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Here, we report how the tetraspanin CD82 modulates the molecular organization and signaling of the EGF receptor (EGFR), a key molecule involved in cellular proliferation, differentiation, and survival. Combining multicolor super-resolution microscopy with advanced image reconstruction and analysis techniques, we demonstrate that CD82 selectively associates with EGFR, promotes receptor oligomerization, and acts as a regulator of ligand-independent receptor phosphorylation in a palmitoylation-dependent manner. Additionally, CD82 promotes a more compact molecular organization of EGFR, which correlates with altered endocytosis and downstream signaling outcomes. These findings underscore the importance of tetraspanins in the spatial and functional regulation of cell surface receptors, with implications for controlling aberrant signaling in disease and positions CD82 as a potential target for developing therapeutic strategies aimed at modulating EGFR signaling by influencing receptor organization.<\/jats:p>","DOI":"10.1083\/jcb.202505190","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T07:21:12Z","timestamp":1770189672000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Tetraspanin CD82 shapes EGFR signaling outcomes through nanoscale receptor organization"],"prefix":"10.1083","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1165-4282","authenticated-orcid":true,"given":"Sebastian","family":"Restrepo Cruz","sequence":"first","affiliation":[{"name":"University of New Mexico Health Sciences Center 1 Department of Pathology, , Albuquerque, NM,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3520-7605","authenticated-orcid":true,"given":"Michael J.","family":"Wester","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05fs6jp91","id-type":"ROR","asserted-by":"publisher"}],"name":"University of New Mexico 2 Department of Mathematics and Statistics, , Albuquerque, NM,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3742-040X","authenticated-orcid":true,"given":"Vernon S.","family":"Pankratz","sequence":"additional","affiliation":[{"name":"University of New Mexico Health Sciences Center 3 Department of Internal Medicine, , Albuquerque, NM,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/05kx2e072","id-type":"ROR","asserted-by":"publisher"}],"name":"University of New Mexico Comprehensive Cancer Center 4 , Albuquerque, NM,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8533-6029","authenticated-orcid":true,"given":"Diane S.","family":"Lidke","sequence":"additional","affiliation":[{"name":"University of New Mexico Health Sciences Center 1 Department of Pathology, , Albuquerque, NM,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/05kx2e072","id-type":"ROR","asserted-by":"publisher"}],"name":"University of New Mexico Comprehensive Cancer Center 4 , Albuquerque, NM,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9328-4318","authenticated-orcid":true,"given":"Keith A.","family":"Lidke","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05kx2e072","id-type":"ROR","asserted-by":"publisher"}],"name":"University of New Mexico Comprehensive Cancer Center 4 , Albuquerque, NM,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/05fs6jp91","id-type":"ROR","asserted-by":"publisher"}],"name":"University of New Mexico 5 Department of Physics and Astronomy, , Albuquerque, NM,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2285-5136","authenticated-orcid":true,"given":"Jennifer M.","family":"Gillette","sequence":"additional","affiliation":[{"name":"University of New Mexico Health Sciences Center 1 Department of Pathology, , Albuquerque, NM,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/05kx2e072","id-type":"ROR","asserted-by":"publisher"}],"name":"University of New Mexico Comprehensive Cancer Center 4 , Albuquerque, NM,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"2026051513114309000_bib1","doi-asserted-by":"publisher","first-page":"6428","DOI":"10.1021\/acs.nanolett.7b03425","article-title":"Fast, background-free DNA-PAINT imaging using FRET-based probes","volume":"17","author":"Auer","year":"2017","journal-title":"Nano Lett."},{"key":"2026051513114309000_bib2","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1016\/j.biocel.2012.01.020","article-title":"Tetraspanins: Interactions and interplay with integrins","volume":"44","author":"Bassani","year":"2012","journal-title":"Int. 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