Toll-like receptor signaling in colorectal cancer: Carcinogenesis to cancer therapy

Figure 1 Toll-like receptor signaling pathways. There are 2 major toll-like receptor (TLR) pathways: One is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. With the exception of TLR3, all other TLRs commonly use MYD88 as the downstream adapter protein. Activated TLRs recruit MYD88, leading to subsequent activation of the downstream targets. TLR2 and TLR4 combine with their respective ligands to form dimeric complexes and change their configuration, and then recruit specific adapters within cells, including MYD88, TIR domain-containing adaptor protein (TIRAP)/MYD88 adaptor-like (Mal), TIR domain-containing adaptor-inducing interferon (IFN)-β (TRIF) and TRIF-related adaptor molecule (TRAM). The subsequent activation of the IKK complex, consisting of TBK1/TRAF3/IKKε, NEMO/IKBKE, induces phosphorylation of IKBKE, leading to the activation of transcription factors. TLRs bind bacterial and viral PAMPs, leading to activation of proinflammatory and anti-viral signaling pathways including NF-κB1 and IFN regulatory factor-3 (IRF3) and 7 (IRF7), then activation of transcription factors and production of inflammatory cytokines, leading to inflammation, immune regulation, survival, proliferation and tumorigenesis.