The proto-oncogene SRC phosphorylates cGAS to inhibit an antitumor immune response.
The proto-oncogene SRC phosphorylates cGAS to inhibit an antitumor immune response.
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DOI：
10.1172/jci.insight.167270
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发表时间：
2023-06-22
期刊：
影响因子：
8
通讯作者：
Woodward, Joshua J.
中科院分区：
文献类型：
--
作者：
Dunker, William;Zaver, Shivam A.;Pineda, Jose Mario Bello;Howard, Cameron J.;Bradley, Robert K.;Woodward, Joshua J.
环状GMP-AMP合成酶(CGAS)是一种DNA传感器，负责诱导抗肿瘤免疫反应。最近的研究表明，cGAS在癌症中经常被抑制，而促进抗肿瘤cGAS功能的治疗靶点仍然难以捉摸。SRC是一种原癌基因酪氨酸激酶，在许多癌症中高水平表达。在此，我们证明SRC在原发癌和转移性膀胱癌中的表达与天然免疫基因的表达和免疫细胞的浸润呈负相关。我们确定SRC通过SRC小分子抑制剂、耗竭和过度表达来限制人类细胞系中的cGAS信号。CGAS和SRC在细胞内和体外相互作用，而SRC直接抑制cGAS的酶活性和DNA结合，这是一种依赖于激酶的方式。SRC使cGAS磷酸化，抑制cGAS Y248的磷酸化部分降低了SRC的抑制作用。总而言之，我们的研究证明cGAS抗肿瘤信号被原癌基因SRC阻止，并描述了癌症相关蛋白如何调节天然免疫系统。
Cyclic GMP-AMP synthase (cGAS) is a DNA sensor and responsible for inducing an antitumor immune response. Recent studies reveal that cGAS is frequently inhibited in cancer, and therapeutic targets to promote antitumor cGAS function remain elusive. SRC is a proto-oncogene tyrosine kinase and is expressed at elevated levels in numerous cancers. Here, we demonstrate that SRC expression in primary and metastatic bladder cancer negatively correlates with innate immune gene expression and immune cell infiltration. We determine that SRC restricts cGAS signaling in human cell lines through SRC small molecule inhibitors, depletion, and overexpression. cGAS and SRC interact in cells and in vitro, while SRC directly inhibits cGAS enzymatic activity and DNA binding in a kinase-dependent manner. SRC phosphorylates cGAS, and inhibition of cGAS Y248 phosphorylation partially reduces SRC inhibition. Collectively, our study demonstrates that cGAS antitumor signaling is hindered by the proto-oncogene SRC and describes how cancer-associated proteins can regulate the innate immune system.
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影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
7.3
作者：
Campisi M;Sundararaman SK;Shelton SE;Knelson EH;Mahadevan NR;Yoshida R;Tani T;Ivanova E;Cañadas I;Osaki T;Lee SWL;Thai T;Han S;Piel BP;Gilhooley S;Paweletz CP;Chiono V;Kamm RD;Kitajima S;Barbie DA
通讯作者：
Barbie DA
影响因子：
30.5
作者：
Buerckstuemmer, Tilmann;Baumann, Christoph;Superti-Furga, Giulio
通讯作者：
Superti-Furga, Giulio
影响因子：
14.9
作者：
Flicek P;Ahmed I;Amode MR;Barrell D;Beal K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fairley S;Fitzgerald S;Gil L;García-Girón C;Gordon L;Hourlier T;Hunt S;Juettemann T;Kähäri AK;Keenan S;Komorowska M;Kulesha E;Longden I;Maurel T;McLaren WM;Muffato M;Nag R;Overduin B;Pignatelli M;Pritchard B;Pritchard E;Riat HS;Ritchie GR;Ruffier M;Schuster M;Sheppard D;Sobral D;Taylor K;Thormann A;Trevanion S;White S;Wilder SP;Aken BL;Birney E;Cunningham F;Dunham I;Harrow J;Herrero J;Hubbard TJ;Johnson N;Kinsella R;Parker A;Spudich G;Yates A;Zadissa A;Searle SM
通讯作者：
Searle SM
影响因子：
64.5
作者：
CARTWRIGHT, CA;ECKHART, W;KAPLAN, PL
通讯作者：
KAPLAN, PL