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

Haeng Eun Song, Yoonji Lee, Eunmi Kim, Chang Yun Cho, Oisun Jung, Doohyung Lee, Eun Goo Lee, Seo Hee Nam, Minkyung Kang, Stephani Joy Y. Macalino, Ji Eon Kim, Jae Woo Jung, Sung Won Kwon, Sun Choi, Jung Weon Lee

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Pages (from-to)8092-8111
Number of pages20
JournalTheranostics
Volume11
Issue number16
DOIs
StatePublished - 2021

Keywords

  • Metastasis
  • PTPIB
  • Protein-protein interaction
  • TM4SF5
  • c-Src

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this