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 ␤-catenin that links desmosomal cadherins to intermediate filaments. Plakoglobin can also substitute for ␤-catenin in adherens junctions, providing a connection between E-cadherin and ␣-catenin. Association of ␤-catenin with E-cadherin and ␣-catenin is regulated by phosphorylation of specific tyrosine residues; modification of ␤-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 ␤-catenin, this modification is not always associated with disrupted association with junctional components. Protein tyrosine kinases present distinct specificities on ␤-catenin and plakoglobin, and phosphorylation of ␤-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 ␤-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 ␤-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 ␤-catenin-Tcf-4 complex observed in many epithelial tumor cells.␤-Catenin and plakoglobin (also known as ␥-catenin) are two closely related proteins essential for the establishment and maintenance of cell-cell contacts among epithelial cells. In adherens junctions, ␤-catenin links the cytosolic domain of the transmembrane protein E-cadherin to ␣-catenin, which in turn directly or indirectly associates with the actin cytoskeleton (2, 33, 38). Plakoglobin can substitute for ␤-catenin in adherens junctions. In addition, plakoglobin is a component of the desmosomes, where it mediates the association of desmosomal cadherins, desmocollin and desmoglein, to desmoplakin and the intermediate filament cytoskeleton (15,21). This role of plakoglobin is specific and cannot be exerted by ␤-catenin, even though both proteins are structurally similar. Besides this role, ␤-catenin also has a signaling activity as a member of the Wnt pathway. When released from E-cadherin and ␣-catenin, ␤-catenin can migrate to the nucleus where, through its interaction with the Tcf family of transcription factors, it can activate the transcription of a rapidly increasing number of genes involved in embryonic development and tumorigenesis (5, 37).Probably as a consequence of the importance of this pathway, the translocation of ␤-catenin to the nucleus is tightly controlled thro...

β-Catenin and Plakoglobin N- and C-tails Determine Ligand Specificity

“…Data from our group indicate that, although ␤-catenin and plakoglobin are closely related, the same kinases phosphorylate different residues in each. Moreover phosphorylation of equivalent residues has different effects on the interaction of plakoglobin and ␤-catenin with their cellular partners (28).…”

150thAnniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and Its Impairments in Pemphigus

“…Src, which interacts with EGFR, mainly phosphorylates Tyr86 in ( b -catenin, modifi es Tyr643 in PG, decreasing the interaction with E-cadherin and α -catenin and increasing the interaction with the α -catenin-equivalent protein in desmosomes, DPK (Miravet et al, 2003). These results suggest that tyrosine kinases like Src or Fer modulate desmosomes and adherens junctions differently.…”

Interactions of Plakoglobin and β-Catenin with Desmosomal Cadherins

“…It is also possible that posttranslational modifications of plakoglobin and/or Dsg modify the strength of their interaction, as has been documented for the phosphorylation of E-cadherin (7,33). Dsg2 is phosphorylated by the epidermal growth factor receptor (46), and several tyrosine kinases, including epidermal growth factor receptor, Src, and Fer/Fyn, have been reported to phosphorylate plakoglobin (47,48). It is not known, however, whether these modifications affect the affinity of plakoglobin-cadherin interactions.…”