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Cancer-associated mutations are preferentially distributed in protein kinase functional sites

Izarzugaza, JMG; Redfern, OC; Orengo, CA; Valencia, A; (2009) Cancer-associated mutations are preferentially distributed in protein kinase functional sites. PROTEINS , 77 (4) 892 - 903. 10.1002/prot.22512.

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Abstract

Protein kinases are a superfamily involved in many crucial cellular processes, including signal transmission and regulation of cell cycle. As a consequence of this role, kinases have been reported to be associated with many types of cancer and are considered as potential therapeutic targets. We analyzed the distribution of pathogenic somatic point mutations (drivers) in the protein kinase superfamily with respect to their location in the protein, such as in structural, evolutionary, and functionally relevant regions. We find these driver mutations are more clearly associated with key protein features than other somatic mutations (passengers) that have not been directly linked to tumor progression. This observation fits well with the expected implication of the alterations in protein kinase function in cancer pathogenicity. To explain the relevance of the detected association of cancer driver mutations at the molecular level in the human kinome, we compare these with genetically inherited mutations (SNPs). We find that the subset of nonsynonymous SNPs that are associated to disease, but sufficiently mild to the point of being widespread in the population, tend to avoid those key protein regions, where they could be more detrimental for protein function. This tendency contrasts with the one detected for cancer associated-driver-mutations, which seems to be more directly implicated in the alteration of protein function. The detailed analysis of protein kinase groups and a number of relevant examples, confirm the relation between cancer associated-driver-mutations and key regions for protein kinase structure and function. Proteins 2009; 77:892-903. (C) 2009 Wiley-Liss, Inc.

Type: Article
Title: Cancer-associated mutations are preferentially distributed in protein kinase functional sites
DOI: 10.1002/prot.22512
Keywords: cancer, kinase, kinome, functional, somatic mutation, point mutation, driver mutation, passenger mutation, polymorphism, SNP, single nucleotide polymorphism, SEVERE INSULIN RESISTANCE, ACANTHOSIS NIGRICANS, PATHOLOGICAL MUTATIONS, COLORECTAL CANCERS, GENETIC-VARIATION, HUMAN BREAST, POLYMORPHISMS, RECEPTOR, DATABASE, RESIDUES
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: http://discovery.ucl.ac.uk/id/eprint/1298879
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