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Testis\u2010Specific Protein, Y\u2010Encoded\u2010Like (TSPYL) is a newly arisen NAP family in mammals. TSPYL2 can be transcriptionally induced by DNA damage and TGF\u03b2 causing proliferation arrest. TSPYL1, another TSPYL family member, has been poorly characterized and is the only TSPYL family member known to be causal of a lethal recessive disease in humans. This study shows that TSPYL1 and TSPYL2 play an opposite role in TGF\u03b2 signaling. TSPYL1 partners with the transcription factor FOXA1 and histone methyltransferase EZH2, and at the same time represses <jats:italic>TGFBR1<\/jats:italic> and epithelial\u2010mesenchymal transition (EMT). Depletion of TSPYL1 increases <jats:italic>TGFBR1<\/jats:italic> expression, upregulates TGF\u03b2 signaling, and elevates the protein stability of TSPYL2. Intriguingly, TSPYL2 forms part of the SMAD2\/3\/4 signal transduction complex upon stimulation by TGF\u03b2 to execute the transcriptional responses. Depletion of TSPYL2 rescues the EMT phenotype of TSPYL1 knockdown in A549 lung carcinoma cells. The data demonstrates the prime role of TSPYL2 in causing the dramatic defects in TSPYL1 deficiency. An intricate counter\u2010balancing role of TSPYL1 and TSPYL2 in regulating TGF\u03b2 signaling is also unraveled.<\/jats:p>","DOI":"10.1002\/advs.202306486","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T09:39:53Z","timestamp":1712569193000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["TSPYL1 as a Critical Regulator of TGF\u03b2 Signaling through Repression of TGFBR1 and TSPYL2"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2206-1381","authenticated-orcid":false,"given":"Huiqi","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong  Hong Kong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mia 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