4.8 Article

Raf Kinase Inhibitory Protein regulates the cAMP-dependent protein kinase signaling pathway through a positive feedback loop

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.2121867119

Keywords

Raf Kinase Inhibitory Protein (RKIP); protein kinase A (PKA); phosphatidylethanolamine binding protein (PEBP); nuclear magnetic resonance (NMR)

Funding

  1. NIH [GM087630, GM121735, GM100310]
  2. Deutsche Forschungsgemeinschaft [SFB1116/A09, SFB/TR296/P10]

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Phosphorylation of RKIP at S153 by PKC triggers a switch from inhibition of Raf to inhibition of GRK2, enhancing signaling by beta-AR that activates PKA. PKA-phosphorylated RKIP at S51 promotes beta-AR-activated PKA signaling by triggering feedback activation of PKA. This allosteric regulatory mechanism may have therapeutic potential for regulating PKA signaling in disease states.
Raf Kinase Inhibitory Protein (RKIP) maintains cellular robustness and prevents the progression of diseases such as cancer and heart disease by regulating key kinase cascades including MAP kinase and protein kinase A (PKA). Phosphorylation of RKIP at S153 by Protein Kinase C (PKC) triggers a switch from inhibition of Raf to inhibition of the G protein coupled receptor kinase 2 (GRK2), enhancing signaling by the beta-adrenergic receptor (beta-AR) that activates PKA. Here we report that PKA-phosphorylated RKIP promotes beta-AR-activated PKA signaling. Using biochemical, genetic, and biophysical approaches, we show that PKA phosphorylates RKIP at S51, increasing S153 phosphorylation by PKC and thereby triggering feedback activation of PKA. The S51V mutation blocks the ability of RKIP to activate PKA in prostate cancer cells and to induce contraction in primary cardiac myocytes in response to the beta-AR activator isoproterenol, illustrating the functional importance of this positive feedback circuit. As previously shown for other kinases, phosphorylation of RKIP at S51 by PKA is enhanced upon RKIP destabilization by the P74L mutation. These results suggest that PKA phosphorylation at S51 may lead to allosteric changes associated with a higher-energy RKIP state that potentiates phosphorylation of RKIP at other key sites. This allosteric regulatory mechanism may have therapeutic potential for regulating PKA signaling in disease states.

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