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

Detalhes bibliográficos
Autor(a) principal: Faria, Márcia
Data de Publicação: 2021
Outros Autores: Domingues, Rita, Bugalho, Maria João, Silva, Ana Luísa, Matos, Paulo
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.18/7926
Resumo: This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis
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spelling 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 CancerThyroid CancerNISRAC1 SignalingRAI-refractoryPlasma Membrane LocalizationGTPase SignalingTumorigenesisVias de Transdução de Sinal e Patologias AssociadasThis article belongs to the Special Issue Role of Small GTPase Signaling in TumorigenesisThe functional expression of the sodium-iodide 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.This work was funded by Bolsa Edward Limbert Merck/SPEDM -2021 (from Merck/SPEDM, Portugal) and Fundação para a Ciência e a Tecnologia (FCT), Portugal, through grants PTDC/BIAMOL/31787/2017 (to ALS and PM) and UID/MULTI/04046/2019 (to BioISI). MF was the recipient of FCT fellowship PD/BD/114388/2016, within the BioSYS PhD programme from BioISI.MDPIRepositório Científico do Instituto Nacional de SaúdeFaria, MárciaDomingues, RitaBugalho, Maria JoãoSilva, Ana LuísaMatos, Paulo2022-02-03T17:12:19Z2021-10-302021-10-30T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/7926engCancers (Basel). 2021 Oct 30;13(21):5460. doi: 10.3390/cancers132154602072-669410.3390/cancers13215460info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:42:19Zoai:repositorio.insa.pt:10400.18/7926Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:42:36.412479Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv 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
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
spellingShingle 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
Faria, Márcia
Thyroid Cancer
NIS
RAC1 Signaling
RAI-refractory
Plasma Membrane Localization
GTPase Signaling
Tumorigenesis
Vias de Transdução de Sinal e Patologias Associadas
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
author Faria, Márcia
author_facet Faria, Márcia
Domingues, Rita
Bugalho, Maria João
Silva, Ana Luísa
Matos, Paulo
author_role author
author2 Domingues, Rita
Bugalho, Maria João
Silva, Ana Luísa
Matos, Paulo
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Repositório Científico do Instituto Nacional de Saúde
dc.contributor.author.fl_str_mv Faria, Márcia
Domingues, Rita
Bugalho, Maria João
Silva, Ana Luísa
Matos, Paulo
dc.subject.por.fl_str_mv Thyroid Cancer
NIS
RAC1 Signaling
RAI-refractory
Plasma Membrane Localization
GTPase Signaling
Tumorigenesis
Vias de Transdução de Sinal e Patologias Associadas
topic Thyroid Cancer
NIS
RAC1 Signaling
RAI-refractory
Plasma Membrane Localization
GTPase Signaling
Tumorigenesis
Vias de Transdução de Sinal e Patologias Associadas
description This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis
publishDate 2021
dc.date.none.fl_str_mv 2021-10-30
2021-10-30T00:00:00Z
2022-02-03T17:12:19Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10400.18/7926
url http://hdl.handle.net/10400.18/7926
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Cancers (Basel). 2021 Oct 30;13(21):5460. doi: 10.3390/cancers13215460
2072-6694
10.3390/cancers13215460
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
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