Fyn is a downstream target of the pleiotrophin/receptor protein tyrosine phosphatase β/ζ-signaling pathway: Regulation of tyrosine phosphorylation of Fyn by pleiotrophin

Pleiotrophin (PTN the protein, Ptn the gene) signals downstream targets through inactivation of its receptor, the transmembrane receptor protein tyrosine phosphatase (RPTP)β/ζ, disrupting the balanced activity of RPTPβ/ζ and the activity of a constitutively active tyrosine kinase. As a consequence of the inactivation of RPTPβ/ζ, PTN stimulates a sharp increase in the levels of tyrosine phosphorylation of the substrates of RPTPβ/ζ in PTN-stimulated cells. We now report that the Src family member Fyn interacts with the intracellular domain of RPTPβ/ζ in a yeast two-hybrid system. We further demonstrate that Fyn is a substrate of RPTPβ/ζ, and that tyrosine phosphorylation of Fyn is sharply increased in PTN-stimulated cells. In previous studies, we demonstrated that β-catenin and β-adducin are targets of the PTN/RPTPβ/ζ-signaling pathway and defined the mechanisms through which tyrosine phosphorylation of β-catenin and β-adducin disrupts cytoskeletal protein complexes. We conclude that Fyn is a downstream target of the PTN/RPTPβ/ζ-signaling pathway and suggest that PTN coordinately regulates tyrosine phosphorylation of β-catenin, β-adducin, and Fyn through the PTN/RPTPβ/ζ-signaling pathway and that together Fyn, β-adducin, and β-catenin may be effectors of the previously described PTN-stimulated disruption of cytoskeletal stability, increased cell plasticity, and loss of cell-cell adhesion that are characteristic of PTN-stimulated cells and a feature of many human malignant cells in which mutations have established constitutive expression of the Ptn gene.