Gain and loss of phosphorylation sites in human cancer

Abstract

In this study, we investigate the role of phosphorylation in somatic cancer mutations and inherited diseases. Somatic cancer mutation datasets were shown to have a significant enrichment for mutations that cause gain or loss of phosphorylation when compared to our control datasets (putatively neutral nsSNPs and random amino acid substitutions). Of the somatic cancer mutations, those in kinase genes represent the most enriched set of mutations that disrupt phosphorylation sites, suggesting phosphorylation target site mutation is an active cause of phosphorylation deregulation. Overall, this evidence suggests both gain and loss of a phosphorylation site in a target protein may be important features for predicting cancer-causing mutations and may represent a molecular cause of disease for a number of inherited and somatic mutations.

Inhibition of Protein Phosphatase 2A Enhances Cytotoxicity and Accessibility of Chemotherapeutic Drugs to Hepatocellular Carcinomas

“…Protein kinases and phosphatases are global regulators of protein activity, and their dysfunction or aberrant activation results in a wide spectrum of diseases including cancers (33,34). Cancers are widely characterized by abnormal activation of protein kinases such as Akt, tyrosine kinase, casein kinase, etc.…”

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“…These modifications thereby translate the modification of the target protein into biological action by affecting the interaction between their targets and other cellular factors or proteins [52]. Mutations in the post translational target sites leading to gain or loss of the PTMs may be involved in the human diseases [53,54]. We investigated the putative PTM sites in the PCNA protein and found that Serine at 39 th position was a recognizable phosphorylation site whereas lysine at 248 th position was the putative acetylation site.…”

Translating cancer ‘omics’ to improved outcomes: Figure 1.

“…However, nonsilent mutations, which include missense, nonsense, insertions, deletions, and mutations affecting splicing, are not all functionally equivalent, and as several groups have found, not equally selected for (Radivojac et al 2008;Mort et al 2010;Fischer et al 2011;Youn and Simon 2011). For example, mutations introducing stop codons (nonsense), those affecting splicing, or resulting in functional alterations to phosphorylation sites occur at significantly higher rates than other non-silent mutations, which may signify their selection and importance to cancer cells (Greenman et al 2006;Radivojac et al 2008;Fischer et al 2011;Youn and Simon 2011). Moreover, mutations occurring in a tumor sample with very few mutations overall, compared with a tumor sample with thousands, are likely relevant to tumor biology (Youn and Simon 2011).…”