Periodic Signaling Controlled by an Oscillatory Circuit That Includes Protein Kinases ERK2 and PKA

Abstract

Self-regulating systems often use robust oscillatory circuits. One such system controls the chemotactic signaling mechanism of Dictyostelium, where pulses of adenosine 3',5'-monophosphate (cAMP) are generated with a periodicity of 7 minutes. We have observed spontaneous oscillations in activation of the mitogen-activated protein (MAP) kinase ERK2 that occur in phase with peaks of cAMP, and we show that ERK2 modulates cAMP levels through the phosphodiesterase RegA. Computer modeling and simulations of the underlying circuit faithfully account for the ability of the cells to spontaneously generate periodic pulses during specific stages of development. Similar oscillatory processes may occur in cells of many different species.

Oscillatory signaling and network responses during the development of Dictyostelium discoideum

“…regA-nulls have elevated cAMP, while erk2-nulls have very low cAMP levels. regA/erk2-nulls have high levels of cAMP, similar to that of regA-nulls (Maeda et al, 2004). Biochemical data are also consistent with ERK2 acting negatively upstream of RegA (Brzostowski and Kimmel, 2006).…”

“…Apart from activating a myriad of downstream effectors, PKA may also participate in an inhibitory feedback loop to downregulate cAMP accumulation. Cells that overexpress the catalytic subunit of PKA or that lack the inhibitory subunit accumulate only low levels of cAMP (Maeda et al, 2004). While several targets for PKA action have been postulated, none are consistent with experimental evidence (Brzostowski and Kimmel, 2006).…”

“…Different cyclic nucleotide phosphodiesterases (PDEs) act on the intracellular and extracellular pools of cAMP to generate AMP. Disruption or overexpression of the various PDEs interferes with aggregation (Maeda et al, 2004;Sawai et al, 2005). Extracellular cAMP is degraded by a secreted PDE (Franke et al, 1991), whose activity is regulated by a secreted glycoprotein phosphodiesterase inhibitor (PDI).…”

“…Intracellular cAMP is degraded by a different PDE, RegA, among others (Shaulsky et al, 1998). RegA activity is subject to inhibitory regulation by phosphorylation via ERK2 (Maeda et al, 2004). regA-nulls have elevated cAMP, while erk2-nulls have very low cAMP levels.…”

“…One can theoretically model the cAMP oscillation circuit in Dictyostelium through the negative feedback to CAR1 or ACA, (e.g. Martiel and Goldbeter, 1985;Maeda et al, 2004) and while such partial models can successfully predict an accurate ~6 min. cAMP oscillation frequency, they do not fully incorporate relevant experimental data or explain the more rapid activation/inactivation cycle of PI3K and other components in comparison to that of ACA (Brzostowski and Kimmel, 2006).…”