EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis.
EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis.
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EHD1 依赖性 IGF-1 受体向细胞表面的运输对于尤文肉瘤肿瘤的发生和转移至关重要。
DOI：
10.1038/s42003-023-05125-1
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发表时间：
2023-07-20
影响因子：
5.9
通讯作者：
Band, Hamid
中科院分区：
文献类型：
--
作者：
Chakraborty, Sukanya;Bhat, Aaqib M. M.;Mushtaq, Insha;Luan, Haitao;Kalluchi, Achyuth;Mirza, Sameer;Storck, Matthew D. D.;Chaturvedi, Nagendra;Lopez-Guerrero, Jose Antonio;Llombart-Bosch, Antonio;Machado, Isidro;Scotlandi, Katia;Meza, Jane L. L.;Ghosal, Gargi;Coulter, Donald W. W.;Rowley, M. Jordan;Band, Vimla;Mohapatra, Bhopal C. C.;Band, Hamid
Eps15同源结构域包含1(EHD1)蛋白的过度表达与肿瘤的发生有关，但其核心功能是否作为细胞表面受体的细胞内交通调节在肿瘤的发生中发挥作用尚不清楚。我们发现EHD1在尤文肉瘤(EWS)中高表达，EHD1mRNA的高表达表明患者的生存期较短。ShRNA敲除和CRISPR敲除与小鼠EHD1的拯救建立了EHD1在肿瘤发生和转移中的要求。RTK抗体阵列证实IGF-1R是EWS中EHD1调节的靶点。在机制上，我们证明了EHD1对内吞循环和高尔基体对IGF-1R质膜运输的要求，以维持其表面表达和下游信号转导。相反，依赖于EHD1过度表达的夸大致癌特征需要IGF-1R的表达和激酶活性。我们的发现将RTK交通调节定义为EHD1过度表达依赖的肿瘤发生的一种近端机制，影响EWS中的IGF-1R，支持IGF-1R和EHD1共同靶向的可能性。EHD1在尤文肉瘤中过表达，在调节IGF-1R的细胞转运和质膜表达的同时，也是转移和肿瘤发生所必需的。
Overexpression of the EPS15 Homology Domain containing 1 (EHD1) protein has been linked to tumorigenesis but whether its core function as a regulator of intracellular traffic of cell surface receptors plays a role in oncogenesis remains unknown. We establish that EHD1 is overexpressed in Ewing sarcoma (EWS), with high EHD1 mRNA expression specifying shorter patient survival. ShRNA-knockdown and CRISPR-knockout with mouse Ehd1 rescue established a requirement of EHD1 for tumorigenesis and metastasis. RTK antibody arrays identified IGF-1R as a target of EHD1 regulation in EWS. Mechanistically, we demonstrate a requirement of EHD1 for endocytic recycling and Golgi to plasma membrane traffic of IGF-1R to maintain its surface expression and downstream signaling. Conversely, EHD1 overexpression-dependent exaggerated oncogenic traits require IGF-1R expression and kinase activity. Our findings define the RTK traffic regulation as a proximal mechanism of EHD1 overexpression-dependent oncogenesis that impinges on IGF-1R in EWS, supporting the potential of IGF-1R and EHD1 co-targeting. EHD1 is overexpressed in Ewing sarcoma and required for metastasis and tumorigenesis while regulating cellular trafficking and plasma membrane expression of IGF-1R.
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影响因子：
6.4
作者：
Antonio Lopez-Guerrero, Jose;Machado, Isidro;Llombart-Bosch, Antonio
通讯作者：
Llombart-Bosch, Antonio
哺乳动物细胞和秀丽隐杆线虫中的生化和功能比较揭示了EHD蛋白的共享和不同作用。
影响因子：
--
作者：
George, Manju;Ying, GuoGuang;Rainey, Mark A.;Solomon, Aharon;Parikh, Pankit T.;Gao, Qingshen;Band, Vimla;Band, Hamid
通讯作者：
Band, Hamid
影响因子：
3.7
作者：
Cironi, Luisa;Riggi, Nicolo;Stamenkovic, Ivan
通讯作者：
Stamenkovic, Ivan
影响因子：
50.3
作者：
Ebinger S;Özdemir EZ;Ziegenhain C;Tiedt S;Castro Alves C;Grunert M;Dworzak M;Lutz C;Turati VA;Enver T;Horny HP;Sotlar K;Parekh S;Spiekermann K;Hiddemann W;Schepers A;Polzer B;Kirsch S;Hoffmann M;Knapp B;Hasenauer J;Pfeifer H;Panzer-Grümayer R;Enard W;Gires O;Jeremias I
通讯作者：
Jeremias I
影响因子：
8
作者：
Gazdar, A. F.
通讯作者：
Gazdar, A. F.