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Phosphorylation at tyrosine 26 (Y26) of OTUB1 recently emerged as a key regulatory switch that stabilizes Raptor (central component of mTORC1), thereby enhancing mTORC1 activity and influencing cell growth and metabolism. Selective modulation of Y26 phosphorylation offers an opportunity to elucidate the noncanonical roles of OTUB1 without perturbing its catalytic activity. However, genetic or kinase inhibition strategies lack the specificity to separate these functions. Here, a tyrosine\u2010specific targeted protein dephosphorylation strategy was developed by recruiting the protein tyrosine phosphatase, SHP2, to OTUB1 via a peptide\u2010based bifunctional molecule, termed bioPhosTAC. This bioPhosTAC comprises an OTUB1\u2010binding peptide linked to an SHP2\u2010binding peptide through a short linker, enabling proximity\u2010induced Y26 dephosphorylation. The bioPhosTAC selectively\u00a0reduced OTUB1 Y26 phosphorylation resulted in Raptor\u2010related mitochondrial fusion and Bim upregulation. This study represents the first demonstration of a peptide\u2010based SHP2\u2010mediated bioPhosTAC system for selective tyrosine dephosphorylation through induced proximity. These findings provide a new chemical biology tool for dissecting the noncanonical roles of OTUB1 and broaden the scope of targeted protein dephosphorylation strategies to tyrosine phosphorylation, potentially allowing precise modulation of phospho\u2010dependent signaling.<\/jats:p>","DOI":"10.1002\/advs.77265","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:56:13Z","timestamp":1787219773000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selective Modulation of OTUB1 Noncanonical Function via a bioPhosTAC Strategy"],"prefix":"10.1002","author":[{"given":"Seung Un","family":"Seo","sequence":"first","affiliation":[{"name":"Department of Immunology School of Medicine Keimyung University  Daegu South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seon Min","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of Immunology School 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