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Kinome-wide decoding of network-attacking mutations rewiring cancer signaling.

Creixell P, Schoof EM, Simpson CD, Longden J, Miller CJ, Lou HJ, Perryman L, Cox TR, Zivanovic N, Palmeri A, Wesolowska-Andersen A, Helmer-Citterich M, Ferkinghoff-Borg J, Itamochi H, Bodenmiller B, Erler JT, Turk BE, Linding R - Cell (2015)

Bottom Line: However, global analysis of these events is currently limited.Here, we identify six types of network-attacking mutations (NAMs), including changes in kinase and SH2 modulation, network rewiring, and the genesis and extinction of phosphorylation sites.We identified and experimentally validated several NAMs, including PKCγ M501I and PKD1 D665N, which encode specificity switches analogous to the appearance of kinases de novo within the kinome.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.

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Overview of NAMs in Cancer Cell Lines and in the Global Repository of Cancer Somatic Mutations as Predicted by ReKINectFor each cell line and for the global repository of cancer somatic mutations we show the number of unique missense variants and how many of these variants fall within kinase proteins, SH2 proteins or phosphorylation sites (using a five-residue flanking region window surrounding the phosphorylation site). From these we then illustrate the fraction of variants falling within the respective domains and the fraction that can be interpreted by ReKINect. In the case of ES2, all of the 27 variants hitting an SH2 protein, hit outside SH2 domains, thus ReKINect could not make any predictions as to their effect (ghosted). It should be noted that the genesis of phosphorylation sites cannot be predicted from in silico analysis alone but require genome-specific-MS experiments. See also Figure S1.
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fig2: Overview of NAMs in Cancer Cell Lines and in the Global Repository of Cancer Somatic Mutations as Predicted by ReKINectFor each cell line and for the global repository of cancer somatic mutations we show the number of unique missense variants and how many of these variants fall within kinase proteins, SH2 proteins or phosphorylation sites (using a five-residue flanking region window surrounding the phosphorylation site). From these we then illustrate the fraction of variants falling within the respective domains and the fraction that can be interpreted by ReKINect. In the case of ES2, all of the 27 variants hitting an SH2 protein, hit outside SH2 domains, thus ReKINect could not make any predictions as to their effect (ghosted). It should be noted that the genesis of phosphorylation sites cannot be predicted from in silico analysis alone but require genome-specific-MS experiments. See also Figure S1.

Mentions: Having defined the different NAMs, we next intended to assess their existence and abundance in cancer. We thus collected a set of 678,050 unique missense somatic cancer variants from COSMIC (version 67) (Forbes et al., 2011) and deployed ReKINect on this set to predict a large number of instances across the NAM classes (Figure 2).


Kinome-wide decoding of network-attacking mutations rewiring cancer signaling.

Creixell P, Schoof EM, Simpson CD, Longden J, Miller CJ, Lou HJ, Perryman L, Cox TR, Zivanovic N, Palmeri A, Wesolowska-Andersen A, Helmer-Citterich M, Ferkinghoff-Borg J, Itamochi H, Bodenmiller B, Erler JT, Turk BE, Linding R - Cell (2015)

Overview of NAMs in Cancer Cell Lines and in the Global Repository of Cancer Somatic Mutations as Predicted by ReKINectFor each cell line and for the global repository of cancer somatic mutations we show the number of unique missense variants and how many of these variants fall within kinase proteins, SH2 proteins or phosphorylation sites (using a five-residue flanking region window surrounding the phosphorylation site). From these we then illustrate the fraction of variants falling within the respective domains and the fraction that can be interpreted by ReKINect. In the case of ES2, all of the 27 variants hitting an SH2 protein, hit outside SH2 domains, thus ReKINect could not make any predictions as to their effect (ghosted). It should be noted that the genesis of phosphorylation sites cannot be predicted from in silico analysis alone but require genome-specific-MS experiments. See also Figure S1.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644236&req=5

fig2: Overview of NAMs in Cancer Cell Lines and in the Global Repository of Cancer Somatic Mutations as Predicted by ReKINectFor each cell line and for the global repository of cancer somatic mutations we show the number of unique missense variants and how many of these variants fall within kinase proteins, SH2 proteins or phosphorylation sites (using a five-residue flanking region window surrounding the phosphorylation site). From these we then illustrate the fraction of variants falling within the respective domains and the fraction that can be interpreted by ReKINect. In the case of ES2, all of the 27 variants hitting an SH2 protein, hit outside SH2 domains, thus ReKINect could not make any predictions as to their effect (ghosted). It should be noted that the genesis of phosphorylation sites cannot be predicted from in silico analysis alone but require genome-specific-MS experiments. See also Figure S1.
Mentions: Having defined the different NAMs, we next intended to assess their existence and abundance in cancer. We thus collected a set of 678,050 unique missense somatic cancer variants from COSMIC (version 67) (Forbes et al., 2011) and deployed ReKINect on this set to predict a large number of instances across the NAM classes (Figure 2).

Bottom Line: However, global analysis of these events is currently limited.Here, we identify six types of network-attacking mutations (NAMs), including changes in kinase and SH2 modulation, network rewiring, and the genesis and extinction of phosphorylation sites.We identified and experimentally validated several NAMs, including PKCγ M501I and PKD1 D665N, which encode specificity switches analogous to the appearance of kinases de novo within the kinome.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.

Show MeSH
Related in: MedlinePlus