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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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Network-Attacking Mutations(A) Six distinct types of network-attacking mutations (NAMs) can be defined based on perturbations of signaling network dynamics, network structure, and dysregulation of phosphorylation sites. Cancer mutations could generate or destroy molecular logic gates, for example by creating new, or by removing existing, phosphorylation sites. Alternatively, mutant proteins could become activated by new upstream proteins (incoming edges) or start perturbing new downstream substrates (outgoing edges). Finally mutations could turn signaling proteins (e.g., protein kinases) constitutively “on” or “off.” The effect of these NAMs on the cue-signal-output flow of information is illustrated for each comparing the wild-type (WT) and mutant (Mut) cases.(B) After mapping mutations at the genomic and proteomic level, every NAM class defined in (A) is modeled on the different protein domains and motifs currently included in ReKINect following a distinct procedure: mutations on the essential residues of the kinase and SH2 domains are classified as node inactivating. Acidic mutations mimicking the phosphorylated/active state of kinases are classified as node activating. Mutations perturbing phosphorylation motifs and causing changes in the upstream kinase phosphorylating the target protein are classified as upstream rewiring. On the other hand, mutations in residues that determine specificity of the kinase or SH2 domains (Creixell et al., 2015) perturb domain specificity and are classified as downstream rewiring. Finally, our genome-specific MS experiments enable the identification of mutations generating phosphorylatable residues or the extinction of phosphorylation sites by mutating away from phosphorylatable residues.See also Supplemental Experimental Procedures.
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fig1: Network-Attacking Mutations(A) Six distinct types of network-attacking mutations (NAMs) can be defined based on perturbations of signaling network dynamics, network structure, and dysregulation of phosphorylation sites. Cancer mutations could generate or destroy molecular logic gates, for example by creating new, or by removing existing, phosphorylation sites. Alternatively, mutant proteins could become activated by new upstream proteins (incoming edges) or start perturbing new downstream substrates (outgoing edges). Finally mutations could turn signaling proteins (e.g., protein kinases) constitutively “on” or “off.” The effect of these NAMs on the cue-signal-output flow of information is illustrated for each comparing the wild-type (WT) and mutant (Mut) cases.(B) After mapping mutations at the genomic and proteomic level, every NAM class defined in (A) is modeled on the different protein domains and motifs currently included in ReKINect following a distinct procedure: mutations on the essential residues of the kinase and SH2 domains are classified as node inactivating. Acidic mutations mimicking the phosphorylated/active state of kinases are classified as node activating. Mutations perturbing phosphorylation motifs and causing changes in the upstream kinase phosphorylating the target protein are classified as upstream rewiring. On the other hand, mutations in residues that determine specificity of the kinase or SH2 domains (Creixell et al., 2015) perturb domain specificity and are classified as downstream rewiring. Finally, our genome-specific MS experiments enable the identification of mutations generating phosphorylatable residues or the extinction of phosphorylation sites by mutating away from phosphorylatable residues.See also Supplemental Experimental Procedures.

Mentions: The first and relatively well-described type of NAM is one that disrupts signaling network dynamics by constitutively activating or inactivating a protein kinase, thereby maintaining the information flow either “on” or “off” uninterrupted over time. Examples of such “on” mutations are those substitutions that mimic activation loop phosphorylations, whereas examples of “off” mutations include those that alter catalytically essential residues of kinases, or residues in SH2 domains that are critical for phospho-tyrosine binding. Since the timely activation and termination of signals is critical for the proper cellular homeostasis as well as phenotypic responses to environmental stimuli, such mutations lead to aberrant information processing (Figure 1A).


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)

Network-Attacking Mutations(A) Six distinct types of network-attacking mutations (NAMs) can be defined based on perturbations of signaling network dynamics, network structure, and dysregulation of phosphorylation sites. Cancer mutations could generate or destroy molecular logic gates, for example by creating new, or by removing existing, phosphorylation sites. Alternatively, mutant proteins could become activated by new upstream proteins (incoming edges) or start perturbing new downstream substrates (outgoing edges). Finally mutations could turn signaling proteins (e.g., protein kinases) constitutively “on” or “off.” The effect of these NAMs on the cue-signal-output flow of information is illustrated for each comparing the wild-type (WT) and mutant (Mut) cases.(B) After mapping mutations at the genomic and proteomic level, every NAM class defined in (A) is modeled on the different protein domains and motifs currently included in ReKINect following a distinct procedure: mutations on the essential residues of the kinase and SH2 domains are classified as node inactivating. Acidic mutations mimicking the phosphorylated/active state of kinases are classified as node activating. Mutations perturbing phosphorylation motifs and causing changes in the upstream kinase phosphorylating the target protein are classified as upstream rewiring. On the other hand, mutations in residues that determine specificity of the kinase or SH2 domains (Creixell et al., 2015) perturb domain specificity and are classified as downstream rewiring. Finally, our genome-specific MS experiments enable the identification of mutations generating phosphorylatable residues or the extinction of phosphorylation sites by mutating away from phosphorylatable residues.See also Supplemental Experimental Procedures.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4644236&req=5

fig1: Network-Attacking Mutations(A) Six distinct types of network-attacking mutations (NAMs) can be defined based on perturbations of signaling network dynamics, network structure, and dysregulation of phosphorylation sites. Cancer mutations could generate or destroy molecular logic gates, for example by creating new, or by removing existing, phosphorylation sites. Alternatively, mutant proteins could become activated by new upstream proteins (incoming edges) or start perturbing new downstream substrates (outgoing edges). Finally mutations could turn signaling proteins (e.g., protein kinases) constitutively “on” or “off.” The effect of these NAMs on the cue-signal-output flow of information is illustrated for each comparing the wild-type (WT) and mutant (Mut) cases.(B) After mapping mutations at the genomic and proteomic level, every NAM class defined in (A) is modeled on the different protein domains and motifs currently included in ReKINect following a distinct procedure: mutations on the essential residues of the kinase and SH2 domains are classified as node inactivating. Acidic mutations mimicking the phosphorylated/active state of kinases are classified as node activating. Mutations perturbing phosphorylation motifs and causing changes in the upstream kinase phosphorylating the target protein are classified as upstream rewiring. On the other hand, mutations in residues that determine specificity of the kinase or SH2 domains (Creixell et al., 2015) perturb domain specificity and are classified as downstream rewiring. Finally, our genome-specific MS experiments enable the identification of mutations generating phosphorylatable residues or the extinction of phosphorylation sites by mutating away from phosphorylatable residues.See also Supplemental Experimental Procedures.
Mentions: The first and relatively well-described type of NAM is one that disrupts signaling network dynamics by constitutively activating or inactivating a protein kinase, thereby maintaining the information flow either “on” or “off” uninterrupted over time. Examples of such “on” mutations are those substitutions that mimic activation loop phosphorylations, whereas examples of “off” mutations include those that alter catalytically essential residues of kinases, or residues in SH2 domains that are critical for phospho-tyrosine binding. Since the timely activation and termination of signals is critical for the proper cellular homeostasis as well as phenotypic responses to environmental stimuli, such mutations lead to aberrant information processing (Figure 1A).

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