Identification of critical paralog groups with indispensable roles in the regulation of signaling flow

Abstract

Extensive cross-talk between signaling pathways is required to integrate the myriad of extracellular signal combinations at the cellular level. Gene duplication events may lead to the emergence of novel functions, leaving groups of similar genes - termed paralogs - in the genome. To distinguish critical paralog groups (CPGs) from other paralogs in human signaling networks, we developed a signaling network-based method using cross-talk annotation and tissue-specific signaling flow analysis. 75 CPGs were found with higher degree, betweenness centrality, closeness, and ‘bowtieness’ when compared to other paralogs or other proteins in the signaling network. CPGs had higher diversity in all these measures, with more varied biological functions and more specific post-transcriptional regulation than non-critical paralog groups (non-CPG). Using TGF-beta, Notch and MAPK pathways as examples, SMAD2/3, NOTCH1/2/3 and MEK3/6-p38 CPGs were found to regulate the signaling flow of their respective pathways. Additionally, CPGs showed a higher mutation rate in both inherited diseases and cancer, and were enriched in drug targets. In conclusion, the results revealed two distinct types of paralog groups in the signaling network: CPGs and non-CPGs. Thus highlighting the importance of CPGs as compared to non-CPGs in drug discovery and disease pathogenesis.

Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes

“…None of the candidate pairs is found on the (short) list of heteromers, and ~3% of queries or biomarkers are annotated as homomers (Supplementary Figure 3d). We also compared our list of candidate pairs to the Critical Paralog Groups (CPGs) defined by Modos et al 49 , i.e. paralog groups that play important roles in signaling flow and pathway cross-talk.…”

Zebrafish Paralogs brd2a and brd2b Are Needed for Proper Circulatory, Excretory and Central Nervous System Formation and Act as Genetic Antagonists during Development

“…Just as importantly, the study of Brd2 paralogs in zebrafish may provide novel insights into possible functions, activities, and interactions of human Brd2, which as a member of the BET family of epigenetic co-regulators, stands at the intersection of multiple regulatory pathways, including those involved in carcinogenesis and neurodegeneration. Master regulatory proteins such as Brd2 are likely to belong to “critical paralog groups”—the subset of paralogs that are more central to signaling pathways, more varied in biological function and complex in post-transcriptional regulation, and more likely to be mutated in genetic diseases and cancer [ 69 ]. Their investigation presents a unique opportunity for understanding the mechanisms of control circuits critical for development and normal biological function, as well as their evolution and complexification over time.…”

Double missense mutations in cardiac myosin‐binding protein C and myopalladin genes: A case report with diffuse coronary disease, complete atrioventricular block, and progression to dilated cardiomyopathy

“…Palladin may also play a role in the pathology of myocardial infarction; several lines of evidence suggest that palladin is involved in vascular smooth muscle cell phenotypic switching and migration, contributing to formation and repair of lesion in response to vascular injury or atherosclerosis disease (Shiffman et al, ). In our patient suffering from diffuse coronary artery disease without the common cardiovascular risk factors, we hypothesized that the myopalladin mutation could favor the atherosclerosis process due to its similarity with the palladin, a critical paralog implicated in vascular plaque progression (Modos et al, ; Waard, Achterberg, Beauchamp, Pannekoek, & Vries, ). Whether confirmed in future studies, we would much more take in consideration genetic profiling in cardiac ischemic disease, ensuing strict cardiovascular risk assessment in patient offspring.…”