Kinome-wide decoding of network-attacking mutations rewiring cancer signaling.
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.
Affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.Show MeSH
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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).
Affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.