Molecular basis for MMP9 induction and disruption of epithelial cell-cell contacts by galectin-3.
Dynamic modulation of the physical contacts between neighboring cells is integral to epithelial processes such as tissue repair and cancer dissemination. Induction of matrix metalloproteinase (MMP) activity contributes to the disassembly of intercellular junctions and the degradation of the extracellular matrix, thus mitigating the physical constraint to cell movement. Using the cornea as a model, we show here that a carbohydrate-binding protein, galectin-3, promotes cell-cell detachment and redistribution of the tight junction protein occludin through its N-terminal polymerizing domain. Notably, we demonstrate that galectin-3 initiates cell-cell disassembly by inducing matrix metalloproteinase expression in a manner that is dependent on the interaction with and clustering of the matrix metalloproteinase inducer CD147 (also known as EMMPRIN and basigin) on the cell surface. Using galectin-3-knockout mice in an in vivo model of wound healing, we further show that increased synthesis of MMP9 at the leading edge of migrating epithelium is regulated by galectin-3. These findings establish a new galectin-3-mediated regulatory mechanism for induction of metalloproteinase expression and disruption of cell-cell contacts required for cell motility in migrating epithelia.
Schepens Eye Research Institute and Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
Jerome
J
Mauris
Schepens Eye Research Institute and Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
Ashley M
AM
Woodward
New England Eye Center and Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02111, USA.
Zhiyi
Z
Cao
New England Eye Center and Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02111, USA Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA.
Noorjahan
N
Panjwani
Schepens Eye Research Institute and Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA pablo_argueso@meei.harvard.edu.
Pablo
P
Argüeso
D000818:Animals; D051926:Basigin / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D037502:Galectin 3 / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014162:Transfection
D037502:Galectin 3; D051926:Basigin; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
Cellular plasticity; Galectin-3; Migrating epithelia