MET Activation by a Macrocyclic Peptide Agonist that Couples to Biological Responses Differently from HGF in a Context-Dependent Manner.
MET Activation by a Macrocyclic Peptide Agonist that Couples to Biological Responses Differently from HGF in a Context-Dependent Manner.
复制标题
DOI：
10.3390/ijms19103141
复制
发表时间：
2018-10-12
影响因子：
5.6
通讯作者：
Matsumoto K
中科院分区：
文献类型：
--
作者：
Miao W;Sakai K;Imamura R;Ito K;Suga H;Sakuma T;Yamamoto T;Matsumoto K
生长因子受体的非天然配体具有不同的化学性质和不同的生物活性，具有潜在的治疗应用价值。我们之前使用二价大环肽制备了MET/肝细胞生长因子（HGF）受体激动剂。最高的met激活激动剂表现出与HGF效果难以区分的生物活性。在这项研究中，我们研究了被称为aML5-PEG11的大环肽部分激动剂诱导的MET激活、信号特征和生物反应。aML5-PEG11诱导MET的弱酪氨酸磷酸化，同时以与HGF相当的效力增强细胞迁移。aML5-PEG11诱导显著的AKT（蛋白激酶B）和ERK（细胞外信号调节激酶）激活，其效力和时间依赖性与HGF相当，这表明细胞运动的增强可归因于这些分子的激活。在胶原凝胶中的胆管癌细胞三维培养中，HGF诱导了MET、ERK和AKT的强烈激活，这与参与胆管发育和随后的管生成分支的基因表达增强有关。相比之下，aML5-PEG11诱导MET、ERK和AKT的边缘激活（接近检测限的水平），这与未能增强参与胆管发育的基因表达和缺乏管源性反应有关。因此，与HGF不同，aML5-PEG11激活MET与细胞外环境相关的生物反应是不同的。
Non-native ligands for growth factor receptors with distinct chemical properties and different biological activities have the potential to become therapeutic applications. We previously generated MET/hepatocyte growth factor (HGF) receptor agonists using bivalent macrocyclic peptides. The highest MET-activating agonists exhibited biological activity that was indistinguishable from the effects of HGF. In this study, we investigated MET activation, signal characteristics, and biological responses induced by a macrocyclic peptide partial agonist known as aML5-PEG11. aML5-PEG11 induced weak tyrosine phosphorylation of MET while enhancing cell migration with potency comparable to HGF. aML5-PEG11 induced marked AKT (protein kinase B) and ERK (extracellular signal-regulated kinase) activation at a comparable potency and time-dependency to HGF, which suggests that enhancement of cell motility is attributable to activation of these molecules. In a 3-D culture of bile duct cancer cells in collagen gel, HGF induced robust activation of MET, ERK, and AKT, which was associated with enhanced expression of genes involved in bile duct development and subsequent branching of tubulogenesis. In contrast, aML5-PEG11 induced marginal activation of MET, ERK, and AKT (levels near the detection limits), which was associated with failure to enhance the expression of genes involved in bile duct development and a lack of tubulogenic response. Thus, MET activation by aML5-PEG11 couples to biological responses differently from HGF in an extracellular context-dependent manner.
登录
查看更多内容
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
影响因子：
64.5
作者：
Ho CCM;Chhabra A;Starkl P;Schnorr PJ;Wilmes S;Moraga I;Kwon HS;Gaudenzio N;Sibilano R;Wehrman TS;Gakovic M;Sockolosky JT;Tiffany MR;Ring AM;Piehler J;Weissman IL;Galli SJ;Shizuru JA;Garcia KC
通讯作者：
Garcia KC
影响因子：
3.6
作者：
Harstad, EB;Guite, CA;Bradfield, CA
通讯作者：
Bradfield, CA
影响因子：
16
作者：
Heinrich, R;Neel, BG;Rapoport, TA
通讯作者：
Rapoport, TA
影响因子：
7.3
作者：
Bevan, D;Gherardi, E;Warn, R
通讯作者：
Warn, R