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The protein tyrosine phosphatase PTP1B is required for efficient delivery of N-cadherin to the cell surface.

ABSTRACT: PTP1B bound to mature N-cadherin promotes the association of beta-catenin into the complex, the stable expression of the complex at cell surface, and cadherin-mediated adhesion. Here we show that PTP1B is also required for N-cadherin precursor trafficking through early stages of the secretory pathway. This function does not require association of PTP1B with the precursor. In PTP1B null cells, the N-cadherin precursor showed higher sensitivity to endoglycosidase H than in cells reconstituted with the wild-type enzyme. It also showed slower kinetics of ER-to-Golgi translocation and processing. Trafficking of the viral stomatitis vesicular glycoprotein, VSV-G, however, revealed no differences between PTP1B null and reconstituted cells. N-cadherin precursor complexes contained similar levels of alpha- and beta-catenin regardless of PTP1B expression. In contrast, the associated p120 catenin (p120) was significantly reduced in absence of PTP1B expression. An N-cadherin precursor construct defective in p120 binding, and expressed in PTP1B reconstituted cells, showed higher sensitivity to endoglycosidase H and slower kinetics of processing than the wild-type precursor. Our results suggest that PTP1B promotes the association of p120 to the N-cadherin precursor, facilitating the trafficking of the complex from the ER to the Golgi complex.

SUBMITTER: Hernandez MV

PROVIDER: S-EPMC2854096 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:CD148 is a transmembrane tyrosine phosphatase that is expressed at cell junctions. Recent studies have shown that CD148 associates with the cadherin/catenin complex and p120 catenin (p120) may serve as a substrate. However, the role of CD148 in cadherin cell-cell adhesion remains unknown. Therefore, here we addressed this issue using a series of stable cells and cell-based assays. Wild-type (WT) and catalytically inactive (CS) CD148 were introduced to A431D (lacking classical cadherins), A431D/E-cadherin WT (expressing wild-type E-cadherin), and A431D/E-cadherin 764AAA (expressing p120-uncoupled E-cadherin mutant) cells. The effects of CD148 in cadherin adhesion were assessed by Ca2+ switch and cell aggregation assays. Phosphorylation of E-cadherin/catenin complex and Rho family GTPase activities were also examined. Although CD148 introduction did not alter the expression levels and complex formation of E-cadherin, p120, and β-catenin, CD148 WT, but not CS, promoted cadherin contacts and strengthened cell-cell adhesion in A431D/E-cadherin WT cells. This effect was accompanied by an increase in Rac1, but not RhoA and Cdc42, activity and largely diminished by Rac1 inhibition. Further, we demonstrate that CD148 reduces the tyrosine phosphorylation of p120 and β-catenin; causes the dephosphorylation of Y529 suppressive tyrosine residue in Src, a well-known CD148 site, increasing Src activity and enhancing the phosphorylation of Y228 (a Src kinase site) in p120, in E-cadherin contacts. Consistent with these findings, CD148 dephosphorylated both p120 and β-catenin in vitro. The shRNA-mediated CD148 knockdown in A431 cells showed opposite effects. CD148 showed no effects in A431D and A431D/E-cadherin 764AAA cells. In aggregate, these findings provide the first evidence that CD148 promotes E-cadherin adhesion by regulating Rac1 activity concomitant with modulation of p120, β-catenin, and Src tyrosine phosphorylation. This effect requires E-cadherin and p120 association.

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The protein tyrosine phosphatase PTP1B is required for efficient delivery of N-cadherin to the cell surface.

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