Thrombomodulin is an ezrin-interacting protein that controls epithelial morphology and promotes collective cell migration
Resource
FASEB JOURNAL, 26(8), 3440-3452
Journal
The FASEB Journal
Pages
3440-3452
Date Issued
2012
Date
2012
Author(s)
Hsu, Yun-Yan
Shi, Guey-Yueh
Kuo, Cheng-Hsiang
Liu, Shu-Lin
Wu, Ching-Ming
Ma, Chih-Yuan
Lin, Feng-Yi
Yang, Hsi-Yuan
Wu, Hua-Lin
Abstract
Adhesive interactions between cells are needed to maintain tissue architecture during development, tissue renewal and wound healing. Thrombomodulin (TM) is an integral membrane protein that participates in cell-cell adhesion through its extracellular lectin-like domain. However, the molecular basis of TM-mediated cell-cell adhesion is poorly understood. Here, we demonstrate that TM is linked to the actin cytoskeleton via ezrin. In vitro binding assays showed that the TM cytoplasmic domain bound directly to the N-terminal domain of ezrin. Mutational analysis of the TM cytoplasmic domain identified (522)RKK(524) as important ezrin-binding residues. In epidermal epithelial A431 cells, TM colocalized with ezrin and actin filaments at cell-cell contacts. Knockdown of endogenous TM expression by RNA interference induced morphological changes and accelerated cell migration in A431 cells. Moreover, epidermal growth factor, upstream of ezrin activation, stimulated the interaction between ezrin and TM. In skin wound healing of mice, TM and ezrin were highly expressed in neoepidermis, implying that both proteins are key molecules in reepithelialization that requires collective cell migration of epithelial cells. Finally, exogenous expression of TM in TM-deficient melanoma A2058 cells promoted collective cell migration. In summary, TM, which associates with ezrin and actin filaments, maintains epithelial morphology and promotes collective cell migration.
Type
journal article
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