PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain.
PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain.
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DOI：
10.1016/j.gendis.2022.11.003
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发表时间：
2023-07
期刊：
影响因子：
6.8
通讯作者：
Wang, Zhenghe
中科院分区：
文献类型：
--
作者：
Li, Yamu;Liu, Zhonghua;Zhao, Yiqing;Yang, Jie;Xiao, Tsan Sam;Conlon, Ronald A.;Wang, Zhenghe
癌症中PD - L1的表达是如何调控的，人们知之甚少。在此，我们报道ERBB3假激酶的ATP结合活性调控结直肠癌（CRCs）中PD - L1基因的表达。ERBB3是表皮生长因子受体家族四个成员之一，都具有蛋白酪氨酸激酶结构域。ERBB3是一种对ATP具有高结合亲和力的假激酶。我们发现ERBB3的ATP结合失活突变体在基因工程小鼠模型中降低了致瘤性，并抑制了结直肠癌细胞系的异种移植肿瘤生长。ERBB3的ATP结合突变体细胞显著降低了干扰素 - γ诱导的PD - L1表达。从机制上讲，ERBB3通过IRS1 - PI3K - PDK1 - RSK - CREB信号轴调控干扰素 - γ诱导的PD - L1表达。CREB是调控结直肠癌细胞中PD - L1基因表达的转录因子。在激酶结构域敲入一种源自肿瘤的ERBB3突变，可使小鼠结肠癌对抗PD1抗体治疗敏感，这表明ERBB3突变可能是适合免疫检查点治疗的肿瘤的预测性生物标志物。
How PD-L1 expression is regulated in cancer is poorly understood. Here, we report that the ATP-binding activity of ERBB3 pseudokinase regulates PD-L1 gene expression in colorectal cancers (CRCs). ERBB3 is one of the four members of the EGF receptor family, all with protein tyrosine kinase domains. ERBB3 is a pseudokinase with a high binding affinity to ATP. We showed that ERBB3 ATP-binding inactivation mutant reduces tumorigenicity in genetically engineered mouse models and impairs xenograft tumor growth of CRC cell lines. The ERBB3 ATP-binding mutant cells dramatically reduce IFN-γ-induced PD-L1 expression. Mechanistically, ERBB3 regulates IFN-γ-induced PD-L1 expression through the IRS1-PI3K-PDK1-RSK-CREB signaling axis. CREB is the transcription factor that regulates PD-L1 gene expression in CRC cells. Knockin of a tumor-derived ERBB3 mutation located in the kinase domain sensitizes mouse colon cancers to anti-PD1 antibody therapy, suggesting that ERBB3 mutations could be predictive biomarkers for tumors amenable to immune checkpoint therapy.
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DOI：
10.1073/pnas.91.17.8132
发表时间：
1994-08-16
影响因子：
11.1
作者：
GUY, PM;PLATKO, JV;CARRAWAY, KL
通讯作者：
CARRAWAY, KL
影响因子：
7.4
作者：
Knowlden, Janice M.;Gee, Julia M. W.;Hutcheson, Iain R.
通讯作者：
Hutcheson, Iain R.
影响因子：
64.8
作者：
Riethmacher, D;SonnenbergRiethmacher, E;Birchmeier, C
通讯作者：
Birchmeier, C
影响因子：
50.3
作者：
Li CW;Lim SO;Chung EM;Kim YS;Park AH;Yao J;Cha JH;Xia W;Chan LC;Kim T;Chang SS;Lee HH;Chou CK;Liu YL;Yeh HC;Perillo EP;Dunn AK;Kuo CW;Khoo KH;Hsu JL;Wu Y;Hsu JM;Yamaguchi H;Huang TH;Sahin AA;Hortobagyi GN;Yoo SS;Hung MC
通讯作者：
Hung MC
胆囊癌的全外显子组和靶向基因测序鉴定了 ErbB 通路中的复发突变
影响因子：
30.8
作者：
Li, Maolan;Zhang, Zhou;Liu, Yingbin
通讯作者：
Liu, Yingbin