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T?RIII/?-arrestin2 regulates integrin ?5?1 trafficking, function, and localization in epithelial cells.

ABSTRACT: The type III TGF-? receptor (T?RIII) is a ubiquitous co-receptor for TGF-? superfamily ligands with roles in suppressing cancer progression, in part through suppressing cell motility. Here we demonstrate that T?RIII promotes epithelial cell adhesion to fibronectin in a ?-arrestin2 dependent and TGF-?/BMP independent manner by complexing with active integrin ?5?1, and mediating ?-arrestin2-dependent ?5?1 internalization and trafficking to nascent focal adhesions. T?RIII-mediated integrin ?5?1 trafficking regulates cell adhesion and fibronectin fibrillogenesis in epithelial cells, as well as ?5 localization in breast cancer patients. We further demonstrate that increased T?RIII expression correlates with increased ?5 localization at sites of cell-cell adhesion in breast cancer patients, while higher T?RIII expression is a strong predictor of overall survival in breast cancer patients. These data support a novel, clinically relevant role for T?RIII in regulating integrin ?5 localization, reveal a novel crosstalk mechanism between the integrin and TGF-? superfamily signaling pathways and identify ?-arrestin2 as a regulator of ?5?1 trafficking.

SUBMITTER: Mythreye K

PROVIDER: S-EPMC3835656 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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TβRIII/β-arrestin2 regulates integrin α5β1 trafficking, function, and localization in epithelial cells.

Mythreye K K Knelson E H EH Gatza C E CE Gatza M L ML Blobe G C GC

Oncogene 20120507 11

The type III TGF-β receptor (TβRIII) is a ubiquitous co-receptor for TGF-β superfamily ligands with roles in suppressing cancer progression, in part through suppressing cell motility. Here we demonstrate that TβRIII promotes epithelial cell adhesion to fibronectin in a β-arrestin2 dependent and TGF-β/BMP independent manner by complexing with active integrin α5β1, and mediating β-arrestin2-dependent α5β1 internalization and trafficking to nascent focal adhesions. TβRIII-mediated integrin α5β1 tra ...[more]

PMID: 22562249

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Project description:Dendritic cell (DC) expression of CD103, the α subunit of αEβ7 integrin, is thought to enable DC interactions with E-cadherin-expressing gastrointestinal epithelia for improved mucosal immunosurveillance. In the stomach, efficient DC surveillance of the epithelial barrier is crucial for the induction of immune responses to H. pylori, the causative agent of peptic ulcers and gastric cancer. However, gastric DCs express only low levels of surface CD103, as we previously showed. We here tested the hypothesis that intracellular pools of CD103 in human gastric DCs can be redistributed to the cell surface for engagement of epithelial cell-expressed E-cadherin to promote DC-epithelial cell adhesion. In support of our hypothesis, immunofluorescence analysis of tissue sections showed that CD103+ gastric DCs were preferentially localized within the gastric epithelial layer. Flow cytometry and imaging cytometry revealed that human gastric DCs expressed intracellular CD103, corroborating our previous findings in monocyte-derived DCs (MoDCs). Using confocal microscopy, we show that CD103 was present in endosomal compartments, where CD103 partially co-localized with clathrin, early endosome antigen-1 and Rab11, suggesting that CD103 undergoes endosomal trafficking similar to β1 integrins. Dynamic expression of CD103 on human MoDCs was confirmed by internalization assay. To analyze whether DC-expressed CD103 promotes adhesion to E-cadherin, we performed adhesion and spreading assays on E-cadherin-coated glass slides. In MoDCs generated in the presence of retinoic acid, which express increased CD103, intracellular CD103 significantly redistributed toward the E-cadherin-coated glass surface. However, DCs spreading and adhesion did not differ between E-cadherin-coated slides and slides coated with serum alone. In adhesion assays using E-cadherin-positive HT-29 cells, DC binding was significantly improved by addition of Mn2+ and decreased in the presence of EGTA, consistent with the dependence of integrin-based interactions on divalent cations. However, retinoic acid failed to increase DC adhesion, and a CD103 neutralizing antibody was unable to inhibit DC binding to the E-cadherin positive cells. In contrast, a blocking antibody to DC-expressed E-cadherin significantly reduced DC binding to the epithelium. Overall, these data indicate that CD103 engages in DC-epithelial cell interactions upon contact with epithelial E-cadherin, but is not a major driver of DC adhesion to gastrointestinal epithelia.

Dataset Information

T?RIII/?-arrestin2 regulates integrin ?5?1 trafficking, function, and localization in epithelial cells.

Publications

TβRIII/β-arrestin2 regulates integrin α5β1 trafficking, function, and localization in epithelial cells.

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