Protein kinase A inhibitor proteins (PKIs) divert GPCR-Gαs-cAMP signaling toward EPAC and ERK activation and are involved in tumor growth.

The PKA-inhibitor (PKI) family members PKI alpha, PKI beta, and PKI gamma bind with high affinity to PKA and block its kinase activity, modulating the extent, and duration of PKA-mediated signaling events. While PKA is a well-known regulator of physiological and oncogenic events, the role of PKI proteins in these pathways has remained elusive. Here, by measuring activation of the MAPK pathway downstream of GPCR-G alpha s-cAMP signaling, we show that the expression levels of PKI proteins can alter the balance of activation of two major cAMP targets: PKA and EPAC. Our results indicate that PKA maintains repressive control over MAPK signaling as well as a negative feedback on cAMP concentration. Overexpression of PKI and its subsequent repression of PKA dysregulates these signaling pathways, resulting in increased intracellular cAMP, and enhanced activation of EPAC and MAPK. We also find that amplifications ofPKIAare common in prostate cancer and are associated with reduced progression free survival. Depletion ofPKIAin prostate cancer cells leads to reduced migration, increased sensitivity to anoikis and reduced tumor growth. By altering PKA activity PKI can act as a molecular switch, driving GPCR-G alpha s-cAMP signaling toward activation of EPAC-RAP1 and MAPK, ultimately modulating tumor growth.