CD47型
癌症研究
免疫疗法
蛋白质酪氨酸磷酸酶
脱磷
结直肠癌
生物
癌症免疫疗法
免疫系统
原癌基因酪氨酸蛋白激酶Src
癌症
磷酸酶
磷酸化
免疫学
细胞生物学
遗传学
作者
Yiqing Li,Hui Zhou,Pan Liu,Dandan Lv,Yong Shi,Bufu Tang,Jiaqi Xu,Tingting Zhong,Wangting Xu,Jie Zhang,Jianying Zhou,Kejing Ying,Yongchao Zhao,Yi Sun,Zhinong Jiang,Hongqiang Cheng,Xue Zhang,Yuehai Ke
摘要
SIPRα on macrophages binds with CD47 to resist proengulfment signals, but how the downstream signal of SIPRα controls tumor-infiltrating macrophages (TIMs) is still poorly clarified. Here, we report that the CD47/signal regulatory protein α (SIRPα) axis requires the deneddylation of tyrosine phosphatase SHP2. Mechanistically, Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) was constitutively neddylated on K358 and K364 sites; thus, its autoinhibited conformation was maintained. In response to CD47-liganded SIRPα, SHP2 was deneddylated by sentrin-specific protease 8 (SENP8), which led to the dephosphorylation of relevant substrates at the phagocytic cup and subsequent inhibition of macrophage phagocytosis. Furthermore, neddylation inactivated myeloid-SHP2 and greatly boosted the efficacy of colorectal cancer (CRC) immunotherapy. Importantly, we observed that supplementation with SHP2 allosteric inhibitors sensitized immune treatment-resistant CRC to immunotherapy. Our results emphasize that the CRC subtype that is unresponsive to immunotherapy relies on SIRPαhiSHP2hiNEDD8lo TIMs and highlight the need to further explore the strategy of SHP2 targeting in CRC therapy.
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