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Transforming growth factor \u03b2 (TGF-\u03b2) affects a wide spectrum of biological processes, including cell proliferation, apoptosis, differentiation and migration, during embryonic development and oncogenesis. TGF-\u03b2 regulates cell proliferation in a cell-context-dependent manner; loss of TGF-\u03b2-mediated growth inhibition is a major characteristic of cancer cells. SHP2 regulates canonical and non-canonical TGF-\u03b2 signaling in cancer cells and fibroblasts, however, the mechanism by which TGF-\u03b2 activates SHP2 and the role of SHP2 in TGF-\u03b2-mediated growth inhibition has remained unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The phosphorylation and activation of SHP2 was assessed after TGF-\u03b2 stimulation of normal and breast cancer cells. The interaction between SHP2 and SRC was determined by co-immunoprecipitation (co-IP) assay. Pharmacological inhibition and gRNA-mediated knockout were applied to assess the role of SHP2 in TGF-\u03b2 signaling, and RNA-sequencing to identify gene expression patterns in SHP2 knockout cells treated with TGF-\u03b2. Functional studies were performed using breast cancer cells to validate the role of SHP2 in TGF-\u03b2 -mediated growth inhibition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We report that TGF-\u03b2 activated SHP2 by promoting its tyrosine phosphorylation by SRC. SHP2 depletion in breast cancer cells reduced ubiquitination and degradation of T\u03b2RI by impeding the interaction between T\u03b2RI and SMAD7, which is a negative regulator of T\u03b2RI. Pharmacological or genetic inhibition of SHP2 facilitated TGF-\u03b2-induced SMAD2 phosphorylation and transcriptional responses. Consequently, inhibition of SHP2 profoundly enhanced TGF-\u03b2-induced cell growth arrest and senescence, including promotion of TGF-\u03b2-induced expression of the cell cycle inhibitor p15 at both gene and protein level.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings uncover a mechanism by which SHP2 is activated by TGF-\u03b2 in a SRC-dependent manner, and functions in a negative feedback mechanism to regulate TGF-\u03b2 signaling.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12964-026-03043-3","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T12:39:24Z","timestamp":1783082364000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SHP2 negatively regulates TGF-\u03b2 signaling by destabilizing the TGF-\u03b2 type I receptor"],"prefix":"10.1186","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1546-373X","authenticated-orcid":false,"given":"Cen","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1860-5369","authenticated-orcid":false,"given":"Ihor","family":"Yakymovych","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariya","family":"Yakymovych","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1907-1629","authenticated-orcid":false,"given":"Pengwei","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9508-896X","authenticated-orcid":false,"given":"Carl-Henrik","family":"Heldin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"issue":"2","key":"3043_CR1","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1006\/bbrc.1998.9170","volume":"249","author":"M Afrakhte","year":"1998","unstructured":"Afrakhte M, Mor\u00e9n A, Jossan S, Itoh S, Sampath K, Westermark B, et al. 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