Pariser Harold, Ezquerra Laura, Herradon Gonzalo, Perez-Pinera Pablo, Deuel Thomas F
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Biochem Biophys Res Commun. 2005 Jul 8;332(3):664-9. doi: 10.1016/j.bbrc.2005.05.007.
Pleiotrophin (PTN the protein, Ptn the gene) signals downstream targets through inactivation of its receptor, the transmembrane receptor protein tyrosine phosphatase (RPTP)beta/zeta, disrupting the balanced activity of RPTPbeta/zeta and the activity of a constitutively active tyrosine kinase. As a consequence of the inactivation of RPTPbeta/zeta, PTN stimulates a sharp increase in the levels of tyrosine phosphorylation of the substrates of RPTPbeta/zeta in PTN-stimulated cells. We now report that the Src family member Fyn interacts with the intracellular domain of RPTPbeta/zeta in a yeast two-hybrid system. We further demonstrate that Fyn is a substrate of RPTPbeta/zeta, 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/RPTPbeta/zeta-signaling pathway and defined the mechanisms 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/RPTPbeta/zeta-signaling pathway and suggest that PTN coordinately regulates tyrosine phosphorylation of beta-catenin, beta-adducin, and Fyn through the PTN/RPTPbeta/zeta-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 mutations have established constitutive expression of the Ptn gene.
多效生长因子（蛋白质为PTN，基因为Ptn）通过使其受体——跨膜受体蛋白酪氨酸磷酸酶（RPTP）β/ζ失活来向下游靶点发出信号，从而破坏RPTPβ/ζ的平衡活性以及一种组成型活性酪氨酸激酶的活性。由于RPTPβ/ζ失活，多效生长因子在其刺激的细胞中会刺激RPTPβ/ζ底物的酪氨酸磷酸化水平急剧升高。我们现在报告，Src家族成员Fyn在酵母双杂交系统中与RPTPβ/ζ的细胞内结构域相互作用。我们进一步证明Fyn是RPTPβ/ζ的底物，并且在多效生长因子刺激的细胞中Fyn的酪氨酸磷酸化急剧增加。在先前的研究中，我们证明β-连环蛋白和β-内收蛋白是多效生长因子/RPTPβ/ζ信号通路的靶点，并确定了β-连环蛋白和β-内收蛋白的酪氨酸磷酸化破坏细胞骨架蛋白复合物的机制。我们得出结论，Fyn是多效生长因子/RPTPβ/ζ信号通路的下游靶点，并表明多效生长因子通过多效生长因子/RPTPβ/ζ信号通路协调调节β-连环蛋白、β-内收蛋白和Fyn的酪氨酸磷酸化，并且Fyn、β-内收蛋白和β-连环蛋白可能共同作为先前描述的多效生长因子刺激导致的细胞骨架稳定性破坏、细胞可塑性增加以及细胞间黏附丧失的效应分子，这些是多效生长因子刺激细胞的特征，也是许多人类恶性细胞的特征，在这些恶性细胞中已发生突变导致Ptn基因的组成型表达。
