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Molecular and Cellular Biology, October 2003, p. 7391-7402, Vol. 23, No. 20
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.20.7391-7402.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Unitat de Biofísica, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra,¹ Unitat de Biologia Cel·lular i Molecular, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, E-08003 Barcelona, Spain²

Received 9 June 2003/ Accepted 8 July 2003

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

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