SKAP2 suppresses inflammation-mediated tumorigenesis by regulating SHP-1 and SHP-2
SKAP2 suppresses inflammation-mediated tumorigenesis by regulating SHP-1 and SHP-2
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DOI：
10.1038/s41388-021-02153-1
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发表时间：
2022-01
期刊：
影响因子：
8
通讯作者：
Kurara Takagane;Michinobu Umakoshi;Go Itoh;S. Kuriyama;A. Goto;Masamitsu Tanaka
中科院分区：
文献类型：
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作者：
Kurara Takagane;Michinobu Umakoshi;Go Itoh;S. Kuriyama;A. Goto;Masamitsu Tanaka
炎症性肠病，如溃疡性结肠炎和克罗恩病，经常伴有结直肠癌。然而，结肠炎相关癌症的潜在机制尚未完全了解。Src激酶相关磷蛋白2（SKAP 2）是Src家族激酶的底物，在巨噬细胞中高度表达。在这里，我们研究了SKAP 2对由氧化偶氮甲烷/葡聚糖硫酸钠诱导的结肠炎肿瘤发生小鼠模型中炎症反应的影响。SKAP 2基因敲除增加了结肠炎和肿瘤发生的严重程度，以及脂多糖（LPS）诱导的急性炎症。SKAP 2减弱了巨噬细胞中由摄取癌细胞来源的外泌体诱导的炎症信号传导。SKAP 2 −/−小鼠的特征为NF-κB信号传导的激活以及细胞因子（包括TNFα、IL-1β、IL-6、CXCL-9/-10/-13和sICAM 1）的上调和释放; SKAP 2过表达减弱NF-κB激活。SKAP 2通过与Sirpα跨膜受体结合，与SHP-1酪氨酸磷酸酶形成复合物。SKAP 2还与MyD 88的TIR结构域、TIRAP和TRAM（toll样受体4（TLR 4）的衔接子）物理相关。SKAP 2介导的Sirpα/SHP-1复合物向TLR 4的募集减弱了炎症反应，而SKAP 2与SHP-2的直接相互作用降低了SHP-2的活化。SHP-2是有效激活NF-κB所必需的，并抑制TRAM/TRIF-INFβ通路;因此，SKAP 2介导的SHP-2抑制作用影响来自TLR 4的两个信号传导轴。目前的研究结果表明，SKAP 2通过抑制TLR 4-NF-κB通路来防止过度炎症，并且其通过SHP-1和SHP-2激活TLR 4-IFNβ通路，从而抑制炎症介导的肿瘤发生。
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.