Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues

Autores
Molina Vila, Miguel A; Nabau Moretó, Nuria; Tornador, Cristian; Sabnis, Amit J; Rosell, Rafael; Estivill, Xavier; Bivona, Trever G; Marino, Cristina Ester
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Mutations leading to activation of proto-oncogenic protein kinases (PKs) are a type of drivers crucial for understanding tumorogenesis and as targets for antitumor drugs. However, bioinformatics tools so far developed to differentiate driver mutations, typically based on conservation considerations, systematically fail to recognize activating mutations in PKs. Here, we present the first comprehensive analysis of the 407 activating mutations described in the literature, which affect 41 PKs. Unexpectedly, we found that these mutations do not associate with conserved positions and do not directly affect ATP binding or catalytic residues. Instead, they cluster around three segments that have been demonstrated to act, in some PKs, as "molecular brakes" of the kinase activity. This finding led us to hypothesize that an auto inhibitory mechanism mediated by such "brakes" is present in all PKs and that the majority of activating mutations act by releasing it. Our results also demonstrate that activating mutations of PKs constitute a distinct group of drivers and that specific bioinformatics tools are needed to identify them in the numerous cancer sequencing projects currently underway. The clustering in three segments should represent the starting point of such tools, a hypothesis that we tested by identifying two somatic mutations in EPHA7 that might be functionally relevant.
Fil: Molina Vila, Miguel A. Universitat Autònoma de Barcelona. Hospital Universitari Dexeus; España
Fil: Nabau Moretó, Nuria. Universitat de Barcelona. Institut de Biologia; España
Fil: Tornador, Cristian. Center for Genomic Regulation. Bioinformatics and Genomics Program; España. Universitat Pompeu Fabra; España
Fil: Sabnis, Amit J. Benioff Children’s Hospital. Pediatric Hematology-Oncology; Estados Unidos. Helen Diller Family Comprehensive Cancer Center. Department of Medicine; Estados Unidos
Fil: Rosell, Rafael. Universitat Autònoma de Barcelona. Hospital Universitari Dexeus; España
Fil: Estivill, Xavier. Universitat Pompeu Fabra; España. Center for Genomic Regulation. Bioinformatics and Genomics Program; España
Fil: Bivona, Trever G. Helen Diller Family Comprehensive Cancer Center. Department of Medicine; Estados Unidos
Fil: Marino, Cristina Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
Materia
Cancer
Activating Mutation
Driver Mutations
Prediction Tools
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/8352
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/8352
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic ResiduesMolina Vila, Miguel ANabau Moretó, NuriaTornador, CristianSabnis, Amit JRosell, RafaelEstivill, XavierBivona, Trever GMarino, Cristina EsterCancerActivating MutationDriver MutationsPrediction Toolshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Mutations leading to activation of proto-oncogenic protein kinases (PKs) are a type of drivers crucial for understanding tumorogenesis and as targets for antitumor drugs. However, bioinformatics tools so far developed to differentiate driver mutations, typically based on conservation considerations, systematically fail to recognize activating mutations in PKs. Here, we present the first comprehensive analysis of the 407 activating mutations described in the literature, which affect 41 PKs. Unexpectedly, we found that these mutations do not associate with conserved positions and do not directly affect ATP binding or catalytic residues. Instead, they cluster around three segments that have been demonstrated to act, in some PKs, as "molecular brakes" of the kinase activity. This finding led us to hypothesize that an auto inhibitory mechanism mediated by such "brakes" is present in all PKs and that the majority of activating mutations act by releasing it. Our results also demonstrate that activating mutations of PKs constitute a distinct group of drivers and that specific bioinformatics tools are needed to identify them in the numerous cancer sequencing projects currently underway. The clustering in three segments should represent the starting point of such tools, a hypothesis that we tested by identifying two somatic mutations in EPHA7 that might be functionally relevant.Fil: Molina Vila, Miguel A. Universitat Autònoma de Barcelona. Hospital Universitari Dexeus; EspañaFil: Nabau Moretó, Nuria. Universitat de Barcelona. Institut de Biologia; EspañaFil: Tornador, Cristian. Center for Genomic Regulation. Bioinformatics and Genomics Program; España. Universitat Pompeu Fabra; EspañaFil: Sabnis, Amit J. Benioff Children’s Hospital. Pediatric Hematology-Oncology; Estados Unidos. Helen Diller Family Comprehensive Cancer Center. Department of Medicine; Estados UnidosFil: Rosell, Rafael. Universitat Autònoma de Barcelona. Hospital Universitari Dexeus; EspañaFil: Estivill, Xavier. Universitat Pompeu Fabra; España. Center for Genomic Regulation. Bioinformatics and Genomics Program; EspañaFil: Bivona, Trever G. Helen Diller Family Comprehensive Cancer Center. Department of Medicine; Estados UnidosFil: Marino, Cristina Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaWiley2014-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/8352Molina Vila, Miguel A; Nabau Moretó, Nuria; Tornador, Cristian; Sabnis, Amit J; Rosell, Rafael; et al.; Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues; Wiley; Human Mutation; 35; 3; 3-2014; 318-3281059-7794enginfo:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/wol1/doi/10.1002/humu.22493/abstractinfo:eu-repo/semantics/altIdentifier/doi/10.1002/humu.22493info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:33:26Zoai:ri.conicet.gov.ar:11336/8352instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:33:26.392CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues
title Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues
spellingShingle Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues
Molina Vila, Miguel A
Cancer
Activating Mutation
Driver Mutations
Prediction Tools
title_short Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues
title_full Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues
title_fullStr Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues
title_full_unstemmed Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues
title_sort Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues
dc.creator.none.fl_str_mv Molina Vila, Miguel A
Nabau Moretó, Nuria
Tornador, Cristian
Sabnis, Amit J
Rosell, Rafael
Estivill, Xavier
Bivona, Trever G
Marino, Cristina Ester
author Molina Vila, Miguel A
author_facet Molina Vila, Miguel A
Nabau Moretó, Nuria
Tornador, Cristian
Sabnis, Amit J
Rosell, Rafael
Estivill, Xavier
Bivona, Trever G
Marino, Cristina Ester
author_role author
author2 Nabau Moretó, Nuria
Tornador, Cristian
Sabnis, Amit J
Rosell, Rafael
Estivill, Xavier
Bivona, Trever G
Marino, Cristina Ester
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cancer
Activating Mutation
Driver Mutations
Prediction Tools
topic Cancer
Activating Mutation
Driver Mutations
Prediction Tools
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Mutations leading to activation of proto-oncogenic protein kinases (PKs) are a type of drivers crucial for understanding tumorogenesis and as targets for antitumor drugs. However, bioinformatics tools so far developed to differentiate driver mutations, typically based on conservation considerations, systematically fail to recognize activating mutations in PKs. Here, we present the first comprehensive analysis of the 407 activating mutations described in the literature, which affect 41 PKs. Unexpectedly, we found that these mutations do not associate with conserved positions and do not directly affect ATP binding or catalytic residues. Instead, they cluster around three segments that have been demonstrated to act, in some PKs, as "molecular brakes" of the kinase activity. This finding led us to hypothesize that an auto inhibitory mechanism mediated by such "brakes" is present in all PKs and that the majority of activating mutations act by releasing it. Our results also demonstrate that activating mutations of PKs constitute a distinct group of drivers and that specific bioinformatics tools are needed to identify them in the numerous cancer sequencing projects currently underway. The clustering in three segments should represent the starting point of such tools, a hypothesis that we tested by identifying two somatic mutations in EPHA7 that might be functionally relevant.
Fil: Molina Vila, Miguel A. Universitat Autònoma de Barcelona. Hospital Universitari Dexeus; España
Fil: Nabau Moretó, Nuria. Universitat de Barcelona. Institut de Biologia; España
Fil: Tornador, Cristian. Center for Genomic Regulation. Bioinformatics and Genomics Program; España. Universitat Pompeu Fabra; España
Fil: Sabnis, Amit J. Benioff Children’s Hospital. Pediatric Hematology-Oncology; Estados Unidos. Helen Diller Family Comprehensive Cancer Center. Department of Medicine; Estados Unidos
Fil: Rosell, Rafael. Universitat Autònoma de Barcelona. Hospital Universitari Dexeus; España
Fil: Estivill, Xavier. Universitat Pompeu Fabra; España. Center for Genomic Regulation. Bioinformatics and Genomics Program; España
Fil: Bivona, Trever G. Helen Diller Family Comprehensive Cancer Center. Department of Medicine; Estados Unidos
Fil: Marino, Cristina Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
description Mutations leading to activation of proto-oncogenic protein kinases (PKs) are a type of drivers crucial for understanding tumorogenesis and as targets for antitumor drugs. However, bioinformatics tools so far developed to differentiate driver mutations, typically based on conservation considerations, systematically fail to recognize activating mutations in PKs. Here, we present the first comprehensive analysis of the 407 activating mutations described in the literature, which affect 41 PKs. Unexpectedly, we found that these mutations do not associate with conserved positions and do not directly affect ATP binding or catalytic residues. Instead, they cluster around three segments that have been demonstrated to act, in some PKs, as "molecular brakes" of the kinase activity. This finding led us to hypothesize that an auto inhibitory mechanism mediated by such "brakes" is present in all PKs and that the majority of activating mutations act by releasing it. Our results also demonstrate that activating mutations of PKs constitute a distinct group of drivers and that specific bioinformatics tools are needed to identify them in the numerous cancer sequencing projects currently underway. The clustering in three segments should represent the starting point of such tools, a hypothesis that we tested by identifying two somatic mutations in EPHA7 that might be functionally relevant.
publishDate 2014
dc.date.none.fl_str_mv 2014-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/8352
Molina Vila, Miguel A; Nabau Moretó, Nuria; Tornador, Cristian; Sabnis, Amit J; Rosell, Rafael; et al.; Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues; Wiley; Human Mutation; 35; 3; 3-2014; 318-328
1059-7794
url http://hdl.handle.net/11336/8352
identifier_str_mv Molina Vila, Miguel A; Nabau Moretó, Nuria; Tornador, Cristian; Sabnis, Amit J; Rosell, Rafael; et al.; Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues; Wiley; Human Mutation; 35; 3; 3-2014; 318-328
1059-7794
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/wol1/doi/10.1002/humu.22493/abstract
info:eu-repo/semantics/altIdentifier/doi/10.1002/humu.22493
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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