In our previous study, a venom-based peptide named Gonearrestide (also named P13) was identified and demonstrated with an effective inhibition in the proliferation of colon cancer cells. In this study, we explored if P13 and its potent mutant M6 could promote the proliferation of human embryonic stem cells and even maintain their self-renewal. The structure-function relationship analysis on P13 and its potent mutant M6 were explored from the molecular mechanism of corresponding receptor activation by a series of inhibitor assay plus molecular and dynamics simulation studies. An interesting phenomenon is that P13 (and its potent mutant M6), an 18AA short peptide, can activate both FGF and TGFβ signaling pathways. We demonstrated that the underlying molecular mechanisms of P13 and M6 could cooperate with proteoglycans to complete the “dimerization” of FGFR and TGFβ receptors. Taken together, this study is the first research finding on a venom-based peptide that works on the FGF and TGF-β signaling pathways to maintain the self-renewal of hESCs.

中文翻译：

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基于毒液的新型肽（P13及其衍生物-M6）通过激活FGF和TGFβ信号通路来维持人类胚胎干细胞的自我更新。

在我们之前的研究中，鉴定了一种基于毒液的肽，名为Gonearrestide（也称为P13），并被证明可有效抑制结肠癌细胞的增殖。在这项研究中，我们探索了P13及其有效的突变体M6是否可以促进人类胚胎干细胞的增殖，甚至维持其自我更新。通过一系列抑制剂试验以及分子和动力学模拟研究，从相应受体激活的分子机理中探索了P13及其有效突变体M6的结构-功能关系分析。一个有趣的现象是P13（及其有效的突变体M6）是一种18AA短肽，可以激活FGF和TGFβ信号通路。我们证明了P13和M6的潜在分子机制可以与蛋白聚糖协同完成FGFR和TGFβ受体的“二聚化”。综上所述，这项研究是对基于毒液的肽的首次研究发现，该肽基于FGF和TGF-β信号通路来维持hESC的自我更新。