Pleiotrophin Regulates Serine Phosphorylation and the Cellular Distribution of β-Adducin through Activation of Protein Kinase C

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 35; pp. 12407 - 12412
• Main Authors: Pariser, Harold, Herradon, Gonzalo, Ezquerra, Laura, Perez-Pinera, Pablo, Deuel, Thomas F., Beutler, Ernest
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 30.08.2005; National Acad Sciences
• Subjects: Actins; Antibodies; Biological Sciences; Biological Transport, Active - drug effects; Calmodulin-Binding Proteins - chemistry; Calmodulin-Binding Proteins - metabolism; Carrier Proteins - metabolism; Carrier Proteins - pharmacology; Cell division; Cell nucleus; Cellular biology; Centrioles; Chromatin; Cytokines - metabolism; Cytokines - pharmacology; Endothelial cells; Enzyme Activation - drug effects; Epithelial cells; HeLa Cells; Humans; Microscopy, Confocal; Models, Biological; Phosphorylation; Protein Kinase C - metabolism; Proteins; Serine - chemistry; Serine - metabolism; Subcellular Fractions - drug effects; Subcellular Fractions - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0505901102

Pleiotrophin (PTN) was found to regulate tyrosine phosphorylation of β-adducin through the PTN/receptor protein tyrosine phosphatase (RPTP)β/ζ 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 β-adducin through activation of either PKC α or β. We also demonstrate that PTN stimulates translocation of phosphoserine 713 and 726 β-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 β-adducin in PTN-stimulated cells. Phosphorylation of serines 713 and 726 in β-adducin is known to markedly reduce the affinity of β-adducin for spectrin and actin and to uncouple actin/spectrin/β-adducin multimeric complexes needed for cytoskeletal stability. The data thus suggest that the PTN-stimulated phosphorylation of serines 713 and 726 in β-adducin disrupts cytoskeletal protein complexes and integrity, features demonstrated in both PTN-stimulated cells and of highly malignant cells that constitutively express the endogenous Ptn gene. The data also support the important conclusion that PTN determines the cellular location of β-adducin phosphorylated in serines 713 and 726 and raise the possibility that β-adducin functions in support of structure of heterochromatin and centrioles during mitosis.