title: The importance of claudin-7 palmitoylation on membrane subdomain localization and metastasis-promoting activities.
abstract: BACKGROUND
  Claudin-7 (cld7), a tight junction (TJ) component, is also found basolaterally and in the cytoplasm. Basolaterally located cld7 is enriched in glycolipid-enriched membrane domains (GEM), where it associates with EpCAM (EpC). The conditions driving cld7 out of TJ into GEM, which is associated with a striking change in function, were not defined. Thus, we asked whether cld7 serines or palmitoylation affect cld7 location and protein, particularly EpCAM, associations.
  
  
  RESULTS
  HEK cells were transfected with EpCAM and wild type cld7 or cld7, where serine phopsphorylation or the palmitoylation sites (AA184, AA186) (cld7(mPalm)) were mutated. Exchange of individual serine phosphorylation sites did not significantly affect the GEM localization and the EpCAM association. Instead, cld7(mPalm) was poorly recruited into GEM. This has consequences on migration and invasiveness as palmitoylated cld7 facilitates integrin and EpCAM recruitment, associates with cytoskeletal linker proteins and cooperates with MMP14, CD147 and TACE, which support motility, matrix degradation and EpCAM cleavage. On the other hand, only cld7(mPalm) associates with TJ proteins.
  
  
  CONCLUSIONS
  Cld7 palmitoylation prohibits TJ integration and fosters GEM recruitment. Via associated molecules, palmitoylated cld7 supports motility and invasion.
authors.affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, Im Neuenheimer Feld 365, 69120, Heidelberg, Germany. Sarah.Heiler@uni-heidelberg.de.
authors.forename: Sarah
authors.initials: S
authors.lastname: Heiler
authors.affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, Im Neuenheimer Feld 365, 69120, Heidelberg, Germany. Wei.Mu@uni-heidelberg.de.
authors.forename: Wei
authors.initials: W
authors.lastname: Mu
authors.affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, Im Neuenheimer Feld 365, 69120, Heidelberg, Germany. m.zoeller@uni-hd.de.
authors.forename: Margot
authors.initials: M
authors.lastname: Zöller
authors.affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, Im Neuenheimer Feld 365, 69120, Heidelberg, Germany. Florian.Thuma@uni-heidelberg.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Thuma
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D057167:Claudins / Q000235:genetics / Q000378:metabolism*; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D054878:Lipoylation; D021962:Membrane Microdomains / Q000378:metabolism*; D009154:Mutation; D009362:Neoplasm Metastasis / Q000473:pathology; D019108:Tight Junctions / Q000378:metabolism; D014162:Transfection
chemical_list: D000951:Antigens, Neoplasm; C473255:CLDN7 protein, human; D015815:Cell Adhesion Molecules; D057167:Claudins; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule