that LIF induced tyrosine phosphorylation of Gab1, leading to association of Gab1 with SHP2 and p85 in cardiomyocytes.
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Tyrosine Phosphorylation of Gab1 and Association of Gab1 With SHP2 in AdGab1WT or AdGab1F627/659-Treated Cardiomyocytes
We constructed recombinant adenovirus vectors expressing Gab1WT and Gab1F627/659. Figure 3A shows a schematic representation of these adenovirus vectors, which are named AdGab1WT and AdGab1F627/659. We examined tyrosine phosphorylation of Gab1 in Adß-galtreated, AdGab1WTtreated, or AdGab1F627/659-treated cardiomyocytes. As shown in Figure 3B, tyrosine phosphorylation of Gab1 and the amount of coprecipitated SHP2 with Gab1 were increased in AdGab1WT-treated cardiomyocytes after LIF stimulation, compared with Adß-galtreated cardiomyocytes. In AdGab1F627/659-treated cardiomyocytes, tyrosine phosphorylation of Gab1 was observed in the same manner as in AdGab1WT-treated cardiomyocytes, but SHP2 was not coprecipitated with Gab1. As shown in Figure 3C, Gab1 was not coprecipitated with SHP2 in AdGab1F627/659-treated cardiomyocytes. These results indicate that Gab1WT and Gab1F627/659, which were overexpressed through adenovirus-mediated gene transfer, could function effectively in cardiomyocytes.
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Elongation of Cardiomyocytes Induced by LIF Is Enhanced in AdGab1WT-Treated Cardiomyocytes but Suppressed in AdGab1F627/659-Treated Cardiomyocytes
To elucidate the biological roles of Gab1 in gp130-signaling pathway in cardiomyocytes, we examined the morphological effects of Gab1WT and Gab1F627/659 on cardiomyocyte hypertrophy in response to LIF. As shown in Figures 4A and 4D, LIF induced longitudinal elongation in Adß-galtreated cardiomyocytes. In AdGab1WT-treated cardiomyocytes, elongation of cardiomyocytes induced by LIF was enhanced compared with Adß-galtreated cardiomyocytes (Figures 4B and 4E). On the contrary, in cardiomyocytes expressing Gab1F627/659, this morphological change was significantly inhibited (Figures 4C and 4F).
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We quantified the cell surface area of cardiomyocytes infected with these adenovirus vectors. As shown in Figure 4G, LIF increased cell surface area by 70% in Adß-galtreated or AdGab1WT-treated cardiomyocytes. However, in AdGab1F627/659-treated cardiomyocytes, the increase in cell surface area induced by LIF was almost abolished. To characterize the hypertrophic phenotype of these cardiomyocytes, we measured cell length and cell width according to a previously reported method.20 As shown in Figure 4H, cell length was significantly increased in AdGab1WT-treated cardiomyocytes, compared with that in Adß-galtreated cardiomyocytes. In contrast, increase in cell length was significantly suppressed in AdGab1F627/659-treated cardiomyocytes. Cell width was significantly decreased in response to LIF in AdGab1WT-treated cardiomyocytes but not altered in Adß-galtreated or AdGab1F627/659-treated cardiomyocytes (Figure 4I). Compared with Adß-galtreated cardiomyocytes, the cell length to width ratio was significantly increased in AdGab1WT-treated cardiomyocytes but suppressed significantly in AdGab1F627/659-treated cardiomyocytes (Figure 4J). These findings indicate that elongation of cardiomyocytes in response to LIF is enhanced by overexpression of Gab1WT but suppressed by that of Gab1F627/659, suggesting that the interaction of Gab1 with SHP2 plays a crucial role in longitudinal elongation of cardiomyocytes in response to LIF.
Gab1 Regulates LIF-Induced Embryonic Gene Expression Through Interaction With SHP2
Reactivation of embryonic phenotype genes, such as atrial natriuretic factor (ANF), BNP, and SKA, is known to be associated with hypertrophic responses in cardiomyocytes. We examined how the interaction of Gab1 with SHP2 contributes to the induction of BNP and SKA mRNA expression after LIF stimulation. BNP mRNA was upregulated by LIF in AdGab1WT-treated cardiomyocytes to the same extent as in Adß-galtreated cardiomyocytes. On the contrary, induction of BNP mRNA was abrogated in AdGab1F627/659-treated cardiomyocytes (Figures 5A and 5B). In contrast, SKA mRNA expression was slightly increased in response to LIF in Adß-galtreated cardiomyocytes but was almost completely suppressed in AdGab1WT-treated cardiomyocytes both in basal level and after LIF stimulation. In AdGab1F627/659-treated cardiomyocytes, the expression of SKA mRNA was restored to the same extent as in Adß-galtreated cardiomyocytes (Figures 5A and 5C). These results indicate that the interaction of Gab1 with SHP2 is involved in the regulation of embryonic gene expression after stimulation with LIF.
