MET Activation by a Macrocyclic Peptide Agonist that Couples to Biological Responses Differently from HGF in a Context-Dependent Manner
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 ME...
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doaj-8e46a1946cd74e83b57544ad633c158f2020-11-25T01:32:42ZengMDPI AGInternational Journal of Molecular Sciences1422-00672018-10-011910314110.3390/ijms19103141ijms19103141MET Activation by a Macrocyclic Peptide Agonist that Couples to Biological Responses Differently from HGF in a Context-Dependent MannerWenyu Miao0Katsuya Sakai1Ryu Imamura2Kenichiro Ito3Hiroaki Suga4Tetsushi Sakuma5Takashi Yamamoto6Kunio Matsumoto7Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa 920-1192, JapanDivision of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa 920-1192, JapanDivision of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa 920-1192, JapanDepartment of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, JapanDepartment of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, JapanDepartment of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, JapanDepartment of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, JapanDivision of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa 920-1192, JapanNon-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.http://www.mdpi.com/1422-0067/19/10/3141HGFMET receptorsurrogate agonistpartial activationsignal transduction |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wenyu Miao Katsuya Sakai Ryu Imamura Kenichiro Ito Hiroaki Suga Tetsushi Sakuma Takashi Yamamoto Kunio Matsumoto |
spellingShingle |
Wenyu Miao Katsuya Sakai Ryu Imamura Kenichiro Ito Hiroaki Suga Tetsushi Sakuma Takashi Yamamoto Kunio Matsumoto MET Activation by a Macrocyclic Peptide Agonist that Couples to Biological Responses Differently from HGF in a Context-Dependent Manner International Journal of Molecular Sciences HGF MET receptor surrogate agonist partial activation signal transduction |
author_facet |
Wenyu Miao Katsuya Sakai Ryu Imamura Kenichiro Ito Hiroaki Suga Tetsushi Sakuma Takashi Yamamoto Kunio Matsumoto |
author_sort |
Wenyu Miao |
title |
MET Activation by a Macrocyclic Peptide Agonist that Couples to Biological Responses Differently from HGF in a Context-Dependent Manner |
title_short |
MET Activation by a Macrocyclic Peptide Agonist that Couples to Biological Responses Differently from HGF in a Context-Dependent Manner |
title_full |
MET Activation by a Macrocyclic Peptide Agonist that Couples to Biological Responses Differently from HGF in a Context-Dependent Manner |
title_fullStr |
MET Activation by a Macrocyclic Peptide Agonist that Couples to Biological Responses Differently from HGF in a Context-Dependent Manner |
title_full_unstemmed |
MET Activation by a Macrocyclic Peptide Agonist that Couples to Biological Responses Differently from HGF in a Context-Dependent Manner |
title_sort |
met activation by a macrocyclic peptide agonist that couples to biological responses differently from hgf in a context-dependent manner |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2018-10-01 |
description |
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. |
topic |
HGF MET receptor surrogate agonist partial activation signal transduction |
url |
http://www.mdpi.com/1422-0067/19/10/3141 |
work_keys_str_mv |
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