{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPTPN11 encodes the non‐receptor protein tyrosine phosphatase SHP2, a critical mediator of signals originating from activated growth factor and cytokine receptors. Upon recruitment via its SH2 domains, SHP2 transduces extracellular cues into intracellular signals by modulating the Ras–mitogen‐activated protein kinase cascade and impacting pathways that control cell proliferation, differentiation, adhesion, and migration. For example, bacterial effector proteins like Helicobacter pylori CagA hijack this pathway by binding and activating SHP2 to induce growth factor–like responses and cytoskeletal changes, while normal receptor stimulation (e.g. by epidermal growth factor or interleukin‐6) engages SHP2 to dephosphorylate key substrates such as focal adhesion kinase and paxillin, thereby fine‐tuning cellular adhesion and motility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPerturbations in PTPN11 function are associated with a diverse spectrum of developmental disorders and hematologic malignancies. Germline missense mutations in PTPN11 cause Noonan syndrome and related conditions (including LEOPARD syndrome), typically by disrupting the autoinhibited conformation of SHP2 and resulting in its aberrant activation, which in turn leads to dysregulated Ras signaling. In the hematopoietic compartment, somatic gain‐of‐function mutations are found in juvenile myelomonocytic leukemia, acute lymphoblastic leukemia, and pediatric acute myeloid leukemia, further underscoring how enhanced SHP2 activity drives leukemogenesis. Genotype–phenotype studies have revealed that the precise location and intensity of SHP2 activation dictate the clinical manifestations observed in patients, spanning from growth hormone signaling abnormalities to defects in cardiac and skeletal development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "22"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent studies further reveal that the functions of SHP2 extend into the regulation of tumor microenvironments, immunomodulation, and fibrotic responses, thus opening avenues for therapeutic intervention. In several cancer models, SHP2 activity is implicated in the resistance of tumor cells to targeted kinase inhibitors and in the modulation of receptor tyrosine kinase signaling. Moreover, SHP2 is a key mediator in programmed cell death–1 (PD‑1) inhibitory pathways that restrain T‑cell activation within tumors. In addition, emerging findings implicate SHP2 in controlling inflammatory responses—such as by regulating the NLRP3 inflammasome and TGF‑β–induced JAK2/STAT3 signaling—thereby linking its activity to both oncogenic and fibrotic pathologies. These insights have spurred the development of potent small‑molecule inhibitors and allosteric modulators as novel therapeutic strategies in cancer, inflammatory and fibrotic diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "34"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hideaki Higashi, Ryouhei Tsutsumi, Syuichi Muto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1067147"}], "href": "https://doi.org/10.1126/science.1067147"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11743164"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11743164"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Mignon L Loh, Shashaank Vattikuti, Suzanne Schubbert, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2003-09-3287"}], "href": "https://doi.org/10.1182/blood-2003-09-3287"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14644997"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14644997"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Ute Lehmann, Jochen Schmitz, Manuela Weissenbach, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M210552200"}], "href": "https://doi.org/10.1074/jbc.M210552200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12403768"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12403768"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ryouhei Tsutsumi, Atsushi Takahashi, Takeshi Azuma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.26.1.261-276.2006"}], "href": "https://doi.org/10.1128/MCB.26.1.261-276.2006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16354697"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16354697"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yuan Ren, Songshu Meng, Lin Mei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Roles of Gab1 and SHP2 in paxillin tyrosine dephosphorylation and Src activation in response to epidermal growth factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M312575200"}], "href": "https://doi.org/10.1074/jbc.M312575200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14665621"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14665621"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Marco Tartaglia, Charlotte M Niemeyer, Alessandra Fragale, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1156"}], "href": "https://doi.org/10.1038/ng1156"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12717436"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12717436"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Marco Tartaglia, Kamini Kalidas, Adam Shaw, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/340847"}], "href": "https://doi.org/10.1086/340847"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11992261"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11992261"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Marco Tartaglia, Simone Martinelli, Lorenzo Stella, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/499925"}], "href": "https://doi.org/10.1086/499925"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16358218"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16358218"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Rebecca J Chan, Gen-Sheng Feng "}, {"type": "b", "children": [{"type": "t", "text": "PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2006-07-028829"}], "href": "https://doi.org/10.1182/blood-2006-07-028829"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17053061"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17053061"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Emilie A Bard-Chapeau, Shuangwei Li, Jin Ding, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccr.2011.03.023"}], "href": "https://doi.org/10.1016/j.ccr.2011.03.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21575863"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21575863"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Marco Tartaglia, Simone Martinelli, Giovanni Cazzaniga, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2003-11-3876"}], "href": "https://doi.org/10.1182/blood-2003-11-3876"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14982869"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14982869"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Heike Keilhack, Frank S David, Malcolm McGregor, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M504699200"}], "href": "https://doi.org/10.1074/jbc.M504699200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15987685"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15987685"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Anna Sarkozy, Claudio Carta, Sonia Moretti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.20955"}], "href": "https://doi.org/10.1002/humu.20955"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19206169"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19206169"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Véronique Gelsi-Boyer, Virginie Trouplin, Julien Roquain, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Haematol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2141.2010.08381.x"}], "href": "https://doi.org/10.1111/j.1365-2141.2010.08381.