Exploring the interactions of the RAS family in the human protein network and their potential implications in RAS-directed therapies.

RAS proteins are the founding members of the RAS superfamily of GTPases. They are involved in key signaling pathways regulating essential cellular functions such as cell growth and differentiation. As a result, their deregulation by inactivating mutations often results in aberrant cell proliferation...

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Detalles Bibliográficos
Autores: Bueno, Anibal, Morilla, Ian, Diez, Diego, Moya-Garcia, Aurelio A, Lozano, José, Ranea, Juan A G
Tipo de recurso: artículo
Fecha de publicación:2016
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17115
Acceso en línea:http://hdl.handle.net/20.500.12105/17115
Access Level:acceso abierto
Palabra clave:Ras
cancer
network
signaling
therapy
Molecular interaction database
Multiple sequence alignment
K-ras
Activation
Inhibitors
Discovery
Target
Cancer
Genes
Bind
Amino Acid Sequence
Carrier Proteins
Computational Biology
Conserved Sequence
Databases, Protein
Humans
Mutation
Neoplasms
Phylogeny
Protein Binding
Protein Interaction Mapping
Protein Interaction Maps
Signal Transduction
ras Proteins
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spelling Exploring the interactions of the RAS family in the human protein network and their potential implications in RAS-directed therapies.Bueno, AnibalMorilla, IanDiez, DiegoMoya-Garcia, Aurelio ALozano, JoséRanea, Juan A GRascancernetworksignalingtherapyMolecular interaction databaseMultiple sequence alignmentK-rasActivationInhibitorsInhibitorsInhibitorsDiscoveryTargetCancerGenesBindAmino Acid SequenceCarrier ProteinsComputational BiologyConserved SequenceDatabases, ProteinHumansMutationNeoplasmsPhylogenyProtein BindingProtein Interaction MappingProtein Interaction MapsSignal Transductionras ProteinsRAS proteins are the founding members of the RAS superfamily of GTPases. They are involved in key signaling pathways regulating essential cellular functions such as cell growth and differentiation. As a result, their deregulation by inactivating mutations often results in aberrant cell proliferation and cancer. With the exception of the relatively well-known KRAS, HRAS and NRAS proteins, little is known about how the interactions of the other RAS human paralogs affect cancer evolution and response to treatment. In this study we performed a comprehensive analysis of the relationship between the phylogeny of RAS proteins and their location in the protein interaction network. This analysis was integrated with the structural analysis of conserved positions in available 3D structures of RAS complexes. Our results show that many RAS proteins with divergent sequences are found close together in the human interactome. We found specific conserved amino acid positions in this group that map to the binding sites of RAS with many of their signaling effectors, suggesting that these pairs could share interacting partners. These results underscore the potential relevance of cross-talking in the RAS signaling network, which should be taken into account when considering the inhibitory activity of drugs targeting specific RAS oncoproteins. This study broadens our understanding of the human RAS signaling network and stresses the importance of considering its potential cross-talk in future therapies.[Bueno, Anibal] Univ Malaga, Dept Biol Mol & Bioquim, Malaga, Spain[Lozano, Jose] Univ Malaga, Dept Biol Mol & Bioquim, Malaga, Spain[Ranea, Juan A. G.] Univ Malaga, Dept Biol Mol & Bioquim, Malaga, Spain[Morilla, Ian] Univ Zurich, Inst Mol Life Sci, Zurich, Switzerland[Diez, Diego] Osaka Univ, World Premier Int Immunol Frontier Res Ctr, Quantitat Immunol Res Unit, Suita, Osaka , Japan[Moya-Garcia, Aurelio A.] UCL, Inst Struct & Mol Biol, London, England[Lozano, Jose] Hosp Univ Virgen de la Victoria, Inst Invest Biomed Malaga IBIMA, Malaga, Spain[Ranea, Juan A. G.] Hosp Univ Virgen de la Victoria, Inst Invest Biomed Malaga IBIMA, Malaga , Spain[Ranea, Juan A. G.] CIBER Enfermedades Raras, Madrid, Spain20242024-01-1620162016-01-0120162016-01-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttp://hdl.handle.net/20.500.12105/17115reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/171152026-06-12T12:43:37Z
dc.title.none.fl_str_mv Exploring the interactions of the RAS family in the human protein network and their potential implications in RAS-directed therapies.
title Exploring the interactions of the RAS family in the human protein network and their potential implications in RAS-directed therapies.
spellingShingle Exploring the interactions of the RAS family in the human protein network and their potential implications in RAS-directed therapies.
Bueno, Anibal
Ras
cancer
network
signaling
therapy
Molecular interaction database
Multiple sequence alignment
K-ras
Activation
Inhibitors
Inhibitors
Inhibitors
Discovery
Target
Cancer
Genes
Bind
Amino Acid Sequence
Carrier Proteins
Computational Biology
Conserved Sequence
