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PTEN is a tumor suppressor phosphatase that is frequently phosphorylated at conserved serine\/threonine residues (S380, T382, and T383 clusters) in the C-terminal tail of ATL and various solid cancer cells. Here, we identify SCY1-like protein 2 (SCYL2), with a protein kinase-like domain, as a novel PTEN-binding protein; however, the mechanism by which SCYL2 regulates PTEN phosphorylation remains unclear. SCYL2-associated complex phosphorylates PTEN at STT, and SCYL2 downregulation has anti-tumor effects in ATL via inhibition of the PI3K\/AKT signaling pathway by dephosphorylating PTEN at STT. SCYL2 reportedly binds to the clathrin heavy chain (CHC), which regulates cytoplasmic vesicle formation, trafficking, and signaling pathways. Our results indicate that SCYL2 expression induces the binding of CHC to PTEN. Furthermore, the inhibition of clathrin-coated vesicles (CCVs) by CHC downregulation or inhibition suppresses cell survival by reducing phosphorylated PTEN at the STT, suggesting that SCYL2 enhances PTEN phosphorylation through CCVs as a signaling platform. Our results indicate that SCYL2\/CHC complex plays a pivotal role in regulating the PI3K\/AKT signaling pathway through PTEN phosphorylation, thus leading to tumor development and may be a promising novel target for treating tumors.<\/jats:p>","DOI":"10.1038\/s41417-026-01008-9","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T07:56:47Z","timestamp":1771315007000},"page":"314-322","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Clathrin-associated SCYL2 contributes to the activation of PI3K\/AKT signaling and tumorigenesis through PTEN phosphorylation in adult T-cell leukemia\/lymphoma"],"prefix":"10.1038","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0679-5866","authenticated-orcid":false,"given":"Tomonaga","family":"Ichikawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Shimosaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Nakahata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Suekane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Issay","family":"Kitabayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidekatsu","family":"Iha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2555-8188","authenticated-orcid":false,"given":"Kazuya","family":"Shimoda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9772-2613","authenticated-orcid":false,"given":"Takashi","family":"Murakami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Morishita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,16]]},"reference":[{"key":"1008_CR1","doi-asserted-by":"publisher","unstructured":"El Hajj H, Bazarbachi A. Interplay between innate immunity and the viral oncoproteins Tax and HBZ in the pathogenesis and therapeutic response of HTLV-1 associated adult T cell leukemia. Front Immunol. 2022;13. https:\/\/doi.org\/10.3389\/fimmu.2022.957535.","DOI":"10.3389\/fimmu.2022.957535"},{"key":"1008_CR2","doi-asserted-by":"publisher","unstructured":"Kannagi M, Hasegawa A, Nagano Y, Kimpara S, Suehiro Y. Impact of host immunity on HTLV-1 pathogenesis: potential of tax-targeted immunotherapy against ATL. Retrovirology. 2019;16. https:\/\/doi.org\/10.1186\/s12977-019-0484-z.","DOI":"10.1186\/s12977-019-0484-z"},{"key":"1008_CR3","doi-asserted-by":"publisher","first-page":"26270","DOI":"10.1074\/jbc.M115.684746","volume":"290","author":"MA Cherian","year":"2015","unstructured":"Cherian MA, Baydoun HH, Al-Saleem J, Shkriabai N, Kvaratskhelia M, Green P, et al. Akt pathway activation by human T-cell leukemia virus type 1 tax oncoprotein. 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SS, SN, AS, IK, HI, KS, KM, and TI declare no competing interests in this article.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"It was approved by the Institutional Review Board of the Faculty of Medicine, University of Miyazaki (Approval Code: 972, Approval Data: January 17, 2001), and the Ethical Committee of Saitama Medical University (Approval Code: 2023-013, Approval Data: July 11, 2023). ATL cells were collected from the patients at the time of hospital admission before chemotherapy was initiated with informed consent. All animal experiments were approved by The Animal Experiment Review Board of the University of Miyazaki (Approval Code: 2017-503, Approval Data: 1 April 2017) and the Institutional Animal Care and Use Committee of Saitama Medical University (Approval Code: 3836, Approval Data: 6 December 2023), and was carried out in strict accordance with the recommendations in the Guidelines for Proper Conduct of Animal Experiments (Science Council of Japan, 1 June 2006).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}