Pleiotrophin (PTN the protein, Ptn the gene) signals downstream targets through inactivation of its receptor. the transmembrane receptor protein tyrosine phosphatase (RPTP)beta/xi. disrupting the balanced activity of RPTP beta/xi and the activity of a constitutively active tyrosine kinase. As a consequence of the inactivation of RPTP beta/xi. PTN-Stimulates a sharp increase in the levels of tyrosine phosphorylation of the Substrates of RPTP beta/xi in PTN-stimulated cells, We now report that the Src family member Fyn interacts with the intracellular domain of RPTP beta/xi in a yeast two-hybrid system. We further demonstrate that Fyn is a substrate of RPTP beta/xi and that tyrosine phosphorylation of Fyn is sharply increased in PTN-stimulated cells. In previous studies ,we demonstrated that beta-catenin and beta-adducin are targets of the PTN/RPTP beta/xi-signafing pathway and defined the niechanisins through which tyrosine phosphorylation of beta-catenin and beta-adducin disrupts cytoskeletal protein complexes. We conclude that Fyn is a downstream target of the PTN/RPTP beta/xi-signa ling pathway and suggest that PTN coordinately regulates tyrosine phosphorylation of beta-catenin, beta-adducin, and Fyn through the PTN/RPTP beta/xi-signaling pathway and that together Fyn. beta-adducin and beta-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 Initiations have established constitutive expression of the Ptn gene. (c) 2005 Published by Elsevier Inc.