Integrated screens uncover a cell surface tumor suppressor gene KIRREL involved in Hippo pathway.
Integrated screens uncover a cell surface tumor suppressor gene KIRREL involved in Hippo pathway.
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DOI：
10.1073/pnas.2121779119
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发表时间：
2022-06-21
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
细胞表面蛋白是许多生物过程所必需的。然而，缺乏对参与肿瘤生长和/或存活的细胞表面蛋白的全面功能分析。利用全新设计的靶向1147种细胞表面蛋白的细胞表面sgRNA文库，我们通过体外和体内筛选概述了这些细胞表面蛋白在肿瘤生长中的功能。此外，我们还发现了一种新的肿瘤抑制基因KIRREL。此外，我们发现KIRREL通过KIRREL和SAV1之间的直接相互作用将SAV1招募到细胞膜上，从而激活Hippo通路。因此，我们的整合CRISPR筛选确定了在Hippo信号通路中起作用的肿瘤抑制基因KIRREL。细胞表面蛋白在多种生物过程中发挥着重要作用，并与癌症的发生密切相关。它们也是细胞身份的重要标志和药物干预的靶标。尽管它们在生物医学研究中具有巨大的潜力，但对细胞表面蛋白的全面功能分析仍然很少。在这里，我们利用一个全新设计的靶向细胞表面蛋白的文库，进行了体内CRISPR筛选，以评估细胞表面蛋白对肿瘤存活和增殖的影响。我们发现Kirrel1缺失在体内显著促进肿瘤生长。此外，KIRREL在基于特定Hippo通路报告基因的单独CRISPR筛选中显著富集。进一步的研究表明，KIRREL直接结合SAV1激活Hippo肿瘤抑制通路。总之，我们的综合筛选揭示了参与Hippo通路的细胞表面肿瘤抑制因子，并突出了这些方法在生物医学研究中的潜力。
Cell surface proteins are essential for many biological processes. However, a comprehensive functional analysis of cell surface proteins involved in tumor growth and/or survival is missing. With a de novo designed cell surface sgRNA library targeting 1,147 cell–surface proteins, we provide an overview of the functions of these cell surface proteins in tumor growth through both in vitro and in vivo screens. Moreover, we identified a novel tumor suppressor gene, KIRREL. Furthermore, we showed that KIRREL activates the Hippo pathway by recruiting SAV1 to the cell membrane through a direct interaction between KIRREL and SAV1. Thus, our integrated CRISPR screens identified a tumor suppressor gene, KIRREL, that acts in the Hippo signaling pathway. Cell surface proteins play essential roles in various biological processes and are highly related to cancer development. They also serve as important markers for cell identity and targets for pharmacological intervention. Despite their great potentials in biomedical research, comprehensive functional analysis of cell surface proteins remains scarce. Here, with a de novo designed library targeting cell surface proteins, we performed in vivo CRISPR screens to evaluate the effects of cell surface proteins on tumor survival and proliferation. We found that Kirrel1 loss markedly promoted tumor growth in vivo. Moreover, KIRREL was significantly enriched in a separate CRISPR screen based on a specific Hippo pathway reporter. Further studies revealed that KIRREL binds directly to SAV1 to activate the Hippo tumor suppressor pathway. Together, our integrated screens reveal a cell surface tumor suppressor involved in the Hippo pathway and highlight the potential of these approaches in biomedical research.
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影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
DOI：
10.1073/pnas.1808790115
发表时间：
2018-11-13
影响因子：
11.1
作者：
Bausch-Fluck D;Goldmann U;Müller S;van Oostrum M;Müller M;Schubert OT;Wollscheid B
通讯作者：
Wollscheid B
影响因子：
64.8
作者：
Kojima Y;Volkmer JP;McKenna K;Civelek M;Lusis AJ;Miller CL;Direnzo D;Nanda V;Ye J;Connolly AJ;Schadt EE;Quertermous T;Betancur P;Maegdefessel L;Matic LP;Hedin U;Weissman IL;Leeper NJ
通讯作者：
Leeper NJ
影响因子：
21.3
作者：
Er EE;Valiente M;Ganesh K;Zou Y;Agrawal S;Hu J;Griscom B;Rosenblum M;Boire A;Brogi E;Giancotti FG;Schachner M;Malladi S;Massagué J
通讯作者：
Massagué J
影响因子：
64.5
作者：
Li W;You L;Cooper J;Schiavon G;Pepe-Caprio A;Zhou L;Ishii R;Giovannini M;Hanemann CO;Long SB;Erdjument-Bromage H;Zhou P;Tempst P;Giancotti FG
通讯作者：
Giancotti FG