Kin-Driver: a Database of Driver Mutations in Protein Kinases

Somatic mutations in protein kinases (PKs) are frequent driver events in many human tumors, while germ-line mutations are associated with hereditary diseases. Here we present Kin-driver, the first database that compiles driver mutations in PKs with experimental evidence demonstrating their functional role. Kin-driver is a manual expert-curated database that pays special attention to activating mutations (AMs) and can serve as a validation set to develop new generation tools focused on the prediction of gain-of-function driver mutations. It also offers an easy and intuitive environment to facilitate the visualization and analysis of mutations in PKs. Because all mutations are mapped onto a multiple sequence alignment, analogue positions between kinases can be identified and tentative new mutations can be proposed for studying by transferring annotation. Finally, our database can also be of use to clinical and translational laboratories, helping them to identify uncommon AMs that can correlate with response to new antitumor drugs. The website was developed using PHP and JavaScript, which are supported by all major browsers; the database was built using MySQL server. Kin-driver is available at: http://kin-driver.leloir.org.ar/Fil: Simonetti, Franco Lucio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Tornador, Cristian. Universitat Pompeu Fabra; EspañaFil: Nabau Moretó, Nuria. Universitat de Barcelona. Facultat de Biologia; EspañaFil: Molina Vila, Miguel A.. Hospital Universitari Dexeus; EspañaFil: Marino Buslje, Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentin

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

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; 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; Argentin