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. 2021 Oct;73(4):1326–1368. doi: 10.1124/pharmrev.120.000269

Fig. 10.

Fig. 10

Aberrant protein kinase A pathway activity leads to dysregulation of signaling and transcriptional programs. (A) Wnt and PKA activity drive β-catenin–mediated gene transcription. Canonically, Wnt binds to Frizzled receptors and coreceptors like LPL receptor related protein 6 (LRP 6) on the surface of the cell to inhibit the activity of the destruction complex. Destruction complex members include APC, GSK3, CK1α, and Axin. Inhibition of this complex releases β-catenin to drive target gene transcription through the transcription factor TCF. Production of PGE2 through COX-2 leads to activation of Gαs-coupled GPCRs, E-type prostanoid receptor 2 (EP2), and E-type prostanoid receptor 4 (EP4). Activation of Gαs leads to direct phosphorylation and inhibition of GSK3 as well as stabilizing phosphorylation of β-catenin. These effects coupled with the direct binding of Gαs to Axin lead to accumulation of β-catenin and activation of target gene transcription. (B) PKA inhibits Hippo pathway and YAP/TEAD-mediated transcription. The Hippo pathway is regulated by a kinase cascade whereby the upstream kinase MST phosphorylates and activates LATS kinase. Phosphorylation of YAP by LATS inactivates YAP through cytoplasmic sequestration and degradation. PKA-mediated phosphorylation of LATS, among other mechanisms, also inhibits YAP activity and consequently blocks target gene transcription through TEAD. (C) PKA regulates hedgehog (HH) signaling in the cilium to inhibit GLI transcriptional activity. When HH ligand is present, it binds to and inhibits the receptor Patched (PTCH1), allowing the Gαi-like GPCR SMO to traffic to the ciliary membrane. SMO inhibits cAMP production and PKA activity, allowing GLI-mediated transcription to proceed. When HH ligand is absent, PTCH1 constitutively inhibits SMO and allows the Gαs-coupled GPCR GPR161 to traffic to the ciliary membrane. When present at the membrane, GPR161 stimulates cAMP production and PKA activity. PKA in turn phosphorylates and inhibits GLI, eventually leading to its degradation.