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

Authors

  • Miguel A. Molina-Vila,

    Corresponding author
    1. Breakthrough Cancer Research Unit, Dexeus University Hospital, Barcelona, Spain
    • Correspondence to: Miguel A Molina-Vila, Breakthrough Cancer Research Unit, Dexeus University Hospital, C. Sabino Arana 5-19, Barcelona 08028, Spain. E-mail: mamolina@pangaeabiotech.com.

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    • These authors contributed equally to this work.

  • Nuria Nabau-Moretó,

    1. Computational Genomics Laboratory and Genetics Department, Institut de Biologia Universitat de Barcelona (IBUB), Barcelona, Spain
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    • These authors contributed equally to this work.

  • Cristian Tornador,

    1. Genetic Causes of Disease Group, Bioinformatics and Genomics Program, Center for Genomic Regulation (CRG), Barcelona, Spain
    2. Pompeu Fabra University (UPF), Barcelona, Spain
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    • These authors contributed equally to this work.

  • Amit J. Sabnis,

    1. Pediatric Hematology-Oncology, UCSF Benioff Children's Hospital, San Francisco, California
    2. Division of Hematology/Oncology, Department of Medicine, USCF Helen Diller Family Comprehensive Cancer Center, San Francisco, California
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  • Rafael Rosell,

    1. Breakthrough Cancer Research Unit, Dexeus University Hospital, Barcelona, Spain
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  • Xavier Estivill,

    1. Genetic Causes of Disease Group, Bioinformatics and Genomics Program, Center for Genomic Regulation (CRG), Barcelona, Spain
    2. Pompeu Fabra University (UPF), Barcelona, Spain
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  • Trever G. Bivona,

    1. Division of Hematology/Oncology, Department of Medicine, USCF Helen Diller Family Comprehensive Cancer Center, San Francisco, California
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  • Cristina Marino-Buslje

    1. Fundación Instituto Leloir, Buenos Aires, Argentina
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    • These authors contributed equally to this work.


  • Contract grant sponsors: CONICET (grants PIP1936 and PIP0087).

  • Communicated by Bruce R. Gottlieb

ABSTRACT

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.

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