Proteome-Scale Investigation of Protein Allosteric Regulation Perturbed by Somatic Mutations in 7,000 Cancer Genomes

Abstract

The allosteric regulation triggering the protein's functional activity via conformational changes is an intrinsic function of protein under many physiological and pathological conditions, including cancer. Identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes that they alter during tumor initiation and progression is a central challenge for cancer genomes in the post-genomic era. Here, we mapped more than 47,000 somatic missense mutations observed in approximately 7,000 tumor-normal matched samples across 33 cancer types into protein allosteric sites to prioritize the mutated allosteric proteins and we tested our prediction in cancer cell lines. We found that the deleterious mutations identified in cancer genomes were more significantly enriched at protein allosteric sites than tolerated mutations, suggesting a critical role for protein allosteric variants in cancer. Next, we developed a statistical approach, namely AlloDriver, and further identified 15 potential mutated allosteric proteins during pan-cancer and individual cancer-type analyses. More importantly, we experimentally confirmed that p.Pro360Ala on PDE10A played a potential oncogenic role in mediating tumorigenesis in non-small cell lung cancer (NSCLC). In summary, these findings shed light on the role of allosteric regulation during tumorigenesis and provide a useful tool for the timely development of targeted cancer therapies.

Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco‐induced lung cancer

“…We confirmed that PDE10A protein levels in stage I-II NSCLC patients correlated with decreased survival. The results that we obtained for mRNA and protein expression of PDE10A are consistent among them and also with previous results reported in NSCLC [15]. These results render PDE10A and ATP10D as potentially useful prognostic and therapeutic targets in NSCLC.…”

“…Shen et al. have reported that PDE10A mutations are predicted to influence PDE10A allosteric regulation in lung adenocarcinoma; that high levels of PDE10A expression correlate with worsened lung adenocarcinoma prognosis; and that Pf‐2545920 also suppresses the growth of NSCLC cell lines. Finally, PDE10A somatic mutations have been described in up to 19% of prostate cancers and correlated with increased levels of phosphorylated C‐AMP responsive element binding protein (p‐CREB) .…”

“…The same group recently reported that Pf-2545920, a highly specific PDE10A inhibitor, inhibits colon tumor cell growth at concentrations that increase cGMP and cAMP levels and activate PKG and PKA; and that Pf-2545920 reduces βcatenin-mediated transcription of survivin, resulting in caspase activation and apoptosis [23]. Shen et al [15] have reported that PDE10A mutations are predicted to influence PDE10A allosteric regulation in lung adenocarcinoma; that high levels of PDE10A expression correlate with worsened lung adenocarcinoma prognosis; and that Pf-2545920 also suppresses the growth of NSCLC cell lines. Finally, PDE10A somatic mutations have been described in up to 19% of prostate cancers and correlated with increased levels of phosphorylated C-AMP responsive element binding protein (p-CREB) [24].…”

Tissue-Specific Signaling Networks Rewired by Major Somatic Mutations in Human Cancer Revealed by Proteome-Wide Discovery

“…Currently, how to assess the impact of these somatic mutations in the process of tumorigenesis and disease progression is a main challenge. Considering the existing observations that many somatic mutations promote tumorigenesis by rewiring protein signaling networks (3), one potential strategy is to incorporate somatic mutations with the protein structure information and investigate them at functional sites (e.g., phosphorylation sites) (4–8). Phosphorylation-dependent signaling network is fundamental in cellular physiology and its dysfunction plays a critical role in tumorigenesis.…”

PPPred: Classifying Protein-phenotype Co-mentions Extracted from Biomedical Literature

“…Well known alterations in phenotype brought about * Produces the permission block, and copyright information by changes in one or more proteins or their regulation involved in important biological pathways include Alzheimer's disease, Parkinson's disease, Huntington's disease, cancer, cystic brosis and type II diabetes [3,13,26]. Uncovering novel changes in protein structure, function and regulation, and understanding how these alterations lead to human disorders is a very active area of research in the biological community [3,5,12,13,21,26,33,37].…”