Nonadaptive regulation of ERK2 in Dictyostelium: implications for mechanisms of cAMP relay.

It is assumed that ERK2 in Dictyostelium is subject to adaptive regulation in response to constant extracellular ligand stimulation. We now show, to the contrary, that ERK2 remains active under continuous stimulation, differing from most ligand-activated pathways in chemotactically competent Dictyostelium and other cells. We show that the upstream phosphorylation pathway, responsible for ERK2 activation, transiently responds to receptor stimulation, whereas ERK2 dephosphorylation (deactivation) is inhibited by continuous stimulation. We argue that the net result of these two regulatory actions is a persistently active ERK2 pathway when the extracellular ligand (i.e., cAMP) concentration is held constant and that oscillatory production/destruction of secreted cAMP in chemotaxing cells accounts for the observed oscillatory activity of ERK2. We also show that pathways controlling seven-transmembrane receptor (7-TMR) ERK2 activation/deactivation function independently of G proteins and ligand-induced production of intracellular cAMP and the consequent activation of PKA. Finally, we propose that this regulation enables ERK2 to function both in an oscillatory manner, critical for chemotaxis, and in a persistent manner, necessary for gene expression, as secreted ligand concentration increases during later development. This work redefines mechanisms of ERK2 regulation by 7-TMR signaling in Dictyostelium and establishes new implications for control of signal relay during chemotaxis.