Molecular Principles of Gene Fusion Mediated Rewiring of Protein Interaction Networks in Cancer

Abstract

Gene fusions are common cancer-causing mutations, but the molecular principles by which fusion protein products affect interaction networks and cause disease are not well understood. Here, we perform an integrative analysis of the structural, interactomic, and regulatory properties of thousands of putative fusion proteins. We demonstrate that genes that form fusions (i.e., parent genes) tend to be highly connected hub genes, whose protein products are enriched in structured and disordered interaction-mediating features. Fusion often results in the loss of these parental features and the depletion of regulatory sites such as post-translational modifications. Fusion products disproportionately connect proteins that did not previously interact in the protein interaction network. In this manner, fusion products can escape cellular regulation and constitutively rewire protein interaction networks. We suggest that the deregulation of central, interaction-prone proteins may represent a widespread mechanism by which fusion proteins alter the topology of cellular signaling pathways and promote cancer.

Keywords: cancer genomics; fusion protein; gene fusion; protein interaction networks.

Graphical abstract

Figure 1

Study Outline (A) Investigating how gene fusions and fusion proteins could affect molecular interactions in cancer. (B) Summary of analyses employed. (C) Description of processing procedure applied to the ChiTaRS database of fusion (“chimeric”) mRNA sequences to obtain a data set of fusion proteins. See also Figures S1 and S2 and Table S1.

Figure 2

Network Centrality of Parent Genes and Proteins (A–C) Parent genes possess more interaction partners in PPI networks (A), have higher betweenness centrality (B), and higher hub scores (C). (D) PPIs involving parent proteins occur in more human tissues than interactions not involving parent proteins. (E) The average number of interaction partners for parent proteins and all other proteins by tissue or cell type (gold = blood, bone marrow, and lymph tissues and teal = cancer cells). Throughout this study, distribution outliers are excluded from boxplots for presentation purposes, but included in statistical analyses. See also Figures S3 and S4 and Tables S2 and S3.

Figure 3

Interaction-Mediating Molecular Features in Fusion Proteins (A and B) IMDs in parent proteins (A) and fusion proteins (B). (C and D) The PPI interface residues in parent proteins (C) and fusion proteins (D) are shown. (E and F) The ELM LMs in parent proteins (E) and fusion proteins (F) are shown. (G and H) The predicted ANCHOR LMs in parent proteins (G) and fusion proteins (H) are shown. (I) The putative interaction-regulating PTMs in parent proteins are shown. (J and K) Other PTM sites in parent proteins (J) and fusion proteins (K) are shown. (L) The PTM type enrichments in included and excluded parent protein segments are shown. Within each subplot, Holm’s sequential Bonferroni correction for multiple testing was applied. See also Figure S5 and Tables S4 and S6.

Figure 4

Retained and Novel PPI in Fusion Proteins (A) The repeated inclusion of large portions of specific IMDs in fusion proteins can lead to the retention of domain-mediated interactions or the creation of novel interaction-like links between proteins. (B and C) Subsets of the recurrently retained domain-mediated PPIs (B) and novel links (C) are shown. See also Figure S6 and Table S5.

Figure 5

Fusion-Induced UB Site Gain and Loss in Cancer-Associated Proteins Fusion proteins involving OGs and TSGs can lead to the loss or gain of ubiquitination sites. (A) Example of an OG losing UB sites upon fusion. (B) Example of a TSG gaining UB sites upon fusion. The protein structure cartoons are of EWSR1 (PDB: 2CPE), FLI1 (PDB: 1FLI), and TGFB1 (PDB: 1KLA).

Figure 6

Molecular Principles by which Gene Fusions Can Alter Protein Interaction Networks in Cancer (A) Fusion tends to involve highly central proteins in interaction networks and can alter networks by several mechanisms. Rewiring effects can play key roles in seemingly straightforward fusion events, as in the constitutive kinase activation found in the BCR-ABL1 fusion. (B and C) More generally, fusion can affect molecular interactions of proteins by shuffling interaction-prone regions within ordered (B) and disordered (C) protein segments. See also Figure S7 and Table S7.