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Interaction of Gab1 With SHP2 Plays a Crucial Role in Activation of ERK5 by LIF in Cardiomyocytes
To elucidate a potential mechanism in which Gab1-SHP2 interaction plays a role in gp130-mediated longitudinal elongation of cardiomyocytes, we examined the effects of Gab1WT and Gab1F627/659 on LIF-induced activation of MAP kinases (ERK5 and ERK1/2), AKT, and signal transducer and activator of transcription 3 (STAT3), which are known to mediate biological functions through gp130.21,28,3133 These signaling molecules were rapidly activated by LIF in Adß-galtreated cardiomyocytes. Activation of ERK5 by LIF was augmented in AdGab1WT-treated cardiomyocytes compared with Adß-galtreated cardiomyocytes. On the other hand, activation of ERK5 was reduced in AdGab1F627/659- treated cardiomyocytes (Figure 6B). ERK1/2 was activated to the same extent in AdGab1WT-treated cardiomyocytes as in Adß-galtreated cardiomyocytes. On the contrary, activation of ERK1/2 was reduced in AdGab1F627/659-treated cardiomyocytes compared with Adß-galtreated cardiomyocytes (Figure 6C). Activation of AKT was enhanced in AdGab1WT-treated or AdGab1F627/659-treated cardiomyocytes compared with Adß-galtreated cardiomyocytes (Figure 6D). Activation of STAT3 was not altered in cardiomyocytes infected with Adß-gal, AdGab1WT, or AdGab1F627/659. These results indicate that Gab1 plays a critical role in activation of ERK5 and ERK1/2 by LIF through interaction with SHP2 in cardiomyocytes. Based on a previous report,28 the present finding suggests that the interaction of Gab1 with SHP2 might be involved in LIF-induced elongation of cardiomyocytes through activation of ERK5.
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Overexpression of the Dominant-Negative Form of ERK5 Abrogates the Effect of Gab1WT on Longitudinal Elongation of Cardiomyocytes Induced by LIF
To determine whether ERK5 might participate in the LIF-activated signaling pathway that mediates longitudinal elongation of cardiomyocytes induced by LIF, we constructed recombinant adenovirus vector expressing dominant-negative form of ERK5 (AdERK5AEF). As shown in Figure 7A, overexpression of ERK5AEF almost abrogated LIF-induced longitudinal elongation of cardiomyocytes.
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To test whether overexpression of ERK5AEF abrogates LIF-induced longitudinal elongation of cardiomyocytes overexpressing Gab1WT, cardiomyocytes were dual infected with AdGab1WT and Adß-gal or with AdGab1WT and AdERK5AEF. LIF induced elongation of cardiomyocytes infected with AdGab1WT and Adß-gal. On the contrary, this morphological change was significantly inhibited in cardiomyocytes infected with AdGab1WT and AdERK5AEF (Figure 7B). We quantified the cell surface area, cell length, and cell width of these cardiomyocytes. As shown in Figures 7C and 7D, LIF increased cell surface area by 60% and cell length by 84% in cardiomyocytes infected with AdGab1WT and Adß-gal. However, in cardiomyocytes infected with AdGab1WT and AdERK5AEF, the increases in cell surface area and cell length induced by LIF were almost abrogated. Cell width was significantly decreased in response to LIF in cardiomyocytes infected with AdGab1WT and Adß-gal but not in cardiomyocytes infected with AdGab1WT and AdERK5AEF (Figure 7E). The cell length to width ratio was significantly increased by LIF in cardiomyocytes infected with AdGab1WT and Adß-gal but not in cardiomyocytes infected with AdGab1WT and AdERK5AEF (Figure 7F). Therefore, it seems that ERK5 might be an essential component of LIF-activated signaling pathway, leading to elongated morphology of cardiomyocytes through Gab1-SHP2 interaction.
| Discussion |
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Among several hypertrophic factors, we found that LIF induced remarkable tyrosine phosphorylation of Gab1 and SHP2. On the other hand, GPCR agonists, such as NE, ET-1, and Ang II, did not induce tyrosine phosphorylation of Gab1 and SHP2 in cardiomyocytes. LIF and CT-1 induce cardiomyocyte hypertrophy,20,21 which is distinct from the hypertrophic phenotype observed after stimulation of GPCR agonists, both on a morphological and a molecular level.20 GPCR agonists induce a relatively uniform increase in myocyte size and the addition of new myofibrils in parallel.2527 In contrast, LIF and CT-1 induce a predominant increase in cell length with the addition of new sarcomeric units in series but no concomitant increase in cell width.20 In the present study, we showed that Gab1 enhanced elongation of cardiomyocytes induced by LIF and that overexpression of Gab1F627/659 inhibited increase in cell size and cell length of cardiomyocytes after LIF stimulation. On the other hand, our data showed that overexpression of both Gab1WT and Gab1F627/659 did not affect the morphological change after stimulation with GPCR agonist ET-1 in cardiomyocytes (data not shown). These findings suggest that the interaction of Gab1 with SHP2 specifically contributes to longitudinal elongation of cardiomyocytes induced by stimulation of gp130. However, the LIF-induced increase of cell length was not completely abolished in AdGab1F627/659-treated cardiomyocytes (Figure 4H). This increase may be related to augmented activation of AKT in AdGab1F627/659-treated cardiomyocytes, as shown in Figures 6A and 6D.
