Tyrosine Phosphorylation of Plakoglobin Causes Contrary Effects on Its Association with Desmosomes and Adherens Junction Components and Modulates β-Catenin-Mediated Transcription

Abstract

Plakoglobin is a protein closely related to β-catenin that links desmosomal cadherins to intermediate filaments. Plakoglobin can also substitute for β-catenin in adherens junctions, providing a connection between E-cadherin and α-catenin. Association of β-catenin with E-cadherin and α-catenin is regulated by phosphorylation of specific tyrosine residues; modification of β-catenin Tyr654 and Tyr142 decreases binding to E-cadherin and α-catenin, respectively. We show here that plakoglobin can also be phosphorylated on tyrosine residues, but unlike β-catenin, this modification is not always associated with disrupted association with junctional components. Protein tyrosine kinases present distinct specificities on β-catenin and plakoglobin, and phosphorylation of β-catenin-equivalent Tyr residues of plakoglobin affects its interaction with components of desmosomes or adherens junctions differently. For instance, Src, which mainly phosphorylates Tyr86 in β-catenin, modifies Tyr643 in plakoglobin, decreasing the interaction with E-cadherin and α-catenin and increasing the interaction with the α-catenin-equivalent protein in desmosomes, desmoplakin. The tyrosine kinase Fer, which modifies β-catenin Tyr142, lessening its association with α-catenin, phosphorylates plakoglobin Tyr549 and exerts the contrary effect: it raises the binding of plakoglobin to α-catenin. These results suggest that tyrosine kinases like Src or Fer modulate desmosomes and adherens junctions differently. Our results also indicate that phosphorylation of Tyr549 and the increased binding of plakoglobin to components of adherens junctions can contribute to the upregulation of the transcriptional activity of the β-catenin-Tcf-4 complex observed in many epithelial tumor cells.

ACKNOWLEDGMENTS

We thank D. Garcia-Quintana for critical reading of the manuscript. We also thank H. G. Pálmer for providing the K-ras transfectant clones, A. Mallabiabarrena for help with the confocal microscopy, and A. Ben-Ze'ev, A. Cano, A. Carrera, N. Heisterkamp, and L. Neckers for plasmids.

This work was supported by grants 01/045-00 (from Fundació La Caixa) to A.G.D.H., PM-99-0132 and PM99-0064 (from the Spanish Ministerio de Ciencia y Tecnología) to A.G.D.H. and M.D., respectively, and 2001SGR00410 and 2001SGR00197 (from Direcció General de Recerca). S.M., J.C., and I.R. were recipients of predoctoral fellowships from the Universitat Autònoma de Barcelona, the Spanish Ministerio de Educación y Ciencia, and the Ministerio de Sanidad, respectively.