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

Oncogene volume 41, pages 1087–1099 (2022)Cite this article

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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−/− 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.

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Fig. 1: AOM-DSS-induced colorectal tumors were aggravated in SKAP2−/− mice.
Fig. 2: Upregulation of pro-inflammatory cytokines in AOM-DSS treated SKAP2−/− mice.
Fig. 3: LPS-induced inflammation was increased in SKAP2−/− mice.
Fig. 4: SKAP2 associates with SHP-1 and SHP-2, and regulates the interaction of SHPs with TLR4.
Fig. 5: SKAP2 associates with MyD88, which connects SHPs to TLR4/MyD88.
Fig. 6: Intracellular co-localization of SHP-1 and TLR4 was promoted by SKAP2.

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Acknowledgements

We thank members of the Bioscience Education and Research Support Center (BERSC) of Akita University for technical assistance. This work was supported by JSPS KAKENHI grants (19H03495 to M. Tanaka, 19K07681 to G. Itoh, 18K07192 to S. Kuriyama, 20H01094 to K. Takagane, and 19K07454 to A. Goto), Takeda Science Foundation grants (to M. Tanaka and G. Itoh), a Research Grant from the Princess Takamatsu Cancer Research Fund (19-25123 to M. Tanaka), Smoking Research Foundation to A. Goto, and the Cooperative Research Project Program of Joint Usage/Research Center at the Institute of Development, Aging and Cancer, Tohoku University (G. Itoh).

Funding

This work was supported by JSPS KAKENHI grants (19H03495 to M. Tanaka, 19K07681 to G. Itoh, 21K07090 to S. Kuriyama, 20H01094 to K. Takagane, and 19K07454 to A. Goto), the Takeda Science Foundation grants (to M. Tanaka and G. Itoh), and a Research Grant from the Princess Takamatsu Cancer Research Fund (19-25123 to M. Tanaka).

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Authors and Affiliations

  1. Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan

    Kurara Takagane, Go Itoh, Sei Kuriyama & Masamitsu Tanaka

  2. Technical Division, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan

    Kurara Takagane

  3. Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan

    Michinobu Umakoshi & Akiteru Goto

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  1. Kurara Takagane
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KT: data acquisition, data analysis, manuscript writing; MU, GI, SK: experimental methods, data acquisition; AG: data analysis; MT: funding, supervision, experimental design, data analysis, manuscript writing

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Correspondence to Masamitsu Tanaka.

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Takagane, K., Umakoshi, M., Itoh, G. et al. SKAP2 suppresses inflammation-mediated tumorigenesis by regulating SHP-1 and SHP-2. Oncogene 41, 1087–1099 (2022). https://doi.org/10.1038/s41388-021-02153-1

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