MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation.

Ras homolog enriched in brain (Rheb) is critical for mechanistic target of rapamycin complex 1 (mTORC1) activation in response to growth factors and amino acids (AAs). Whereas growth factors inhibit the tuberous sclerosis complex (TSC1-TSC2), a negative Rheb regulator, the role of AAs in Rheb activa...

Descripción completa

Detalles Bibliográficos
Autores: Fawal, Mohamad-Ali, Brandt, Marta, Djouder, Nabil
Tipo de recurso: artículo
Fecha de publicación:2015
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17551
Acceso en línea:http://hdl.handle.net/20.500.12105/17551
Access Level:acceso abierto
Palabra clave:Adenosine Triphosphate
Amino Acids
Animals
Blotting, Western
Cells, Cultured
Colorectal Neoplasms
Endocytosis
Fibroblasts
Fluorescent Antibody Technique
Humans
Immunoenzyme Techniques
Immunoprecipitation
Integrases
id ES_ef7d387f837d2faf091cc13eb9bc3d95
oai_identifier_str oai:repisalud.isciii.es:20.500.12105/17551
network_acronym_str ES
network_name_str España
repository_id_str
spelling MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation.Fawal, Mohamad-AliBrandt, MartaDjouder, NabilAdenosine TriphosphateAmino AcidsAnimalsBlotting, WesternCells, CulturedColorectal NeoplasmsEndocytosisFibroblastsFluorescent Antibody TechniqueHumansImmunoenzyme TechniquesImmunoprecipitationIntegrasesRas homolog enriched in brain (Rheb) is critical for mechanistic target of rapamycin complex 1 (mTORC1) activation in response to growth factors and amino acids (AAs). Whereas growth factors inhibit the tuberous sclerosis complex (TSC1-TSC2), a negative Rheb regulator, the role of AAs in Rheb activation remains unknown. Here, we identify microspherule protein 1 (MCRS1) as the essential link between Rheb and mTORC1 activation. MCRS1, in an AA-dependent manner, maintains Rheb at lysosome surfaces, connecting Rheb to mTORC1. MCRS1 suppression in human cancer cells using small interference RNA or mouse embryonic fibroblasts using an inducible-Cre/Lox system reduces mTORC1 activity. MCRS1 depletion promotes Rheb/TSC2 interaction, rendering Rheb inactive and delocalizing it from lysosomes to recycling endocytic vesicles, leading to mTORC1 inactivation. These findings have important implications for signaling mechanisms in various pathologies, including diabetes mellitus and cancer.ElsevierFundación Caja NavarraFundación La CaixaMinisterio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)20242024-02-0820152015-04-0620152015-04-06journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/17551reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/175512026-06-12T12:43:37Z
dc.title.none.fl_str_mv MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation.
title MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation.
spellingShingle MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation.
Fawal, Mohamad-Ali
Adenosine Triphosphate
Amino Acids
Animals
Blotting, Western
Cells, Cultured
Colorectal Neoplasms
Endocytosis
Fibroblasts
Fluorescent Antibody Technique
Humans
Immunoenzyme Techniques
Immunoprecipitation
Integrases
title_short MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation.
title_full MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation.
title_fullStr MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation.
title_full_unstemmed MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation.
title_sort MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation.
dc.creator.none.fl_str_mv Fawal, Mohamad-Ali
Brandt, Marta
Djouder, Nabil
author Fawal, Mohamad-Ali
author_facet Fawal, Mohamad-Ali
Brandt, Marta
Djouder, Nabil
author_role author
author2 Brandt, Marta
Djouder, Nabil
author2_role author
author
dc.contributor.none.fl_str_mv Fundación Caja Navarra
Fundación La Caixa
Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
dc.subject.none.fl_str_mv Adenosine Triphosphate
Amino Acids
Animals
Blotting, Western
Cells, Cultured
Colorectal Neoplasms
Endocytosis
Fibroblasts
Fluorescent Antibody Technique
Humans
Immunoenzyme Techniques
Immunoprecipitation
Integrases
topic Adenosine Triphosphate
Amino Acids
Animals
Blotting, Western
Cells, Cultured
Colorectal Neoplasms
Endocytosis
Fibroblasts
Fluorescent Antibody Technique
Humans
Immunoenzyme Techniques
Immunoprecipitation
Integrases
description Ras homolog enriched in brain (Rheb) is critical for mechanistic target of rapamycin complex 1 (mTORC1) activation in response to growth factors and amino acids (AAs). Whereas growth factors inhibit the tuberous sclerosis complex (TSC1-TSC2), a negative Rheb regulator, the role of AAs in Rheb activation remains unknown. Here, we identify microspherule protein 1 (MCRS1) as the essential link between Rheb and mTORC1 activation. MCRS1, in an AA-dependent manner, maintains Rheb at lysosome surfaces, connecting Rheb to mTORC1. MCRS1 suppression in human cancer cells using small interference RNA or mouse embryonic fibroblasts using an inducible-Cre/Lox system reduces mTORC1 activity. MCRS1 depletion promotes Rheb/TSC2 interaction, rendering Rheb inactive and delocalizing it from lysosomes to recycling endocytic vesicles, leading to mTORC1 inactivation. These findings have important implications for signaling mechanisms in various pathologies, including diabetes mellitus and cancer.
publishDate 2015
dc.date.none.fl_str_mv 2015
2015-04-06
2015
2015-04-06
2024
2024-02-08
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/17551
url http://hdl.handle.net/20.500.12105/17551
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869423867988017152
score 15.812455

Similares en LA Referencia