N-terminus-independent activation of c-Src via binding to a tetraspan(in) TM4SF5 in hepatocellular carcinoma is abolished by the TM4SF5 C-terminal peptide application
- Authors
- Song, H.E.; Lee, Y.; Kim, E.; Cho, C.Y.; Jung, O.; Lee, D.; Lee, E.G.; Nam, S.H.; Kang, M.; Macalino, S.J.Y.; Kim, J.E.; Jung, J.W.; Kwon, S.W.; Choi, S.; Lee, J.W.
- Issue Date
- 2021
- Publisher
- Ivyspring International Publisher
- Keywords
- c-Src; Metastasis; Protein-protein interaction; PTPIB; TM4SF5
- Citation
- Theranostics, v.11, no.16, pp 8092 - 8111
- Pages
- 20
- Journal Title
- Theranostics
- Volume
- 11
- Number
- 16
- Start Page
- 8092
- End Page
- 8111
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/62875
- DOI
- 10.7150/THNO.58739
- ISSN
- 1838-7640
- Abstract
- Active c-Src non-receptor tyrosine kinase localizes to the plasma membrane via N-terminal lipid modification. Membranous c-Src causes cancer initiation and progression. Even though transmembrane 4 L six family member 5 (TM4SF5), a tetraspan(in), can be involved in this mechanism, the molecular and structural influence of TM4SF5 on c-Src remains unknown. Methods: Here, we investigated molecular and structural details by which TM4SF5 regulated c-Src devoid of its N-terminus and how cell-penetrating peptides were able to interrupt c-Src activation via interference of c-Src-TM4SF5 interaction in hepatocellular carcinoma models. Results: The TM4SF5 C-terminus efficiently bound the c-Src SH1 kinase domain, efficiently to the inactively-closed form. The complex involved protein tyrosine phosphatase 1B able to dephosphorylate Tyr530. The c-Src SH1 domain alone, even in a closed form, bound TM4SF5 to cause c-Src Tyr419 and FAK Y861 phosphorylation. Homology modeling and molecular dynamics simulation studies predicted the directly interfacing residues, which were further validated by mutational studies. Cell penetration of TM4SF5 C-terminal peptides blocked the interaction of TM4SF5 with c-Src and prevented c-Src-dependent tumor initiation and progression in vivo. Conclusions: Collectively, these data demonstrate that binding of the TM4SF5 C-terminus to the kinase domain of inactive c-Src leads to its activation. Because this binding can be abolished by cell-penetrating peptides containing the TM4SF5 C-terminus, targeting this direct interaction may be an effective strategy for developing therapeutics that block the development and progression of hepatocellular carcinoma. © 2021 Ivyspring International Publisher. All rights reserved.
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Collections - College of Pharmacy > School of Pharmacy > 1. Journal Articles
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