The C-terminal region Mesd peptide mimics full-length Mesd and acts as an inhibitor of Wnt/β-catenin signaling in cancer cells.
The C-terminal region Mesd peptide mimics full-length Mesd and acts as an inhibitor of Wnt/β-catenin signaling in cancer cells.
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DOI：
10.1371/journal.pone.0058102
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Lin C;Lu W;Zhang W;Londoño-Joshi AI;Buchsbaum DJ;Bu G;Li Y
虽然MESD被发现是WNT共同受体LRP5和LRP6的特异性分子内质网伴侣，但重组的MESD蛋白能够与细胞表面成熟的LRP5和LRP6结合，并作为LRP5/6调节剂的通用拮抗剂。在我们之前的研究中，我们发现Mesd的C-末端区域是与细胞表面成熟的LRP6结合的必要条件和充分条件，这在无脊椎动物的序列中是缺失的。在目前的研究中，我们进一步研究了C-端区Mesd多肽与LRP5/6的相互作用。我们发现，由Mesd C-端区衍生的多肽也在细胞表面阻断了Mesd与LRP5的结合。我们还发现，在Mesd C-末端有两个LRP5/6结合位点，其中包含几个带正电荷的残基。此外，我们还发现，与全长MESD蛋白一样，MESD C-末端区肽可以阻断WNT 3A和Rspodin1诱导的LRP5和LRP6表达细胞中的WNT/β-连环蛋白信号，抑制人乳腺HS578T细胞和前列腺癌PC-3细胞中的WNT/β-连环蛋白信号，并抑制癌细胞的增殖，尽管全长MESD蛋白比其肽更有效。最后，我们发现，全长Mesd蛋白及其C末端多肽的处理显著增加了化疗药物阿霉素对HS578T和PC-3细胞的细胞毒作用。综上所述，我们的结果表明，Mesd C-末端区域构成了LRP5/6的主要结合域，并且Mesd蛋白及其C-末端区肽在癌症中具有潜在的治疗价值。
While Mesd was discovered as a specialized molecular endoplasmic reticulum chaperone for the Wnt co-receptors LRP5 and LRP6, recombinant Mesd protein is able to bind to mature LRP5 and LRP6 on the cell surface and acts as a universal antagonist of LRP5/6 modulators. In our previous study, we found that the C-terminal region of Mesd, which is absent in sequences from invertebrates, is necessary and sufficient for binding to mature LRP6 on the cell surface. In the present studies, we further characterized the interaction between the C-terminal region Mesd peptide and LRP5/6. We found that Mesd C-terminal region-derived peptides block Mesd binding to LRP5 at the cell surface too. We also showed that there are two LRP5/6 binding sites within Mesd C-terminal region which contain several positively charged residues. Moreover, we demonstrated that the Mesd C-terminal region peptide, like the full-length Mesd protein, blocked Wnt 3A- and Rspodin1-induced Wnt/β-catenin signaling in LRP5- and LRP6- expressing cells, suppressed Wnt/β-catenin signaling in human breast HS578T cells and prostate cancer PC-3 cells, and inhibited cancer cell proliferation, although the full-length Mesd protein is more potent than its peptide. Finally, we found that treatment of the full-length Mesd protein and its C-terminal region peptide significantly increased chemotherapy agent Adriamycin-induced cytotoxicity in HS578T and PC-3 cells. Together, our results suggest that Mesd C-terminal region constitutes the major LRP5/6-binding domain, and that Mesd protein and its C-terminal region peptide have a potential therapeutic value in cancer.
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影响因子：
11.8
作者：
Chen, Shuo;Bubeck, Doryen;MacDonald, Bryan T.;Liang, Wen-Xue;Mao, Jian-Hua;Malinauskas, Tomas;Llorca, Oscar;Aricescu, A. Radu;Siebold, Christian;He, Xi;Jones, E. Yvonne
通讯作者：
Jones, E. Yvonne
影响因子：
4.8
作者：
Bourhis, Eric;Tam, Christine;Hannoush, Rami N.
通讯作者：
Hannoush, Rami N.
影响因子：
64.5
作者：
Culi, J;Mann, RS
通讯作者：
Mann, RS
影响因子：
64.5
作者：
Hsieh, JC;Lee, L;Holdener, BC
通讯作者：
Holdener, BC
影响因子：
4
作者：
Li, YH;Chen, JL;Bu, GJ
通讯作者：
Bu, GJ