{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T14:28:36Z","timestamp":1776954516289,"version":"3.51.4"},"reference-count":90,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,30]],"date-time":"2021-10-30T00:00:00Z","timestamp":1635552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The functional expression of the sodium\u2013iodide symporter (NIS) at the membrane of differentiated thyroid cancer (DTC) cells is the cornerstone for the use of radioiodine (RAI) therapy in these malignancies. However, NIS gene expression is frequently downregulated in malignant thyroid tissue, and 30% to 50% of metastatic DTCs become refractory to RAI treatment, which dramatically decreases patient survival. Several strategies have been attempted to increase the NIS mRNA levels in refractory DTC cells, so as to re-sensitize refractory tumors to RAI. However, there are many RAI-refractory DTCs in which the NIS mRNA and protein levels are relatively abundant but only reduced levels of iodide uptake are detected, suggesting a posttranslational failure in the delivery of NIS to the plasma membrane (PM), or an impaired residency at the PM. Because little is known about the molecules and pathways regulating NIS delivery to, and residency at, the PM of thyroid cells, we here employed an intact-cell labeling\/immunoprecipitation methodology to selectively purify NIS-containing macromolecular complexes from the PM. Using mass spectrometry, we characterized and compared the composition of NIS PM complexes to that of NIS complexes isolated from whole cell (WC) lysates. Applying gene ontology analysis to the obtained MS data, we found that while both the PM-NIS and WC-NIS datasets had in common a considerable number of proteins involved in vesicle transport and protein trafficking, the NIS PM complexes were particularly enriched in proteins associated with the regulation of the actin cytoskeleton. Through a systematic validation of the detected interactions by co-immunoprecipitation and Western blot, followed by the biochemical and functional characterization of the contribution of each interactor to NIS PM residency and iodide uptake, we were able to identify a pathway by which the PM localization and function of NIS depends on its binding to SRC kinase, which leads to the recruitment and activation of the small GTPase RAC1. RAC1 signals through PAK1 and PIP5K to promote ARP2\/3-mediated actin polymerization, and the recruitment and binding of the actin anchoring protein EZRIN to NIS, promoting its residency and function at the PM of normal and TC cells. Besides providing novel insights into the regulation of NIS localization and function at the PM of TC cells, our results open new venues for therapeutic intervention in TC, namely the possibility of modulating abnormal SRC signaling in refractory TC from a proliferative\/invasive effect to the re-sensitization of these tumors to RAI therapy by inducing NIS retention at the PM.<\/jats:p>","DOI":"10.3390\/cancers13215460","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T11:47:38Z","timestamp":1635767258000},"page":"5460","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Analysis of NIS Plasma Membrane Interactors Discloses Key Regulation by a SRC\/RAC1\/PAK1\/PIP5K\/EZRIN Pathway with Potential Implications for Radioiodine Re-Sensitization Therapy in Thyroid Cancer"],"prefix":"10.3390","volume":"13","author":[{"given":"M\u00e1rcia","family":"Faria","sequence":"first","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo do CHULN-Hospital Santa Maria, 1649-028 Lisboa, Portugal"},{"name":"BioISI-Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias da Universidade de Lisboa, 1749-016 Lisboa, Portugal"},{"name":"Departamento de Gen\u00e9tica Humana, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal"}]},{"given":"Rita","family":"Domingues","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo do CHULN-Hospital Santa Maria, 1649-028 Lisboa, Portugal"},{"name":"ISAMB-Instituto de Sa\u00fade Ambiental, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0357-7350","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Bugalho","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo do CHULN-Hospital Santa Maria, 1649-028 Lisboa, Portugal"},{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, CHULN and Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"}]},{"given":"Ana Lu\u00edsa","family":"Silva","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo do CHULN-Hospital Santa Maria, 1649-028 Lisboa, Portugal"},{"name":"ISAMB-Instituto de Sa\u00fade Ambiental, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"},{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, CHULN and Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9379-9696","authenticated-orcid":false,"given":"Paulo","family":"Matos","sequence":"additional","affiliation":[{"name":"BioISI-Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias da Universidade de Lisboa, 1749-016 Lisboa, Portugal"},{"name":"Departamento de Gen\u00e9tica Humana, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1210\/er.2012-1015","article-title":"Recent Insights into the Cell Biology of Thyroid Angiofollicular Units","volume":"34","author":"Colin","year":"2013","journal-title":"Endocr. 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