To additionally investigate the molecular mechanisms of Gab1-mediated longitudinal elongation of cardiomyocytes, we examined the downstream signaling pathway of gp130. Interestingly, activation of ERK5 by LIF was enhanced by overexpression of Gab1WT but suppressed by that of Gab1F627/659. Furthermore, in cardiomyocytes dual infected with AdGab1WT and AdERK5AEF, the increases in cell surface area and cell length were almost abrogated. These data indicate that Gab1-SHP2 interaction plays a critical role in gp130-dependent elongation of cardiomyocytes through activation of ERK5. Although it has been reported that the interaction of Gab1 with SHP2 regulates activation of ERK1/2,912,14 the present study is the first demonstration that the interaction of Gab1 with SHP2 also regulates activation of ERK5. Consistent with our results, Nicol et al28 recently reported that activation of ERK5 is necessary and sufficient for elongation of cardiomyocytes induced by LIF, providing the causality between Gab1-mediated ERK5 activation and elongation of cardiomyocytes. Nicol et al28 also demonstrated that the gp130-MEK5-ERK5 pathway has a specific role in inhibition of parallel assembly of sarcomeres using adenovirus vectors expressing constitutive active and dominant-negative MEK5.28 Our data showing that cell width was decreased after LIF stimulation in AdGab1WT-treated cardiomyocytes suggest that Gab1 might enhance gp130-MEK5-ERK5 signaling pathway to inhibit parallel assembly of sarcomeres.
On the other hand, ERK5 was also shown to be activated by GPCR agonist phenylephrine in cardiomyocytes.28 Based on these findings, we could hypothesize that tyrosine phosphorylation of Gab1 and subsequent complex formation of Gab1 and SHP2 are primarily responsible for the specification of gp130-mediated cardiac hypertrophy (Figure 8). However, additional investigation is needed to elucidate the functional role of SHP2 in cardiac hypertrophy.
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In addition to morphological change, stimulation of cardiomyocytes with LIF and CT-1 induced ANF and BNP mRNA expression but not SKA mRNA expression.20,34 In contrast, GPCR agonists induced ANF, BNP, and SKA mRNA expression in a coordinate fashion.2527,35 Although overexpression of Gab1WT or Gab1F627/659 did not alter the upregulation of BNP mRNA after stimulation with GPCR agonist ET-1 in cardiomyocytes (data not shown), our results showed that Gab1-SHP2 interaction mediated LIF-induced BNP and SKA mRNA in different directions. Accordingly, these findings suggest that Gab1-SHP2 interaction contributes to the unique pattern of embryonic gene expression in gp130-mediated cardiac hypertrophy. However, additional investigation is needed to reveal the molecular mechanism underlying Gab1-mediated gene regulation in gp130-mediated cardiac hypertrophy.
Finally, it is very important to investigate the concerned pathological conditions in which gp130-Gab1 pathway is involved in human clinical case or animal models. To our knowledge, one previous study has demonstrated the distinct gene expression pattern in the hearts with pressure overload (PO) and volume overload (VO) in rat model.36 In this report, mRNA levels were quantified in the left ventricular myocardium from rats with cardiac hypertrophy attributable to PO or VO caused by suprarenal aortic constriction or an abdominal aortocaval fistula, respectively. Although PO and VO caused comparable increases in LV weight and prepro-ANF mRNA, PO but not VO increased mRNA levels of SKA. This pattern of gene expression induced by VO in vivo is reminiscent of that observed in cultured cardiomyocytes after LIF stimulation. Additionally, recent reports have shown that the signaling pathway through gp130-dependent pathway is profoundly altered in patients with end-stage heart failure attributable to dilated and ischemic cardiomyopathy.37 Although little is known regarding involvement of Gab1 in human clinical case or animal models, these findings and our findings suggest that Gab1 may play a role in the left ventricular remodeling in volume-overloaded hearts, providing novel insights into a therapeutic strategy for heart failure by manipulating Gab1-SHP2 interaction.
| Acknowledgments |
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| Footnotes |
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Original received February 10, 2003; revision received June 11, 2003; accepted June 26, 2003.
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