YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2023 |
| Outros Autores: | , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10400.18/9104 |
Resumo: | (This article belongs to the Section Molecular Biology) |
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YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1Cystic FibrosisSignalingMAPKSHC1YESF508del-CFTRMAPK PathwayPlasma Membrane Half-lifeFibrose QuísticaVias de Transdução de Sinal e Patologias Associadas(This article belongs to the Section Molecular Biology)Recent developments in CFTR modulator drugs have had a significant transformational effect on the treatment of individuals with Cystic Fibrosis (CF) who carry the most frequent F508del- CFTR mutation in at least one allele. However, the clinical effects of these revolutionary drugs remain limited by their inability to fully restore the plasma membrane (PM) stability of the rescued mutant channels. Here, we shed new light on the molecular mechanisms behind the reduced half-life of rescued F508del-CFTR at the PM of airway cells. We describe that YES1 protein kinase is enriched in F508del-CFTR protein PM complexes, and that its interaction with rescued channels is mediated and dependent on the adaptor protein YAP1. Moreover, we show that interference with this complex, either by depletion of one of these components or inhibiting YES1 activity, is sufficient to significantly improve the abundance and stability of modulator-rescued F508del-CFTR at the surface of airway cells. In addition, we found that this effect was mediated by a decreased phosphorylation of the scaffold protein SHC1, a key regulator of MAPK pathway activity. In fact, we showed that depletion of SHC1 or inhibition of MAPK pathway signaling was sufficient to improve rescued F508del-CFTR surface levels, whereas an ectopic increase in pathway activation downstream of SHC1, through the use of a constitutively active H-RAS protein, abrogated the stabilizing effect of YES1 inhibition on rescued F508del-CFTR. Taken together, our findings not only provide new mechanistic insights into the regulation of modulator-rescued F508del-CFTR membrane stability, but also open exciting new avenues to be further explored in CF research and treatment.Funding: This work was supported by the Grant PTDC/BIA-CEL/28408/2017 (to PJ and PM) and Center Grant UID/MULTI/04046/2019 to BioISI from the Portuguese Fundação para a Ciência e a Tecnologia.MDPIRepositório Científico do Instituto Nacional de SaúdeBarros, PatríciaMatos, Ana M.Matos, PauloJordan, Peter2024-02-14T11:01:30Z2023-06-062023-06-06T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/9104engBiomolecules. 2023 Jun 6;13(6):949. doi: 10.3390/biom130609492218-273X10.3390/biom13060949info: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:RCAAP2024-02-17T01:31:10Zoai:repositorio.insa.pt:10400.18/9104Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T02:38:33.405664Repositório 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 |
YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1 |
| title |
YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1 |
| spellingShingle |
YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1 Barros, Patrícia Cystic Fibrosis Signaling MAPK SHC1 YES F508del-CFTR MAPK Pathway Plasma Membrane Half-life Fibrose Quística Vias de Transdução de Sinal e Patologias Associadas |
| title_short |
YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1 |
| title_full |
YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1 |
| title_fullStr |
YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1 |
| title_full_unstemmed |
YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1 |
| title_sort |
YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1 |
| author |
Barros, Patrícia |
| author_facet |
Barros, Patrícia Matos, Ana M. Matos, Paulo Jordan, Peter |
| author_role |
author |
| author2 |
Matos, Ana M. Matos, Paulo Jordan, Peter |
| author2_role |
author author author |
| dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Nacional de Saúde |
| dc.contributor.author.fl_str_mv |
Barros, Patrícia Matos, Ana M. Matos, Paulo Jordan, Peter |
| dc.subject.por.fl_str_mv |
Cystic Fibrosis Signaling MAPK SHC1 YES F508del-CFTR MAPK Pathway Plasma Membrane Half-life Fibrose Quística Vias de Transdução de Sinal e Patologias Associadas |
| topic |
Cystic Fibrosis Signaling MAPK SHC1 YES F508del-CFTR MAPK Pathway Plasma Membrane Half-life Fibrose Quística Vias de Transdução de Sinal e Patologias Associadas |
| description |
(This article belongs to the Section Molecular Biology) |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023-06-06 2023-06-06T00:00:00Z 2024-02-14T11:01:30Z |
| 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/10400.18/9104 |
| url |
http://hdl.handle.net/10400.18/9104 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
Biomolecules. 2023 Jun 6;13(6):949. doi: 10.3390/biom13060949 2218-273X 10.3390/biom13060949 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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MDPI |
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MDPI |
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reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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