Experimental and Computational Studies Reveal Novel Interaction of Lymphocytes Antigen 6K to TGF-β Receptor Complex.
Experimental and Computational Studies Reveal Novel Interaction of Lymphocytes Antigen 6K to TGF-β Receptor Complex.
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DOI：
10.3390/ijms241612779
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发表时间：
2023-08-14
影响因子：
5.6
通讯作者：
Upadhyay, Geeta
中科院分区：
文献类型：
--
作者：
Andrys-Olek, Justyna;Selvanesan, Benson Chellakkan;Varghese, Sheelu;Arriaza, Ricardo Hernandez;Tiwari, Purushottam Babu;Chruszcz, Maksymilian;Borowski, Tomasz;Upadhyay, Geeta
在晚期转移癌中，转化生长因子-β信号促进癌细胞的迁移、侵袭和远距离定植。转化生长因子-β信号在肿瘤微环境中抑制抗肿瘤免疫反应，使肿瘤持续生长。转化生长因子-β在正常生理中发挥着重要作用，因此，高效、安全的转化生长因子-β抑制剂的高毒性阻碍了其临床开发也就不足为奇了。我们发现，LY6K在癌细胞中的表达增加导致转化生长因子-β信号的增加，而抑制LY6K可能导致转化生长因子-β信号的减少，从而减少体内肿瘤的生长。LY6K是一种高度癌症特异性的蛋白，除了睾丸外，它在正常器官中不表达。因此，LY6K是开发抑制肿瘤细胞转化生长因子-β信号的治疗策略的有效靶点。我们利用体外下拉实验和分子动力学模拟来了解转化生长因子-β受体与LY6K的复合体的结构决定因素。这种结合的方法使我们能够确定LY6K与转化生长因子-β受体复合体相互作用的关键残基和动力学。这些数据对于设计抑制LY6K表达肿瘤转化生长因子-β、诱导抗肿瘤免疫反应、抑制肿瘤生长和转移扩散的新药是至关重要的。
TGF-β signaling promotes migration, invasion, and distant colonization of cancer cells in advanced metastatic cancers. TGF-β signaling suppresses the anti-tumor immune response in a tumor microenvironment, allowing sustained tumor growth. TGF-β plays an important role in normal physiology; thus it is no surprise that the clinical development of effective and safe TGF-β inhibitors has been hampered due to their high toxicity. We discovered that increased expression of LY6K in cancer cells led to increased TGF-β signaling and that inhibition of LY6K could lead to reduced TGF-β signaling and reduced in vivo tumor growth. LY6K is a highly cancer-specific protein, and it is not expressed in normal organs except in the testes. Thus, LY6K is a valid target for developing therapeutic strategies to inhibit TGF-β signaling in cancer cells. We employed in vitro pull-down assays and molecular dynamics simulations to understand the structural determinants of the TGF-β receptor complex with LY6K. This combined approach allowed us to identify the critical residues and dynamics of the LY6K interaction with the TGF-β receptor complex. These data are critical in designing novel drugs for the inhibition of TGF-β in LY6K expressing cancer, induction of anti-tumor immune response, and inhibition of tumor growth and metastatic spread.
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影响因子：
11.2
作者：
AlHossiny M;Luo L;Frazier WR;Steiner N;Gusev Y;Kallakury B;Glasgow E;Creswell K;Madhavan S;Kumar R;Upadhyay G
通讯作者：
Upadhyay G
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
9.7
作者：
Selvanesan，Benson Chellakkan;Varghese，Sheelu;Upadhyay，Geeta
通讯作者：
Upadhyay，Geeta
影响因子：
16
作者：
Groppe, Jay;Hinck, Cynthia S.;Hinck, Andrew P.
通讯作者：
Hinck, Andrew P.
影响因子：
5.5
作者：
Wang L;Han H;Wang Z;Shi L;Yang M;Qin Y
通讯作者：
Qin Y