{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:15:48Z","timestamp":1790709348416,"version":"4.1.0"},"reference-count":64,"publisher":"American Society for Clinical Investigation","issue":"15","funder":[{"name":"NIH\/NHLBI","award":["HL134166"],"award-info":[{"award-number":["HL134166"]}]},{"name":"NIH\/NHLBI","award":["R01 HL134166"],"award-info":[{"award-number":["R01 HL134166"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,6]]},"abstract":"<jats:p>\n                    Noonan syndrome with multiple lentigines (NSML) is a rare autosomal dominant disorder that presents with cardio-cutaneous-craniofacial defects. Hypertrophic cardiomyopathy (HCM) represents the major life-threatening presentation in NSML. Mutations in the\n                    <jats:italic>PTPN11<\/jats:italic>\n                    gene that encodes for the protein tyrosine phosphatase (PTP), SHP2, represents the predominant cause of HCM in NSML. NSML-associated\n                    <jats:italic>PTPN11<\/jats:italic>\n                    mutations render SHP2 catalytically inactive with an \u201copen\u201d conformation. NSML-associated\n                    <jats:italic>PTPN11<\/jats:italic>\n                    mutations cause hypertyrosyl phosphorylation of the transmembrane glycoprotein, protein zero-related (PZR), resulting in increased SHP2 binding. Here we show that NSML mice harboring a tyrosyl phosphorylation\u2013defective mutant of PZR (NSML\/PZR\n                    <jats:sup>Y242F<\/jats:sup>\n                    ) that is defective for SHP2 binding fail to develop HCM. Enhanced AKT\/S6 kinase signaling in heart lysates of NSML mice was reversed in NSML\/PZR\n                    <jats:sup>Y242F<\/jats:sup>\n                    mice, demonstrating that PZR\/SHP2 interactions promote aberrant AKT\/S6 kinase activity in NSML. Enhanced PZR tyrosyl phosphorylation in the hearts of NSML mice was found to drive myocardial fibrosis by engaging an Src\/NF-\u03baB pathway, resulting in increased activation of IL-6. Increased expression of IL-6 in the hearts of NSML mice was reversed in NSML\/PZR\n                    <jats:sup>Y242F<\/jats:sup>\n                    mice, and PZR\n                    <jats:sup>Y242F<\/jats:sup>\n                    mutant fibroblasts were defective for IL-6 secretion and STAT3-mediated fibrogenesis. These results demonstrate that NSML-associated\n                    <jats:italic>PTPN11<\/jats:italic>\n                    mutations that induce PZR hypertyrosyl phosphorylation trigger pathophysiological signaling that promotes HCM and cardiac fibrosis.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.137753","type":"journal-article","created":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T12:02:00Z","timestamp":1593086520000},"source":"Crossref","is-referenced-by-count":25,"title":["Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines"],"prefix":"10.1172","volume":"5","author":[{"given":"Jae-Sung","family":"Yi","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Yale School of Medicine, Yale University, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sravan","family":"Perla","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yale School of Medicine, Yale University, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liz","family":"Enyenihi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Emory University, Atlanta, Georgia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5187-7599","authenticated-orcid":true,"given":"Anton M.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yale School of Medicine, Yale University, New Haven, Connecticut, USA."},{"name":"Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2020,8,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1136\/heart.84.5.476"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.65.092101.142243"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)16358-7"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.2010.02268.x"},{"issue":"4","key":"B5","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1159\/000342251","article-title":"Leopard syndrome: clinical features and gene mutations","volume":"3","author":"Mart\u00ednez-Quintana","year":"2012","journal-title":"Mol Syndromol"},{"key":"B6","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1172-3-13","article-title":"Leopard syndrome","volume":"3","author":"Sarkozy","year":"2008","journal-title":"Orphanet J Rare Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.recesp.2012.09.017"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/ng772"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1086\/499925"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2015.08.005"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20061548"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2006.01.002"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80938-1"},{"issue":"29","key":"B14","doi-asserted-by":"crossref","first-page":"21478","DOI":"10.1016\/S0021-9258(20)80562-6","article-title":"Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor","volume":"268","author":"Lechleider","year":"1993","journal-title":"J Biol Chem"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.01.010"},{"key":"B16","doi-asserted-by":"crossref","DOI":"10.1186\/1472-6807-14-10","article-title":"Structural insights into Noonan\/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11)","volume":"14","author":"Qiu","year":"2014","journal-title":"BMC Struct Biol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M513068200"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1021\/bi5002695"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.308688"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00135-14"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.45.29367"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M306136200"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.8.5453"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801382200"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2013.158"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.21334"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44972"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80396"},{"issue":"20","key":"B29","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.90220","article-title":"Low-dose dasatinib rescues cardiac function in Noonan syndrome","volume":"1","author":"Yi","year":"2016","journal-title":"JCI Insight"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24351"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0178905"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111914200"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.20307"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.109.148635"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00170.2004"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2000.1291"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1385\/CT:3:3:229"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1116584109"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2008.05.076"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2014.12.024"},{"key":"B41"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1517\/14728220802551140"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015060670"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00379.2005"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2005.02.007"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01175.2005"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.189746"},{"issue":"5","key":"B48","doi-asserted-by":"crossref","DOI":"10.1126\/stke.1999.5.re1","article-title":"The NF-kappa B activation pathway: a paradigm in information transfer from membrane to nucleus","volume":"1999","author":"Rothwarf","year":"1999","journal-title":"Sci STKE"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1228704"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M208521200"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00763.2003"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.246173"},{"issue":"4","key":"B53","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1002\/ajmg.a.36982","article-title":"Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: palliative treatment with a rapamycin analog","volume":"167A","author":"Hahn","year":"2015","journal-title":"Am J Med Genet A"},{"issue":"1","key":"B54","first-page":"15","article-title":"Increased nuclear proto-oncogene expression in hypertrophic cardiomyopathy","volume":"4","author":"Hengstenberg","year":"1993","journal-title":"Cardioscience"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1089\/153685903321538071"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(99)00492-1"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(10)80145-7"},{"issue":"11","key":"B58","first-page":"5063","article-title":"Systemic inflammation is associated with myocardial fibrosis, diastolic dysfunction, and cardiac hypertrophy in patients with hypertrophic cardiomyopathy","volume":"9","author":"Fang","year":"2017","journal-title":"Am J Transl Res"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211028200"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12483971"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2016.65"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.04.025"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.08.022"},{"key":"B64"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/137753\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:11:02Z","timestamp":1779192662000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/137753"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,6]]},"references-count":64,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2020,8,6]]},"published-print":{"date-parts":[[2020,8,6]]}},"alternative-id":["10.1172\/jci.insight.137753"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.137753","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,6]]},"article-number":"e137753"}}