Pleiotrophin Regulates Serine Phosphorylation and the Cellular Distribution of Beta-Adducin Through Activation of Protein Kinase C

Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12407-12. doi: 10.1073/pnas.0505901102. Epub 2005 Aug 22.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Biological Transport, Active / drug effects
  • Calmodulin-Binding Proteins / chemistry
  • Calmodulin-Binding Proteins / metabolism*
  • Carrier Proteins / metabolism
  • Carrier Proteins / pharmacology*
  • Cytokines / metabolism
  • Cytokines / pharmacology*
  • Enzyme Activation / drug effects
  • HeLa Cells
  • Humans
  • Microscopy, Confocal
  • Models, Biological
  • Phosphorylation
  • Protein Kinase C / metabolism*
  • Serine / chemistry
  • Serine / metabolism*
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / metabolism

Substances

  • Calmodulin-Binding Proteins
  • Carrier Proteins
  • Cytokines
  • adducin
  • pleiotrophin
  • Serine
  • Protein Kinase C