Cellular signaling and gene expression profiles evoked by a bivalent macrocyclic peptide that serves as an artificial MET receptor agonist.
Cellular signaling and gene expression profiles evoked by a bivalent macrocyclic peptide that serves as an artificial MET receptor agonist.
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DOI：
10.1038/s41598-018-34835-4
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发表时间：
2018-11-07
影响因子：
4.6
通讯作者：
Matsumoto K
中科院分区：
文献类型：
--
作者：
Miao W;Sakai K;Ozawa N;Nishiuchi T;Suzuki Y;Ito K;Morioka T;Umitsu M;Takagi J;Suga H;Matsumoto K
通过化学合成产生的生长因子受体的非天然配体可用于治疗。然而，非天然配体通常以与天然配体不同的方式调节细胞信号传导和生物反应。产生与天然配体相当的替代配体是一个具有挑战性的需求。在这里，我们研究了由能够高亲和力结合MET/肝细胞生长因子（HGF）受体的二价大环肽（aMD 5-PEG 11）引起的信号转导和基因表达的变化。aMD 5-PEG 11与MET胞外区的结合通过缺失IPT 3 − IPT 4结构域而消除，表明IPT 3 − IPT 4参与了aMD 5-PEG 11与MET受体的结合。aMD 5-PEG 11诱导MET受体的二聚化和活化，并促进细胞迁移，这与HGF诱导这些活性相当。信号激活谱表明aMD 5-PEG 11诱导细胞内信号分子的磷酸化，具有与HGF相似的强度和时间依赖性。在3-D培养中，aMD 5-PEG 11以及HGF诱导上皮小管形成并上调参与多细胞生物体发育的功能分类基因的相同集合。因此，由二价大环肽组成的非天然替代配体可以用作人工MET受体激动剂，其在功能上取代天然配体HGF。
Non-native ligands for growth factor receptors that are generated by chemical synthesis are applicable to therapeutics. However, non-native ligands often regulate cellular signaling and biological responses in a different manner than native ligands. Generation of surrogate ligands comparable to native ligands is a challenging need. Here we investigated changes in signal transduction and gene expression evoked by a bivalent macrocyclic peptide (aMD5-PEG11) capable of high-affinity binding to the MET/hepatocyte growth factor (HGF) receptor. Binding of aMD5-PEG11 to the MET extracellular region was abolished by deletion of the IPT3−IPT4 domain, indicating the involvement of IPT3−IPT4 in the binding of aMD5-PEG11 to the MET receptor. aMD5-PEG11 induced dimerization and activation of the MET receptor and promoted cell migration that was comparable to induction of these activities by HGF. Signal activation profiles indicated that aMD5-PEG11 induced phosphorylation of intracellular signaling molecules, with a similar intensity and time dependency as HGF. In 3-D culture, aMD5-PEG11 as well as HGF induced epithelial tubulogenesis and up-regulated the same sets of functionally classified genes involved in multicellular organism development. Thus, a non-native surrogate ligand that consisted of a bivalent macrocyclic peptide can serve as an artificial MET receptor agonist that functionally substitutes for the native ligand, HGF.
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影响因子：
16.6
作者：
Ito, Kenichiro;Sakai, Katsuya;Suzuki, Yoshinori;Ozawa, Naoya;Hatta, Tomohisa;Natsume, Tohru;Matsumoto, Kunio;Suga, Hiroaki
通讯作者：
Suga, Hiroaki
DOI：
10.3390/molecules180910514
发表时间：
2013-08-30
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Hipolito CJ;Tanaka Y;Katoh T;Nureki O;Suga H
通讯作者：
Suga H
影响因子：
64.5
作者：
Moraga I;Wernig G;Wilmes S;Gryshkova V;Richter CP;Hong WJ;Sinha R;Guo F;Fabionar H;Wehrman TS;Krutzik P;Demharter S;Plo I;Weissman IL;Minary P;Majeti R;Constantinescu SN;Piehler J;Garcia KC
通讯作者：
Garcia KC
影响因子：
7.3
作者：
Bevan, D;Gherardi, E;Warn, R
通讯作者：
Warn, R
影响因子：
4.8
作者：
Mungunsukh O;Lee YH;Bottaro DP;Day RM
通讯作者：
Day RM