SKAP2 suppresses inflammation-mediated tumorigenesis by regulating SHP-1 and SHP-2

Inflammatory bowel diseases, like ulcerative colitis and Crohn's disease are frequently accompanied by colorectal cancers. However, the mechanisms underlying colitis-associated cancers are not fully understood. Src Kinase Associated Phosphoprotein 2 (SKAP2), a substrate of Src family kinases, is highly expressed in macrophages. Here, we examined the effects of SKAP2 on inflammatory responses in a mouse model of tumorigenesis with colitis induced by azoxymethane/dextran sulfate sodium. SKAP2 knockout increased the severity of colitis and tumorigenesis, as well as lipopolysaccharide (LPS) induced acute inflammation. SKAP2 attenuated inflammatory signaling in macrophages induced by uptake of cancer cell-derived exosomes. SKAP2(-/-) mice were characterized by the activation of NF-kappa B signaling and the upregulation and release of cytokines including TNF alpha, IL-1 beta, IL-6, CXCL-9/-10/-13, and sICAM1; SKAP2 overexpression attenuated NF-kappa B activation. Mechanistically, SKAP2 formed a complex with the SHP-1 tyrosine phosphatase via association with the Sirp alpha transmembrane receptor. SKAP2 also physically associated with the TIR domain of MyD88, TIRAP, and TRAM, adaptors of toll-like receptor 4 (TLR4). SKAP2-mediated recruitment of the Sirp alpha/SHP-1 complex to TLR4 attenuated inflammatory responses, whereas direct interaction of SKAP2 with SHP-2 decreased SHP-2 activation. SHP-2 is required for efficient NF-kappa B activation and suppresses the TRAM/TRIF-INF beta pathway; therefore, SKAP2-mediated SHP-2 inhibition affected two signaling axes from TLR4. The present findings indicate that SKAP2 prevents excess inflammation by inhibiting the TLR4-NF-kappa B pathway, and it activates the TLR4-IFN beta pathway through SHP-1 and SHP-2, thereby suppressing inflammation-mediated tumorigenesis.

Automated summary

In this study, researchers found that SKAP2 plays a role in regulating inflammation and tumorigenesis by modulating the TLR4-NF-kappa B pathway and TLR4-IFN β pathway.