Biphasic response of Protein Kinase A to cyclic adenosine monophosphate triggers distinct epithelial phenotypes

Protein Kinase A (PKA) is an important cellular signaling hub whose activity has long been assumed to monotonically depend on the level of cyclic adenosine monophosphate (cAMP). Using an optogenetic tool that can inject precise amounts of cAMP, we characterize instead a biphasic response of PKA activity to cAMP concentration in MDCKI cells in which PKA activity increases and then decreases as a function of cAMP. We reveal that this behavior results from the integration of many cellular signals by PKA. In addition to the direct activation of PKA, cAMP also modulates the activity of p38 and ERK MAPK, which then converge on PKA to inhibit it. These interactions and their ensuing biphasic PKA profile have important physiological repercussions, triggering two distinct transcriptional programs elicited by low and high cAMP doses. These transcriptional responses in turn influence the ability of MDCKI cells to proliferate and form acini. Our data, supported by computational analyses, synthesize a set of network interconnections involving PKA and other important signaling pathways into a model that demonstrates how cells can capitalize on signal integration to create a diverse set of responses to cAMP concentration and produce complex input-output relationships.