Pleiotrophin regulates serine phosphorylation and the cellular distribution of beta-adducin through activation of protein kinase C.
Pleiotrophin (PTN) was found to regulate tyrosine phosphorylation of beta-adducin through the PTN/receptor protein tyrosine phosphatase (RPTP)beta/zeta 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 beta-adducin through activation of either PKC alpha or beta. We also demonstrate that PTN stimulates translocation of phosphoserine 713 and 726 beta-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 beta-adducin in PTN-stimulated cells. Phosphorylation of serines 713 and 726 in beta-adducin is known to markedly reduce the affinity of beta-adducin for spectrin and actin and to uncouple actin/spectrin/beta-adducin multimeric complexes needed for cytoskeletal stability. The data thus suggest that the PTN-stimulated phosphorylation of serines 713 and 726 in beta-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 beta-adducin phosphorylated in serines 713 and 726 and raise the possibility that beta-adducin functions in support of structure of heterochromatin and centrioles during mitosis.
Pariser
Harold
H
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Herradon
Gonzalo
G
Ezquerra
Laura
L
Perez-Pinera
Pablo
P
Deuel
Thomas F
TF
D001693:Biological Transport, Active / Q000187:drug effects; D002148:Calmodulin-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D008954:Models, Biological; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D012694:Serine / Q000737:chemistry / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D016207:Cytokines; D011493:Protein Kinase C; D012694:Serine; D000099291:Adducins; C066845:pleiotrophin