Databases, Protein
Humans
Mutation
Neoplasms
Phylogeny
Protein Binding
Protein Interaction Mapping
Protein Interaction Maps
Signal Transduction
ras Proteins
title_short Exploring the interactions of the RAS family in the human protein network and their potential implications in RAS-directed therapies.
title_full Exploring the interactions of the RAS family in the human protein network and their potential implications in RAS-directed therapies.
title_fullStr Exploring the interactions of the RAS family in the human protein network and their potential implications in RAS-directed therapies.
title_full_unstemmed Exploring the interactions of the RAS family in the human protein network and their potential implications in RAS-directed therapies.
title_sort Exploring the interactions of the RAS family in the human protein network and their potential implications in RAS-directed therapies.
dc.creator.none.fl_str_mv Bueno, Anibal
Morilla, Ian
Diez, Diego
Moya-Garcia, Aurelio A
Lozano, José
Ranea, Juan A G
author Bueno, Anibal
author_facet Bueno, Anibal
Morilla, Ian
Diez, Diego
Moya-Garcia, Aurelio A
Lozano, José
Ranea, Juan A G
author_role author
author2 Morilla, Ian
Diez, Diego
Moya-Garcia, Aurelio A
Lozano, José
Ranea, Juan A G
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv [Bueno, Anibal] Univ Malaga, Dept Biol Mol & Bioquim, Malaga, Spain
[Lozano, Jose] Univ Malaga, Dept Biol Mol & Bioquim, Malaga, Spain
[Ranea, Juan A. G.] Univ Malaga, Dept Biol Mol & Bioquim, Malaga, Spain
[Morilla, Ian] Univ Zurich, Inst Mol Life Sci, Zurich, Switzerland
[Diez, Diego] Osaka Univ, World Premier Int Immunol Frontier Res Ctr, Quantitat Immunol Res Unit, Suita, Osaka , Japan
[Moya-Garcia, Aurelio A.] UCL, Inst Struct & Mol Biol, London, England
[Lozano, Jose] Hosp Univ Virgen de la Victoria, Inst Invest Biomed Malaga IBIMA, Malaga, Spain
[Ranea, Juan A. G.] Hosp Univ Virgen de la Victoria, Inst Invest Biomed Malaga IBIMA, Malaga , Spain
[Ranea, Juan A. G.] CIBER Enfermedades Raras, Madrid, Spain
dc.subject.none.fl_str_mv Ras
cancer
network
signaling
therapy
Molecular interaction database
Multiple sequence alignment
K-ras
Activation
Inhibitors
Inhibitors
Inhibitors
Discovery
Target
Cancer
Genes
Bind
Amino Acid Sequence
Carrier Proteins
Computational Biology
Conserved Sequence
Databases, Protein
Humans
Mutation
Neoplasms
Phylogeny
Protein Binding
Protein Interaction Mapping
Protein Interaction Maps
Signal Transduction
ras Proteins
topic Ras
cancer
network
signaling
therapy
Molecular interaction database
Multiple sequence alignment
K-ras
Activation
Inhibitors
Inhibitors
Inhibitors
Discovery
Target
Cancer
Genes
Bind
Amino Acid Sequence
Carrier Proteins
Computational Biology
Conserved Sequence
Databases, Protein
Humans
Mutation
Neoplasms
Phylogeny
Protein Binding
Protein Interaction Mapping
Protein Interaction Maps
Signal Transduction
ras Proteins
description RAS proteins are the founding members of the RAS superfamily of GTPases. They are involved in key signaling pathways regulating essential cellular functions such as cell growth and differentiation. As a result, their deregulation by inactivating mutations often results in aberrant cell proliferation and cancer. With the exception of the relatively well-known KRAS, HRAS and NRAS proteins, little is known about how the interactions of the other RAS human paralogs affect cancer evolution and response to treatment. In this study we performed a comprehensive analysis of the relationship between the phylogeny of RAS proteins and their location in the protein interaction network. This analysis was integrated with the structural analysis of conserved positions in available 3D structures of RAS complexes. Our results show that many RAS proteins with divergent sequences are found close together in the human interactome. We found specific conserved amino acid positions in this group that map to the binding sites of RAS with many of their signaling effectors, suggesting that these pairs could share interacting partners. These results underscore the potential relevance of cross-talking in the RAS signaling network, which should be taken into account when considering the inhibitory activity of drugs targeting specific RAS oncoproteins. This study broadens our understanding of the human RAS signaling network and stresses the importance of considering its potential cross-talk in future therapies.
publishDate 2016
dc.date.none.fl_str_mv 2016
2016-01-01
2016
2016-01-01
2024
2024-01-16
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
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/20.500.12105/17115
url http://hdl.handle.net/20.500.12105/17115
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 4.0 International
http://creativecommons.org/licenses/by/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 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
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
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score 15,811543

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