Abstract
BackgroundClaudin-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.ResultsHEK cells were transfected with EpCAM and wild type cld7 or cld7, where serine phopsphorylation or the palmitoylation sites (AA184, AA186) (cld7mPalm) were mutated. Exchange of individual serine phosphorylation sites did not significantly affect the GEM localization and the EpCAM association. Instead, cld7mPalm 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 cld7mPalm associates with TJ proteins.ConclusionCld7 palmitoylation prohibits TJ integration and fosters GEM recruitment. Via associated molecules, palmitoylated cld7 supports motility and invasion.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-015-0105-y) contains supplementary material, which is available to authorized users.
Highlights
Claudins, a family of closely related four-pass molecules, are essential components of tight junctions (TJ) in the apical region of epithelial cells
We focused on cld7 palmitoylation, as palmitoylation is of critical importance for glycolipid-enriched membrane domains (GEM) localization, complex formation and recruitment of cytoskeletal linker and cytosolic signaling molecules [48,49,50,51]
The molecular basis for driving cld7 out of TJ into GEM as well as the GEM-locationdependent associations remained to be explored. We approached these questions by transfecting HEK293 cells (HEK) cells with cld7, where serine phosphorylation sites and the palmitoylation site at the C-terminal cytoplasmic tail were mutated
Summary
Claudins (cld), a family of closely related four-pass molecules, are essential components of tight junctions (TJ) in the apical region of epithelial cells. As tumor cell dissemination requires loss of cell-cell adhesion, it was expected that claudins be downregulated in cancer. This was not consistently observed [3,5,6,7]. Claudin-7 (cld7), a tight junction (TJ) component, is found basolaterally and in the cytoplasm. Located cld is enriched in glycolipid-enriched membrane domains (GEM), where it associates with EpCAM (EpC). The conditions driving cld out of TJ into GEM, which is associated with a striking change in function, were not defined. We asked whether cld serines or palmitoylation affect cld location and protein, EpCAM, associations
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