Short Linear Motifs in Colorectal Cancer Interactome and Tumorigenesis

Abstract

Colorectal tumorigenesis is driven by alterations in genes and proteins responsible for cancer initiation, progression, and invasion. This multistage process is based on a dense network of protein-protein interactions (PPIs) that become dysregulated as a result of changes in various cell signaling effectors. PPIs in signaling and regulatory networks are known to be mediated by short linear motifs (SLiMs), which are conserved contiguous regions of 3-10 amino acids within interacting protein domains. SLiMs are the minimum sequences required for modulating cellular PPI networks. Thus, several in silico approaches have been developed to predict and analyze SLiM-mediated PPIs. In this review, we focus on emerging evidence supporting a crucial role for SLiMs in driver pathways that are disrupted in colorectal cancer (CRC) tumorigenesis and related PPI network alterations. As a result, SLiMs, along with short peptides, are attracting the interest of researchers to devise small molecules amenable to be used as novel anti-CRC targeted therapies. Overall, the characterization of SLiMs mediating crucial PPIs in CRC may foster the development of more specific combined pharmacological approaches.

Keywords: SLiM-based small molecules; cancer driver protein interactome; colorectal cancer interactome; protein–protein interactions; short linear motifs; targeted therapy.

Figure 1

Schematic representation of a novel in silico methodology developed by our group to search for new interactors of an oncoprotein of interest by taking advantage of a library of SLiMs (tripeptides P1–P19) able to bind it in vitro, as identified by surface plasmon resonance (SPR) analysis [124]. Tripeptides P1–P19 are then used as in silico probes to identify human proteins containing them, which are therefore candidate interactors of the oncoprotein of interest.