{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T02:06:47Z","timestamp":1747188407429,"version":"3.40.5"},"reference-count":21,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T00:00:00Z","timestamp":1627257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Vet Comparative Oncology"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Canine histiocytic sarcoma (HS) is an aggressive and highly metastatic neoplasm. Mutations in src homology 2 domain\u2010containing phosphatase 2 (SHP2; encoded by <jats:italic>PTPN11<\/jats:italic>), which recently have been identified in canine HS tumour cells, could be attractive therapeutic targets for SHP099, an allosteric inhibitor of SHP2. Here, molecular characteristics of wild\u2010type SHP2 and four SHP2 mutants (p.Ala72Gly, p.Glu76Gln, p.Glu76Ala and p.Gly503Val), including one that was newly identified in the present study, were investigated. Furthermore, in vivo effects of SHP099 on a HS cell line carrying SHP2 p.Glu76Ala were examined using a xenograft mouse model. While SHP2 Glu76 mutant cell lines and SHP2 wild\u2010type\/Gly503 mutant cell lines are highly susceptible and non\u2010susceptible to SHP099, respectively, a cell line carrying the newly identified SHP2 p.Ala72Gly mutation exhibited moderate susceptibility to SHP099. Among recombinant wild\u2010type protein and four mutant SHP2 proteins, three mutants (SHP2 p.Ala72Gly, p.Glu76Gln, p.Glu76Ala) were constitutively activated, while no activity was detected in wild\u2010type SHP2 and SHP2 p.Gly503Val. Activities of these constitutively activated proteins were suppressed by SHP099; in particular, Glu76 mutants were highly sensitive. In the xenograft mouse model, SHP099 showed anti\u2010tumour activity against a SHP2 p.Glu76Ala mutant cell line. Thus, there was heterogeneity in molecular characteristics among SHP2 mutants. SHP2 p.Glu76Ala and perhaps p.Glu76Gln, but not wild\u2010type SHP2 or SHP2 p.Gly503Val, were considered to be oncogenic drivers targetable with SHP099 in canine HS. Further studies will be needed to elucidate the potential of SHP2 p.Ala72Gly as a therapeutic target of SHP099 in canine HS.<\/jats:p>","DOI":"10.1111\/vco.12751","type":"journal-article","created":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T14:06:12Z","timestamp":1625839572000},"page":"109-117","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular characterization of canine <scp>SHP2<\/scp> mutants and anti\u2010tumour effect of <scp>SHP2<\/scp> inhibitor, <scp>SHP099<\/scp>, in a xenograft mouse model of canine histiocytic sarcoma"],"prefix":"10.1111","volume":"20","author":[{"given":"Hiroyuki","family":"Tani","sequence":"first","affiliation":[{"name":"Department of Veterinary Clinical Pathology Nippon Veterinary and Life Science University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Pathology Nippon Veterinary and Life Science University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomokazu","family":"Nagashima","sequence":"additional","affiliation":[{"name":"Veterinary Medical Teaching Hospital Nippon Veterinary and Life Science University  Tokyo Japan"},{"name":"Department of Veterinary Pathology Nippon Veterinary and Life Science University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaki","family":"Michishita","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathology Nippon Veterinary and Life Science University  Tokyo Japan"},{"name":"Research Center for Animal Life Science Nippon Veterinary and Life Science University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyoichi","family":"Tamura","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Pathology Nippon Veterinary and Life Science University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0054-7730","authenticated-orcid":false,"given":"Makoto","family":"Bonkobara","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Pathology Nippon Veterinary and Life Science University  Tokyo Japan"},{"name":"Research Center for Animal Life Science Nippon Veterinary and Life Science University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,7,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/vco.12252"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1939-1676.2007.tb02937.x"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1939-1676.2010.0588.x"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cr.7290055"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204699"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0000000000000345"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612824666181106100837"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80938-1"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes10070505"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/vco.12357"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/vco.12524"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.21050"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568009614666140717105001"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature18621"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b00680"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0020-5"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1292\/jvms.68.1343"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.7.1.379-387.1987"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0136981"},{"issue":"6","key":"e_1_2_9_21_1","first-page":"3385","article-title":"Effective treatment of transmissible venereal tumors in dogs with vincristine and IL2","volume":"35","author":"Den Otter W","year":"2015","journal-title":"Anticancer Res."},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.4161\/15384047.2014.972183"}],"container-title":["Veterinary and Comparative 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