title: Differential regulation of cellular functions by the C-termini of transmembrane 4 L six family proteins in 2- or 3-dimensional environment.
abstract: The transmembrane 4 L six family proteins TM4SF1, TM4SF4, and TM4SF5 share 40-50% overall sequence identity, but their C-terminus identity is limited. It may be likely that the C-termini of the members are important and unique for own regulatory functions. We thus examined how the TM4SF5 C-terminus affected cellular functions differentially from other family members. Using colon cancer cells expressing wildtype (WT), C-terminus-deleted, or chimeric mutants, diverse cellular functions were explored in 2-dimensional (2D) and 3-dimensional (3D) condition. The C-termini of the proteins were relatively comparable with respect to 2D cell proliferation, although each C-terminal-deletion mutant exhibited increased proliferation relative to the WT. Using chimeric constructs, we found that the TM4SF5 C-terminus was critical for regulating the diverse metastatic functions of TM4SF5, and could positively replace the C-termini of other family members. Replacement of the TM4SF1 or TM4SF4 C-terminus with that of TM4SF5 increased spheroids growth, transwell migration, and invasive dissemination from spheroids in 3D collagen gels. TM4SF5-mediated effects required its extracellular loop 2 linked to the C-terminus via the transmembrane domain 4, with causing c-Src activation. Altogether, the C-terminus of TM4SF5 appears to mediate pro-migratory roles, depending on a structural relay from the second extracellular loop to the C-terminus.
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Jin-Gyu
authors.initials: JG
authors.lastname: Cheong
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.|Systems Biotechnology Research Center, Korea Institute of Science and Technology (KIST), Gangneung-si, Gangwon-do 25451, Republic of Korea.
authors.forename: Dae-Geun
authors.initials: DG
authors.lastname: Song
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Haeng Eun
authors.initials: HE
authors.lastname: Song
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Fedor
authors.initials: F
authors.lastname: Berditchevski
authors.affiliation: Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Seo Hee
authors.initials: SH
authors.lastname: Nam
authors.affiliation: Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Jae Woo
authors.initials: JW
authors.lastname: Jung
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Ji Eon
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Somi
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Chang Yun
authors.initials: CY
authors.lastname: Cho
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.|Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000954:Antigens, Surface; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; C429031:TM4SF4 protein, human; C111029:TM4SF5 protein, human; C074075:TM4SF1 protein, human
keywords: 3D cell culture; migration; proliferation; spheroids; transmembrane 4 L six family