Kinome-wide Decoding of Network-Attacking Mutations Rewiring Cancer Signaling

Abstract

SummaryCancer cells acquire pathological phenotypes through accumulation of mutations that perturb signaling networks. 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 developed a computational platform (ReKINect) to identify NAMs and systematically interpreted the exomes and quantitative (phospho-)proteomes of five ovarian cancer cell lines and the global cancer genome repository. 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. We discover mutant molecular logic gates, a drift toward phospho-threonine signaling, weakening of phosphorylation motifs, and kinase-inactivating hotspots in cancer. Our method pinpoints functional NAMs, scales with the complexity of cancer genomes and cell signaling, and may enhance our capability to therapeutically target tumor-specific networks.

Systems medicine approaches for peptide array-based protein kinase profiling: progress and prospects

“…A comparison of the primary sequence of kinase domains of otological kinases between species and different kinases within species reveals substantial diversity and reflects the specificity of the reactions catalyzed. Further to specificity comes the non-catalytic protein domains that kinases harbor and that are apparently implicated in the regulation of kinase activity, the interactions with heteromerising protein partners, or their subcellular localization [8,9]. In conjunction, the variation in the catalytic and non-catalytic domains, these attributes can largely explain the variation in kinase reactions catalyzed.…”

Truncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases

“…[22] with the exception of HRD+5 [23] 2 Referred to in the context of the salt bridge in [22] 3 Referred to as glycine--rich region in [22] 4 Referred to as catalytic loop in [22] 5 Referred to as HRD+4 in [23] …”

“…2 and Supplementary Table S4). The top 12 residues identified by this combined score (with a conservation score above 20) were located within a motif known to be critical for kinase activity (Table 1) [22,23]. A total of five novel regions were identified within the top 20 hotspot residues (Table 1, highlighted with blue or grey).…”

Abduction Based Drug Target Discovery Using Boolean Control Network

“…Finding a parsimonious hypothesis introduces the notion of minimal solution which is usually assimilated to a prime implicant. Within this framework, the possibility and the necessity of property (8,9) are formulated as abduction problems in propositional logic (10,11) by considering that p is a propositional formula. Lemma 1 demonstrates this equivalence.…”

“…In [57], the authors relate mutations to their network effect and introduce the notion of edgetic perturbations of molecular networks: nonsense mutation, out-of-frame insertion or deletion and defective splicing are interpreted as node or arc deletions whereas missense mutation and in-frame insertion or deletion can be modelled as node or arc addition. Moreover, in [10], the authors classify mutations according to the way they affect signalling networks and distinguish mutations that constitutively activate or inhibit enzymes and mutations that rewire the network interactions. The effect of mutations on molecular networks can thus be described as elementary topological actions of deletion or insertion of nodes and arcs.…”