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
- 주제(키워드) c-Src , metastasis , protein-protein interaction , PTPIB , TM4SF5
- 주제(기타) Medicine, Research & Experimental
- 설명문(일반) [Song, Haeng Eun; Kim, Eunmi; Cho, Chang Yun; Jung, Oisun; Lee, Doohyung; Lee, Eun Goo; Nam, Seo Hee; Kang, Minkyung; Kim, Ji Eon; Jung, Jae Woo; Kwon, Sung Won; Lee, Jung Weon] Seoul Natl Univ, Coll Pharm, Dept Pharm, Seoul 08826, South Korea; [Song, Haeng Eun; Kim, Eunmi; Cho, Chang Yun; Jung, Oisun; Lee, Doohyung; Lee, Eun Goo; Nam, Seo Hee; Kang, Minkyung; Kim, Ji Eon; Kwon, Sung Won; Lee, Jung Weon] Seoul Natl Univ, Res Inst Pharmaceut Sci, Seoul 08826, South Korea; [Lee, Yoonji; Macalino, Stephani Joy Y.; Choi, Sun] Ewha Womans Univ, Coll Pharm, Global AI Drug Discovery Ctr, Seoul 03760, South Korea; [Lee, Yoonji; Macalino, Stephani Joy Y.; Choi, Sun] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Lee, Yoonji] Chung Ang Univ, Coll Pharm, Seoul 06974, South Korea; [Jung, Jae Woo; Lee, Jung Weon] Seoul Natl Univ, Interdisciplinary Program Genet Engn, Seoul 08826, South Korea
- 등재 SCIE, SCOPUS
- OA유형 gold, Green Published
- 발행기관 IVYSPRING INT PUBL
- 발행년도 2021
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000183510
- 본문언어 영어
- Published As http://dx.doi.org/10.7150/thno.58739
- PubMed https://pubmed.ncbi.nlm.nih.gov/34335982
초록/요약
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.
more