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20880116"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20880116"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Christian P Kratz, Charlotte M Niemeyer, Robert P Castleberry, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2005-02-0531"}], "href": "https://doi.org/10.1182/blood-2005-02-0531"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15928039"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15928039"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "E Legius, C Schrander-Stumpel, E Schollen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PTPN11 mutations in LEOPARD syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.39.8.571"}], "href": "https://doi.org/10.1136/jmg.39.8.571"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12161596"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12161596"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Martin Zenker, Gernot Buheitel, Ralf Rauch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genotype-phenotype correlations in Noonan syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pediatr (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jpeds.2003.11.032"}], "href": "https://doi.org/10.1016/j.jpeds.2003.11.032"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15001945"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15001945"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "G Binder, K Neuer, M B Ranke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2005-0995"}], "href": "https://doi.org/10.1210/jc.2005-0995"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15985475"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15985475"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "M L Loh, M G Reynolds, S Vattikuti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leukemia (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.leu.2403492"}], "href": "https://doi.org/10.1038/sj.leu.2403492"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15385933"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15385933"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Tetsuya Niihori, Yoko Aoki, Hirofumi Ohashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hum Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10038-005-0239-7"}], "href": "https://doi.org/10.1007/s10038-005-0239-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15834506"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15834506"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Zhi-Hong Yu, Jie Xu, Chad D Walls, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural and mechanistic insights into LEOPARD syndrome-associated SHP2 mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.450023"}], "href": "https://doi.org/10.1074/jbc.M113.450023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23457302"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23457302"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "M Cristina Digilio, Anna Sarkozy, Andrea de Zorzi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LEOPARD syndrome: clinical diagnosis in the first year of life."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.31156"}], "href": "https://doi.org/10.1002/ajmg.a.31156"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16523510"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16523510"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Sara Mainardi, Antonio Mulero-Sánchez, Anirudh Prahallad, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41591-018-0023-9"}], "href": "https://doi.org/10.1038/s41591-018-0023-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29808006"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29808006"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Jian Zheng, Xudong Huang, Wen Tan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.3568"}], "href": "https://doi.org/10.1038/ng.3568"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27213290"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27213290"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Lei Dong, Wen-Mei Yu, Hong Zheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature20131"}], "href": "https://doi.org/10.1038/nature20131"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27783593"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27783593"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Jing Li, Hyun-Bae Jie, Yu Lei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-14-1215"}], "href": "https://doi.org/10.1158/0008-5472.CAN-14-1215"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25480946"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25480946"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Nara L M Sobreira, Elizabeth T Cirulli, Dimitrios Avramopoulos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1000991"}], "href": "https://doi.org/10.1371/journal.pgen.1000991"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20577567"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20577567"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Guangya Zhu, Jingjing Xie, Wenna Kong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2020.09.002"}], "href": "https://doi.org/10.1016/j.cell.2020.09.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33002410"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33002410"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Xian Zhang, Yantao He, Sijiu Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/jm901645u"}], "href": "https://doi.org/10.1021/jm901645u"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20170098"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20170098"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Tao Han, Dai-Min Xiang, Wen Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PTPN11/Shp2 overexpression enhances liver cancer progression and predicts poor prognosis of patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hepatol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jhep.2015.03.036"}], "href": "https://doi.org/10.1016/j.jhep.2015.03.036"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25865556"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25865556"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Nikolaos Patsoukis, Jonathan S Duke-Cohan, Apoorvi Chaudhri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Commun Biol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s42003-020-0845-0"}], "href": "https://doi.org/10.1038/s42003-020-0845-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32184441"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32184441"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Wenjie Guo, Wen Liu, Zhen Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tyrosine phosphatase SHP2 negatively regulates NLRP3 inflammasome activation via ANT1-dependent mitochondrial homeostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-017-02351-0"}], "href": "https://doi.org/10.1038/s41467-017-02351-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29255148"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29255148"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Beate Skinningsrud, Eystein S Husebye, Simon H Pearce, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polymorphisms in CLEC16A and CIITA at 16p13 are associated with primary adrenal insufficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2008-0821"}], "href": "https://doi.org/10.1210/jc.2008-0821"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18593762"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18593762"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Ariella Zehender, Jingang Huang, Andrea-Hermina Györfi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-018-05768-3"}], "href": "https://doi.org/10.1038/s41467-018-05768-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30108215"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30108215"}]}]}]}