Protein kinase A-mediated gating of neuregulin-dependent ErbB2-ErbB3 activation underlies the synergistic action of cAMP on Schwann cell proliferation

J Biol Chem. 2008 Dec 5;283(49):34087-100. doi: 10.1074/jbc.M802318200. Epub 2008 Sep 17.

Abstract

In Schwann cells (SCs), cyclic adenosine monophosphate (cAMP) enhances the action of neuregulin, the most potent known mitogen for SCs, by synergistically increasing the activation of two crucial signaling pathways: ERK and Akt. However, the underlying mechanism of cross-talk between neuregulin and cAMP signaling remains mostly undefined. Here, we report that the activation of protein kinase A (PKA), but not that of exchange protein activated by cAMP (EPAC), enhances S-phase entry of SCs by synergistically enhancing the ligand-dependent tyrosine phosphorylation/activation of the neuregulin co-receptor, ErbB2-ErbB3. The role of PKA in neuregulin-ErbB signaling was confirmed using PKA inhibitors, pathway-selective cAMP analogs, and natural ligands stimulating PKA activity in SCs, such as adenosine and epinephrine. Two basic observations defined the synergistic action of PKA as "gating" for neuregulin-ErbB signaling: 1) the activation of PKA was not sufficient to induce S-phase entry or the activation of either ErbB2 or ErbB3; and 2) the presence of neuregulin was strictly required to ignite ErbB activation and thereby ERK and Akt signaling. However, PKA directly phosphorylated ErbB2 on Thr-686, a highly conserved intracellular regulatory site that was required for the PKA-mediated synergistic enhancement of neuregulin-induced ErbB2-ErbB3 activation and proliferation in SCs. The gating action of PKA on neuregulin-induced ErbB2-ErbB3 activation has important biological significance, because it insures signal amplification into the ERK and Akt pathways without compromising either the neuregulin dependence or the high specificity of ErbB signaling pathways.

Publication types

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

MeSH terms

  • Adenosine / metabolism
  • Amino Acid Sequence
  • Animals
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Epinephrine / metabolism
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Molecular Sequence Data
  • Nerve Tissue Proteins / metabolism*
  • Neuregulin-1
  • Receptor, ErbB-2 / metabolism*
  • Receptor, ErbB-3 / metabolism*
  • Schwann Cells / metabolism*
  • Sequence Homology, Amino Acid

Substances

  • NRG1 protein, human
  • Nerve Tissue Proteins
  • Neuregulin-1
  • Cyclic AMP
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Cyclic AMP-Dependent Protein Kinases
  • Adenosine
  • Epinephrine