Pleiotrophin (PTN) was found to regulate tyrosine phosphorylation of -adducin through the PTN͞receptor protein tyrosine phosphatase (RPTP)͞ signaling pathway. We now demonstrate that PTN stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (PK) C substrate domain of -adducin through activation of either PKC ␣ or . We also demonstrate that PTN stimulates translocation of phosphoserine 713 and 726 -adducin either to nuclei, where it associates with nuclear chromatin and with centrioles of dividing cells, or to a membrane-associated site, depending on the phase of cell growth. Furthermore, we demonstrate that PTN stimulates the degradation of -adducin in PTN-stimulated cells. Phosphorylation of serines 713 and 726 in -adducin is known to markedly reduce the affinity of -adducin for spectrin and actin and to uncouple actin͞spectrin͞ -adducin multimeric complexes needed for cytoskeletal stability. The Ptn gene also is a proto-oncogene (12, 13). Its high-level importance in human malignancies is suggested because expression of the endogenous Ptn gene is seen frequently in many different highly malignant human neoplasms (14-22), and introduction of a dominant negative Ptn gene or targeted ribozymes into cells from malignancies with constitutive expression of the Ptn gene reverses the malignant phenotype to the phenotype of the premalignant cells both in vivo and in vitro, indicating that PTN signaling is responsible for the ''switch'' of the premalignant cell to the highly malignant phenotype (11,12,21,23,24).Recent studies have uncovered clues to the mechanisms by which PTN initiates this striking diversity of phenotypes in PTN-stimulated cells. Pleiotrophin signals through two functionally and structurally independent signaling domains (refs. 5, 11, and 12 and N. Zhang, R. Zhong, Z. Y. Wang, and T.F.D., unpublished data), each of which binds heparin (25), and each of which signals very different phenotypes. The N-terminal domain, when expressed with the endogenous signal peptide, transforms murine fibroblasts, whereas the C-terminal domain does not; however, the C-terminal domain of PTN induces rapid growth and a striking angiogenic phenotype when it is expressed with the endogenous signal peptide in the premalignant cell. Thus, the separate domains of PTN function independently of each other, signal different phenotypes, and, a priori, need to signal through two separate receptor-like proteins (5,11,12).One receptor that initiates PTN signaling is the transmembrane receptor protein tyrosine phosphatase (RPTP) ͞. The interaction of PTN with RPTP͞ induces receptor dimerization and inactivates the endogenous tyrosine phosphatase activity of RPTP͞, thereby disrupting the balanced activity of RPTP͞ and an unknown but constitutively active tyrosine kinase(s) on the mutual substrates of RPTP͞ and the tyrosine kinase and thus initiating a sharp and rapid increase in the steady state levels of tyrosine phosphorylation (26). The first substrate of RPTP͞ to be id...
