Multiple post-translational modifications regulate E-cadherin transport during apoptosis.
E-cadherin is synthesized as a precursor and then undergoes cleavage by proprotein convertases. This processing is essential for E-cadherin maturation and cell adhesion. Loss of cell adhesion causes detachment-induced apoptosis, which is called anoikis. Anoikis can be inhibited despite loss of cell-matrix interactions by preserving E-cadherin-mediated cell-cell adhesion. Conversely, acute ... loss of E-cadherin sensitizes cells to apoptosis by unknown post-translational mechanisms. After treatment of breast cancer cells with drugs, we found that two independent modifications of E-cadherin inhibit its cell surface transport. First, O-linked β-N-acetylglucosamine (O-GlcNAc) modification of the cytoplasmic domain retains E-cadherin in the endoplasmic reticulum. Second, incomplete processing by proprotein convertases arrests E-cadherin transport late in the secretory pathway. We demonstrated these E-cadherin modifications (detected by specific lectins and antibodies) do not affect binding to α-catenin, β-catenin or γ-catenin. However, binding of E-cadherin to Type I gamma phosphatidylinositol phosphate kinase (PIPKIγ), a protein required for recruitment of E-cadherin to adhesion sites, was blocked by O-GlcNAc glycosylation (O-GlcNAcylation). Consequently, E-cadherin trafficking to the plasma membrane was inhibited. However, deletion mutants that cannot be O-GlcNAcylated continued to bind PIPKIγ, trafficked to the cell surface and delayed apoptosis, confirming the biological significance of the modifications and PIPKIγ binding. Thus, O-GlyNAcylation of E-cadherin accelerates apoptosis. Furthermore, cell-stress-induced inactivation of proprotein convertases, inhibited E-cadherin maturation, further exacerbating apoptosis. The modifications of E-cadherin by O-GlcNAcylation and lack of pro-region processing represent novel mechanisms for rapid regulation of cell surface transport of E-cadherin in response to intoxication.
Mesh Terms:
Acetylglucosamine, Animals, Apoptosis, Cadherins, Cell Membrane, Dogs, Endoplasmic Reticulum, Glycosylation, HEK293 Cells, Humans, MCF-7 Cells, Madin Darby Canine Kidney Cells, Models, Biological, Peptides, Phosphotransferases (Alcohol Group Acceptor), Protein Processing, Post-Translational, Protein Transport, Sequence Deletion, Stress, Physiological, Thapsigargin, Transfection
Acetylglucosamine, Animals, Apoptosis, Cadherins, Cell Membrane, Dogs, Endoplasmic Reticulum, Glycosylation, HEK293 Cells, Humans, MCF-7 Cells, Madin Darby Canine Kidney Cells, Models, Biological, Peptides, Phosphotransferases (Alcohol Group Acceptor), Protein Processing, Post-Translational, Protein Transport, Sequence Deletion, Stress, Physiological, Thapsigargin, Transfection
J. Cell. Sci.
Date: Jun. 01, 2012
PubMed ID: 22375065
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