Miravet Susana, Piedra José, Castaño Julio, Raurell Imma, Francí Clara, Duñach Mireia, García de Herreros Antonio
Unitat de Biofísica, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
Mol Cell Biol. 2003 Oct;23(20):7391-402. doi: 10.1128/MCB.23.20.7391-7402.2003.
Plakoglobin is a protein closely related to beta-catenin that links desmosomal cadherins to intermediate filaments. Plakoglobin can also substitute for beta-catenin in adherens junctions, providing a connection between E-cadherin and alpha-catenin. Association of beta-catenin with E-cadherin and alpha-catenin is regulated by phosphorylation of specific tyrosine residues; modification of beta-catenin Tyr654 and Tyr142 decreases binding to E-cadherin and alpha-catenin, respectively. We show here that plakoglobin can also be phosphorylated on tyrosine residues, but unlike beta-catenin, this modification is not always associated with disrupted association with junctional components. Protein tyrosine kinases present distinct specificities on beta-catenin and plakoglobin, and phosphorylation of beta-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 beta-catenin, modifies Tyr643 in plakoglobin, decreasing the interaction with E-cadherin and alpha-catenin and increasing the interaction with the alpha-catenin-equivalent protein in desmosomes, desmoplakin. The tyrosine kinase Fer, which modifies beta-catenin Tyr142, lessening its association with alpha-catenin, phosphorylates plakoglobin Tyr549 and exerts the contrary effect: it raises the binding of plakoglobin to alpha-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 beta-catenin-Tcf-4 complex observed in many epithelial tumor cells.
桥粒斑珠蛋白是一种与β-连环蛋白密切相关的蛋白质，它将桥粒钙黏着蛋白与中间丝连接起来。桥粒斑珠蛋白也可以在黏着连接中替代β-连环蛋白，在E-钙黏着蛋白和α-连环蛋白之间建立连接。β-连环蛋白与E-钙黏着蛋白和α-连环蛋白的结合受特定酪氨酸残基磷酸化的调节；β-连环蛋白Tyr654和Tyr142的修饰分别降低了与E-钙黏着蛋白和α-连环蛋白的结合。我们在此表明，桥粒斑珠蛋白也可以在酪氨酸残基上被磷酸化，但与β-连环蛋白不同的是，这种修饰并不总是与与连接成分的结合破坏相关。蛋白酪氨酸激酶对β-连环蛋白和桥粒斑珠蛋白具有不同的特异性，桥粒斑珠蛋白中与β-连环蛋白等效的酪氨酸残基的磷酸化对其与桥粒或黏着连接成分的相互作用有不同的影响。例如，主要使β-连环蛋白中的Tyr86磷酸化的Src使桥粒斑珠蛋白中的Tyr643发生修饰，减少了与E-钙黏着蛋白和α-连环蛋白的相互作用，并增加了与桥粒中与α-连环蛋白等效的蛋白质桥粒斑蛋白的相互作用。修饰β-连环蛋白Tyr142从而减少其与α-连环蛋白结合的酪氨酸激酶Fer，使桥粒斑珠蛋白Tyr549磷酸化并产生相反的效果：它增加了桥粒斑珠蛋白与α-连环蛋白的结合。这些结果表明，像Src或Fer这样的酪氨酸激酶对桥粒和黏着连接的调节方式不同。我们的结果还表明，Tyr549的磷酸化以及桥粒斑珠蛋白与黏着连接成分结合的增加可能导致在许多上皮肿瘤细胞中观察到的β-连环蛋白-Tcf-4复合物转录活性的上调。
