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However, their molecular interplay is largely unclear. TGF-\u03b2 can activate mitogen-activated protein kinase (MAPK) and AKT, but the underlying mechanism is not fully understood. In this study, we report that TGF-\u03b2 enhances HER2 activation, leading to the activation of MAPK and AKT. This process depends on the TGF-\u03b2 type I receptor T\u03b2RI kinase activity. T\u03b2RI phosphorylates HER2 at Ser779, promoting Y1248 phosphorylation and HER2 activation. Mice with HER2 S779A mutation display impaired mammary morphogenesis, reduced ductal elongation, and branching. Furthermore, wild-type HER2, but not S779A mutant, promotes TGF-\u03b2-induced epithelial\u2013mesenchymal transition, cell migration, and lung metastasis of breast cells. Increased HER2 S779 phosphorylation is observed in human breast cancers and positively correlated with the activation of HER2, MAPK, and AKT. Our findings demonstrate the crucial role of TGF-\u03b2-induced S779 phosphorylation in HER2 activation, mammary gland development, and the pro-oncogenic function of TGF-\u03b2 in breast cancer progression.<\/jats:p>","DOI":"10.1083\/jcb.202307138","type":"journal-article","created":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T02:21:27Z","timestamp":1705458087000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["HER2 phosphorylation induced by TGF-\u03b2 promotes mammary morphogenesis and breast cancer progression"],"prefix":"10.1083","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5180-7890","authenticated-orcid":true,"given":"Qiaoni","family":"Shi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03cve4549","id-type":"ROR","asserted-by":"publisher"}],"name":"Tsinghua University 1 The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, , Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9769-4798","authenticated-orcid":true,"given":"Fei","family":"Huang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03cve4549","id-type":"ROR","asserted-by":"publisher"}],"name":"Tsinghua University 1 The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, , Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5477-4488","authenticated-orcid":true,"given":"Yalong","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangzhou National Laboratory 2 , Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6446-9543","authenticated-orcid":true,"given":"Huidong","family":"Liu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03cve4549","id-type":"ROR","asserted-by":"publisher"}],"name":"Tsinghua University 1 The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, , Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9496-1280","authenticated-orcid":true,"given":"Haiteng","family":"Deng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03cve4549","id-type":"ROR","asserted-by":"publisher"}],"name":"Tsinghua University 3 MOE Key Laboratory of Bioinformatics, School of Life Sciences, , Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6701-0065","authenticated-orcid":true,"given":"Ye-Guang","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03cve4549","id-type":"ROR","asserted-by":"publisher"}],"name":"Tsinghua University 1 The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, , Beijing, China"},{"name":"Guangzhou National Laboratory 2 , Guangzhou, China"},{"id":[{"id":"https:\/\/ror.org\/042v6xz23","id-type":"ROR","asserted-by":"publisher"}],"name":"Nanchang University 4 School of Basic Medicine, Jiangxi Medical College, , Nanchang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2024,2,26]]},"reference":[{"key":"2024022614125805300_bib1","doi-asserted-by":"publisher","first-page":"175678","DOI":"10.1016\/j.ejphar.2023.175678","article-title":"TGF-\u03b2 signaling pathway: Therapeutic targeting and potential for anti-cancer immunity","volume":"947","author":"Ali","year":"2023","journal-title":"Eur. 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