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.