{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T13:22:47Z","timestamp":1793020967595,"version":"4.5.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2008,3,18]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>Background\u2014<\/jats:italic>\n            <\/jats:bold>\n            Heart failure is the leading cause of death in the United States. By delineating the pathways that regulate cardiomyocyte function, we can better understand the pathogenesis of cardiac disease. Many cardiomyocyte signaling pathways activate protein tyrosine kinases. However, the role of specific protein tyrosine phosphatases (PTPs) in these pathways is unknown.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods and Results\u2014<\/jats:italic>\n            <\/jats:bold>\n            Here, we show that mice with muscle-specific deletion of\n            <jats:italic>Ptpn11<\/jats:italic>\n            , the gene encoding the SH2 domain\u2013containing PTP Shp2, rapidly develop a compensated dilated cardiomyopathy without an intervening hypertrophic phase, with signs of cardiac dysfunction appearing by the second postnatal month. Shp2-deficient primary cardiomyocytes are defective in extracellular signal\u2013regulated kinase\/mitogen-activated protein kinase (Erk\/MAPK) activation in response to a variety of soluble agonists and pressure overload but show hyperactivation of the RhoA signaling pathway. Treatment of primary cardiomyocytes with Erk1\/2- and RhoA pathway\u2013specific inhibitors suggests that both abnormal Erk\/MAPK and RhoA activities contribute to the dilated phenotype of Shp2-deficient hearts.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusions\u2014<\/jats:italic>\n            <\/jats:bold>\n            Our results identify Shp2 as the first PTP with a critical role in adult cardiac function, indicate that in the absence of Shp2 cardiac hypertrophy does not occur in response to pressure overload, and demonstrate that the cardioprotective role of Shp2 is mediated via control of both the Erk\/MAPK and RhoA signaling pathways.\n          <\/jats:p>","DOI":"10.1161\/circulationaha.107.728865","type":"journal-article","created":{"date-parts":[[2008,3,4]],"date-time":"2008-03-04T01:45:56Z","timestamp":1204595156000},"page":"1423-1435","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":86,"title":["Deletion of\n            <i>Ptpn11<\/i>\n            (Shp2) in Cardiomyocytes Causes Dilated Cardiomyopathy via Effects on the Extracellular Signal\u2013Regulated Kinase\/Mitogen-Activated Protein Kinase and RhoA Signaling Pathways"],"prefix":"10.1161","volume":"117","author":[{"given":"Maria I.","family":"Kontaridis","sequence":"first","affiliation":[{"name":"From the Cancer Biology Program, Division of Hematology\/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (M.I.K., W.Y., K.K.B., B.G.N.); Cardiovascular Medicine Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass (D.C., B.W., R.L.); Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass (N.B., Q.K., P.M.K.); and Cardiovascular Research Program, Hospital for Sick Children and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentian","family":"Yang","sequence":"additional","affiliation":[{"name":"From the Cancer Biology Program, Division of Hematology\/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (M.I.K., W.Y., K.K.B., B.G.N.); Cardiovascular Medicine Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass (D.C., B.W., R.L.); Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass (N.B., Q.K., P.M.K.); and Cardiovascular Research Program, Hospital for Sick Children and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendra K.","family":"Bence","sequence":"additional","affiliation":[{"name":"From the Cancer Biology Program, Division of Hematology\/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (M.I.K., W.Y., K.K.B., B.G.N.); Cardiovascular Medicine Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass (D.C., B.W., R.L.); Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass (N.B., Q.K., P.M.K.); and Cardiovascular Research Program, Hospital for Sick Children and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darragh","family":"Cullen","sequence":"additional","affiliation":[{"name":"From the Cancer Biology Program, Division of Hematology\/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (M.I.K., W.Y., K.K.B., B.G.N.); Cardiovascular Medicine Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass (D.C., B.W., R.L.); Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass (N.B., Q.K., P.M.K.); and Cardiovascular Research Program, Hospital for Sick Children and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Cancer Biology Program, Division of Hematology\/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (M.I.K., W.Y., K.K.B., B.G.N.); Cardiovascular Medicine Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass (D.C., B.W., R.L.); Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass (N.B., Q.K., P.M.K.); and Cardiovascular Research Program, Hospital for Sick Children and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalya","family":"Bodyak","sequence":"additional","affiliation":[{"name":"From the Cancer Biology Program, Division of Hematology\/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (M.I.K., W.Y., K.K.B., B.G.N.); Cardiovascular Medicine Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass (D.C., B.W., R.L.); Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass (N.B., Q.K., P.M.K.); and Cardiovascular Research Program, Hospital for Sick Children and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingen","family":"Ke","sequence":"additional","affiliation":[{"name":"From the Cancer Biology Program, Division of Hematology\/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (M.I.K., W.Y., K.K.B., B.G.N.); Cardiovascular Medicine Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass (D.C., B.W., R.L.); Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass (N.B., Q.K., P.M.K.); and Cardiovascular Research Program, Hospital for Sick Children and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksander","family":"Hinek","sequence":"additional","affiliation":[{"name":"From the Cancer Biology Program, Division of Hematology\/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (M.I.K., W.Y., K.K.B., B.G.N.); Cardiovascular Medicine Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass (D.C., B.W., R.L.); Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass (N.B., Q.K., P.M.K.); and Cardiovascular Research Program, Hospital for Sick Children and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M.","family":"Kang","sequence":"additional","affiliation":[{"name":"From the Cancer Biology Program, Division of Hematology\/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (M.I.K., W.Y., K.K.B., B.G.N.); Cardiovascular Medicine Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass (D.C., B.W., R.L.); Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass (N.B., Q.K., P.M.K.); and Cardiovascular Research Program, Hospital for Sick Children and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronglih","family":"Liao","sequence":"additional","affiliation":[{"name":"From the Cancer Biology Program, Division of Hematology\/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (M.I.K., W.Y., K.K.B., B.G.N.); Cardiovascular Medicine Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass (D.C., B.W., R.L.); Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass (N.B., Q.K., P.M.K.); and Cardiovascular Research Program, Hospital for Sick Children and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin G.","family":"Neel","sequence":"additional","affiliation":[{"name":"From the Cancer Biology Program, Division of Hematology\/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (M.I.K., W.Y., K.K.B., B.G.N.); Cardiovascular Medicine Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass (D.C., B.W., R.L.); Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass (N.B., Q.K., P.M.K.); and Cardiovascular Research Program, Hospital for Sick Children and Department of..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.mjt.0000127150.21184.01"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.21094"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1999.4668"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(00)00196-4"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(03)00091-4"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(00)00831-9"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000033524.92083.64"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.12.5340-5352.2004"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.9.4904"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.3.2416"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.1.599"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200602029"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510876103"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng772"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1086\/340847"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng2073"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20005"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1084"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504699200"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10038-005-0239-7"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1086\/499925"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-11-4207"},{"key":"e_1_3_2_23_2","first-page":"110","volume":"7","year":"1971","unstructured":"Gorlin RJ, Anderson RC, Moller JH. 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