Role of atypical protein kinase C in estradiol-triggered G1/S progression of MCF-7 cells

Mol Cell Biol. 2004 Sep;24(17):7643-53. doi: 10.1128/MCB.24.17.7643-7653.2004.

Abstract

Expression of a dominant negative atypical protein kinase C (aPKC), PKCzeta, prevents nuclear translocation of extracellular regulated kinase 2 (ERK-2), p27 nuclear reduction, and DNA synthesis induced by estradiol in human mammary cancer-derived MCF-7 cells. aPKC action upstream of these events has been analyzed. In hormone-stimulated NIH 3T3 and Cos cells ectopically expressing human estrogen receptor alpha (hERalpha), aPKC is activated by phosphatidylinositol 3-kinase (PI 3-kinase) and, in turn, controls the Ras/MEK-1/ERK cascade. In MCF-7 and Cos cells stimulated by hormone, PI 3-kinase activates PKCzeta by Thr410 phosphorylation. Serine phosphorylation of PKCzeta is simultaneously induced. PKCzeta activation leads to recruitment of Ras to a multimolecular complex that also includes hERalpha, Src, PI 3-kinase, and aPKC. We propose that PKCzeta pushes Ras and the signaling complex close together in such a way that it facilitates the Src-dependent Ras activation. This activation is crucial for the interplay between estradiol-triggered signaling and cell cycle machinery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p27
  • Enzyme Activation
  • Estradiol / metabolism*
  • Estrogen Receptor alpha
  • G1 Phase / physiology*
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • NIH 3T3 Cells
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Protein Subunits / metabolism
  • Protein Transport / physiology
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • S Phase / physiology*
  • Signal Transduction / physiology
  • Tumor Suppressor Proteins / metabolism
  • ras Proteins / metabolism
  • src-Family Kinases / metabolism

Substances

  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • Estrogen Receptor alpha
  • Isoenzymes
  • Protein Subunits
  • Receptors, Estrogen
  • Recombinant Fusion Proteins
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Estradiol
  • Phosphatidylinositol 3-Kinases
  • src-Family Kinases
  • protein kinase C zeta
  • Protein Kinase C
  • Mitogen-Activated Protein Kinase 1
  • ras Proteins