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.
Highlights
Neuregulins comprise an extensive family of growth factors [8], which are the specific ligands for ErbB/HER family of receptor tyrosine kinases (RTKs) [9, 10]
The Activation of protein kinase A (PKA), but Not exchange protein activated by cAMP (EPAC), Is Sufficient to Synergistically Enhance the Neuregulin-stimulated Proliferation of SCs—The mechanism underlying the action of cAMP in neuregulin-induced SC proliferation remains mostly undefined
We investigated the role of PKA or EPAC, by the use of
Summary
Neuregulins comprise an extensive family of growth factors [8], which are the specific ligands for ErbB/HER family of receptor tyrosine kinases (RTKs) [9, 10]. SCs express ErbB2 and ErbB3 isoforms that signal as a heterodimeric complex-activating multiple pathways, including Ras-Raf-MEK-ERK and PI3K-PDK-Akt [12, 13]. The goal of this study was to investigate how signals from neuregulin and cAMP interact to regulate ERK and Akt activation and S-phase progression in SCs. Using a combination of pharmacological inhibitors of PKA and pathway-selective cAMP analogs, we found evidence supporting an involvement of PKA, but not EPAC, in increasing the activation of the ErbB2-ErbB3 co-receptor. PKA activity was sufficient to enhance the neuregulin-induced phosphorylation of specific activating tyrosine residues in both ErbB2 and ErbB3 and thereby enhance both MEK-ERK and PI3K-Akt signaling. We propose a model of ErbB2-ErbB3 regulation by PKA-mediated gating, which guarantees effective signal amplification into key pathways required for proliferation, without compromising the high specificity of the neuregulin-ErbB interaction or downstream signaling events
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