Activation of Akt/PDK signaling in macrophages upon binding of receptor-recognized forms of alpha2-macroglobulin to its cellular receptor: effect of silencing the CREB gene

J Cell Biochem. 2004 Nov 15;93(5):1020-32. doi: 10.1002/jcb.20233.

Abstract

Macrophage binding of receptor-recognized forms of alpha2-macrogobulin (alpha2M*) significantly increases cAMP, CREB, and activated CREB. We have now examined the participation of the PI 3-kinase/PDK/Akt/p70s6k signaling cascade in alpha2M*-induced cellular proliferation and also studied the role of CREB in these events. Exposure of cells to alpha2M* caused an approximately 2-fold increase in CREB and its phosphorylation at Ser133, phosphorylation of the regulatory subunit of PI 3-kinase, Akt phosphorylation at Ser473 or Thr308, and phosphorylated 70s6k. Silencing of the CREB gene with dsRNA homologous in sequence to the target gene, markedly reduced the levels of CREB mRNA activation of CREB, PI 3-kinase, Akt, and p70s6k in alpha2M*-stimulated macrophages. We conclude that in murine peritoneal macrophages, alpha2M*-induced increase of cAMP is involved in cellular proliferation and this process is mediated by the PI 3-kinase signaling cascade.

Publication types

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

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Androstadienes / metabolism
  • Animals
  • Chromones / metabolism
  • Cyclic AMP Response Element-Binding Protein / genetics*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Enzyme Activation
  • Enzyme Inhibitors / metabolism
  • Gene Silencing
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism*
  • Macrophages, Peritoneal / metabolism*
  • Mice
  • Morpholines / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction / physiology*
  • Wortmannin
  • alpha-Macroglobulins / metabolism*

Substances

  • Androstadienes
  • Chromones
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Subunits
  • Proto-Oncogene Proteins
  • alpha-Macroglobulins
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Wortmannin