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

Authors
Molina Vila, Miguel A; Nabau Moretó, Nuria; Tornador, Cristian; Sabnis, Amit J; Rosell, Rafael; Estivill, Xavier; Bivona, Trever G; Marino, Cristina Ester
Publication Year
2014
Language
English
Format
article
Status
Published version
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.
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
Subject
CANCER
ACTIVATING MUTATION
DRIVER MUTATIONS
PREDICTION TOOLS
Otros Tópicos Biológicos
Ciencias Biológicas
CIENCIAS NATURALES Y EXACTAS
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/8352