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SKAP2 suppresses inflammation-mediated tumorigenesis by regulating SHP-1 and SHP-2.
- Source :
-
Oncogene [Oncogene] 2022 Feb; Vol. 41 (8), pp. 1087-1099. Date of Electronic Publication: 2022 Jan 17. - Publication Year :
- 2022
-
Abstract
- 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 <superscript>-/-</superscript> mice were characterized by the activation of NF-κB signaling and the upregulation and release of cytokines including TNFα, IL-1β, IL-6, CXCL-9/-10/-13, and sICAM1; SKAP2 overexpression attenuated NF-κB activation. Mechanistically, SKAP2 formed a complex with the SHP-1 tyrosine phosphatase via association with the Sirpα 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 Sirpα/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-κB activation and suppresses the TRAM/TRIF-INFβ 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-κB pathway, and it activates the TLR4-IFNβ pathway through SHP-1 and SHP-2, thereby suppressing inflammation-mediated tumorigenesis.<br /> (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Animals
Mice
Humans
NF-kappa B metabolism
Signal Transduction
Phosphoproteins metabolism
Phosphoproteins genetics
Colitis metabolism
Colitis pathology
Colitis chemically induced
Colitis genetics
Colitis complications
Toll-Like Receptor 4 metabolism
Toll-Like Receptor 4 genetics
Cytokines metabolism
Mice, Inbred C57BL
Macrophages metabolism
Azoxymethane toxicity
Myeloid Differentiation Factor 88 metabolism
Myeloid Differentiation Factor 88 genetics
Receptors, Immunologic
Intracellular Signaling Peptides and Proteins
Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 6 metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 6 genetics
Mice, Knockout
Inflammation metabolism
Inflammation pathology
Inflammation genetics
Carcinogenesis metabolism
Carcinogenesis genetics
Carcinogenesis pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 41
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 35034964
- Full Text :
- https://doi.org/10.1038/s41388-021-02153-1