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S. M. Gallagher, A. A. Deora, N. J. Philp; A Role for Monocarboxylate Transporters in RPE Cell Migration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2435.
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The retinal pigment epithelium (RPE) is normally non-proliferative, but in response to injury, these cells become both proliferative and migratory. We have recently shown that the proton-coupled monocarboxylate transporter (MCT) 4 is upregulated in metastatic cancer cells and that silencing MCT4 slows cell migration. In vivo, the RPE expresses two MCTs which regulate the transepithelial flux of lactate from the retina to the choroidal vasculature; MCT1 in the apical and MCT3 in the basolateral membrane. When RPE cells are cultured in vitro, there is a downregulation of MCT3 and an upregulation of MCT4 expression. MCT1, 3 and 4 have an accessory subunit, CD147, which was initially identified as a matrix metalloproteinase inducer. CD147 also interacts with β1-integrins, cell-substrate adhesion molecules necessary for cell attachment and migration. In these studies, we examined whether MCTs play a role in RPE cell migration, occurring after retinal injury.
WT and MCT3 KO mice were used to examine interaction of MCT3/CD147 with β1-integrin in situ. ARPE-19 cells were used for biochemical and wounding assays. Immunofluorescence confocal microscopy was used to examine changes in protein expression and distribution after scratch wounding with or without gene silencing.
In mouse RPE, MCT3, but not MCT1, colocalized and coimmunoprecipitated with β1-integrin in the RPE. Loss of MCT3 expression in the RPE led to a redistribution of β1-integrin to the lateral border of RPE cells in aged mice. In vitro, MCT4 colocalized with β1-integrin at the basolateral membrane of ARPE-19 cells and coimmunoprecipitated with both MCT4 and CD147. In scratch wound assays, silencing MCT4 or CD147 resulted in slowed cell migration. In contrast, β1-integrin did not coimmunoprecipitate with MCT1 nor did silencing MCT1 slow RPE migration. Additionally, immunofluorescence confocal microscopy revealed that MCT4 expression is concentrated at the leading edge of migrating cells, where it colocalized with β1-integrin.
These results establish for the first time that MCT3 and MCT4 associate with β1-integrin in vivo and in vitro, indicating that these transporters may be important in stabilizing integrin-mediated attachment. In addition, we have found that MCT4 plays a role in the regulation of cell migration during wound healing in vitro. Taken together, these data suggest that MCT4 may be a potential therapeutic target in the treatment of diseases characterized by uncontrolled cell migration such as PVR.
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