Adhesion-associated and PKC-modulated changes in serine/threonine phosphorylation of p120-catenin.

Xia X, Mariner DJ, Reynolds AB
Biochemistry. 2003 42 (30): 9195-204

PMID: 12885254 · DOI:10.1021/bi034597h

p120-catenin (p120) was originally identified as a tyrosine kinase substrate, and subsequently shown to regulate cadherin-mediated cell-cell adhesion. Binding of the p120 Arm domain to E-cadherin appears to be necessary to maintain adequate cadherin levels for strong adhesion. In contrast, the sequence amino-terminal to the Arm domain confers a negative regulatory function that is likely to be modulated by phosphorylation. Several agents that induce rapid changes in cell-cell adhesion, including PDBu, histamine, thrombin, and LPA, result in significant changes in p120 S/T phosphorylation. In some cases, these changes are PKC-dependent, but the relationship among adhesion, PKC activation, and p120 phosphorylation is unclear, in part because the relevant p120 phosphorylation sites are unknown. As a crucial step toward directly identifying the function of these modifications in adhesion, we have used two-dimensional tryptic mapping and site-directed mutagenesis to pinpoint the constitutive and PKC-modulated sites of p120 S/T phosphorylation. Of eight sites that have been identified, two were selectively phosphorylated in vitro by GSK3 beta, but in vivo treatment of cells with GSK3 beta inhibitors did not eliminate these sites. PKC stimulation in vivo induced potent dephosphorylation at S268, and partial dephosphorylation of several additional sites. Surprisingly, PKC also strongly induced phosphorylation at S873. These data directly link PKC activation to specific changes in p120 phosphorylation, and identify the target sites associated with the mechanism of PKC-dependent adhesive changes induced by agents such as histamine and PDBu.

MeSH Terms (27)

3T3 Cells Amino Acid Sequence Animals Catenins Cell Adhesion Cell Adhesion Molecules Cell Membrane Permeability Conserved Sequence Enzyme Activation Glycogen Synthase Kinase 3 Glycogen Synthase Kinase 3 beta Humans Mice Models, Biological Molecular Sequence Data Mutagenesis, Site-Directed Phosphoamino Acids Phosphoproteins Phosphorylation Protein Kinase C Serine Signal Transduction Species Specificity Staurosporine Substrate Specificity Threonine Tumor Cells, Cultured

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