Suppression of Cyclic GMP-dependent Protein Kinase Is Essential to the Wnt/cGMP/Ca2+ Pathway.
Novel downstream effectors sensing changes in intracellular concentrations of Ca(2+) and cyclic GMP in response to activation of the Wnt/Frizzled-2 pathway were sought. Activation of Frizzled-2 suppressed protein kinase G activity while activating NF-AT-dependent transcription. Each of these responses was abolished by pertussis toxin and by knock-down of the expression of either Galpha(t2) or Galpha(o). Activation of NF-AT-dependent transcription in response to Wnt5a stimulation was suppressed by activation of protein kinase G and by buffering intracellular Ca(2+). Elevation of intracellular cyclic GMP either by inhibition of cyclic GMP phosphodiesterase or by addition of 8-bromocyclic GMP was shown to activate protein kinase G, to block Ca(2+) mobilization, as well as to markedly attenuate activation of NF-AT-dependent transcription in response to Wnt5a stimulation. Chemical inhibition of protein kinase G by Rp-8-pCPT-cGMP, conversely, was shown to provoke increased NF-AT gene transcription and Ca(2+) mobilization in the absence of Wnt stimulation. Protein kinase G is shown to be a critical downstream effector of the noncanonical Wnt-Frizzled-2/cGMP/Ca(2+) pathway.[1]References
- Suppression of Cyclic GMP-dependent Protein Kinase Is Essential to the Wnt/cGMP/Ca2+ Pathway. Ma, L., Wang, H.Y. J. Biol. Chem. (2006) [Pubmed]
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