The MAP kinase ERK2 inhibits the cyclic AMP-specific phosphodiesterase HSPDE4D3 by phosphorylating it at Ser579

Abstract

The extracellular receptor stimulated kinase ERK2 (p42(MAPK))-phosphorylated human cAMP-specific phosphodiesterase PDE4D3 at Ser579 and profoundly reduced ( approximately 75%) its activity. These effects could be reversed by the action of protein phosphatase PP1. The inhibitory state of PDE4D3, engendered by ERK2 phosphorylation, was mimicked by the Ser579-->Asp mutant form of PDE4D3. In COS1 cells transfected to express PDE4D3, challenge with epidermal growth factor (EGF) caused the phosphorylation and inhibition of PDE4D3. This effect was blocked by the MEK inhibitor PD98059 and was not apparent using the Ser579-->Ala mutant form of PDE4D3. Challenge of HEK293 and F442A cells with EGF led to the PD98059-ablatable inhibition of endogenous PDE4D3 and PDE4D5 activities. EGF challenge of COS1 cells transfected to express PDE4D3 increased cAMP levels through a process ablated by PD98059. The activity of the Ser579-->Asp mutant form of PDE4D3 was increased by PKA phosphorylation. The transient form of the EGF-induced inhibition of PDE4D3 is thus suggested to be due to feedback regulation by PKA causing the ablation of the ERK2-induced inhibition of PDE4D3. We identify a novel means of cross-talk between the cAMP and ERK signalling pathways whereby cell stimuli that lead to ERK2 activation may modulate cAMP signalling.

Inhibition of the Phosphodiesterase 4 (PDE4) Enzyme Reverses Memory Deficits Produced by Infusion of the MEK Inhibitor U0126 into the CA1 Subregion of the Rat Hippocampus

“…This is further supported by in vitro studies. In COS-1 cells, ERK2 activation induces a phosphorylation-mediated inhibition of activity of transfected PDE4D3 and PDE4B1 Hoffmann et al, 1999). This mechanism also appears to be active in neurons since it was demonstrated that MEK inhibition increased PDE4 activity in cerebral cortical neurons.…”

“…Previous work has shown that ERK activation can result in a phosphorylation-mediated inhibition of PDE4 activity in F442A cells (Hoffmann et al, 1999); however, it was not known if such a mechanism was active in neurons. In order to determine whether MEK inhibition alters PDE4 activity, the effects of U0126 on phospho-ERK levels and PDE4 activity in primary cultures of rat cerebral cortical neurons were examined.…”

“…In PC12 or CHO-K1 cells, cAMP increases ERK activity; in C6 or NB2A cells, cAMP inhibits ERK activity (Qiu et al, 2000). Conversely, in F442A cells, activation of ERK with epidermal growth factor (EGF) increases cAMP by inhibiting a PDE4 isoenzyme (Hoffmann et al, 1999). Consistently, crosstalk exists between cAMP and ERK signaling in the CA1 subregion of the hippocampus (Patterson et al, 2001;Stork and Schmitt, 2002), which is involved in the mediation of synaptic plasticity (Patterson et al, 2001;Roberson et al, 1999) and ERK signalingmediated long-term memory (Blum et al, 1999).…”

Subcellular Localization of Cyclic Nucleotide Phosphodiesterase Type 10A Variants, and Alteration of the Localization by cAMP-dependent Protein Kinase-dependent Phosphorylation

“…In other PDE families, many splice variants show different tissue expression patterns and distinct subcellular localization and are subjected to unique regulation by protein kinases and associated proteins (8,(17)(18)(19)(20). For example, whereas phosphorylation of the amino terminus of the PDE4D3 variant by PKA increases its activity (21)(22)(23), PDE4D3 is inactivated by extracellular signal-regulated kinase-mediated phosphorylation in vivo (24). PDE4A1, PDE4D, and PDE2A are localized in the Golgi apparatus (25)(26)(27)(28)(29)(30)(31), and PDE3B is associated with the endoplasmic reticulum via its amino-terminal hydrophobic domain (32).…”

Ligand-gated Ion Channels

“…The potency of YM976 at other members of the PDE4 family has not been reported. PDE4B-D long forms are inhibited by extracellular signal-regulated kinase (ERK)-mediated phosphorylation (Hoffmann et al, 1998;Hoffmann et al, 1999). PDE4A-D splice variants can be membrane-bound or cytosolic (Houslay and Adams, 2003 (Michaeli et al, 1993) cAMP >> cGMP (Gardner et al, 2000) cAMP >> cGMP (Fisher et al, 1998a) cAMP >> cGMP (Hayashi et al, 1998) Activators PKA (Corbin et al, 2000), PKG (Corbin et al, 2000) ----Selective inhibitors T0156 (9.5, Mochida et al, 2002), sildenafil (9.0, Turko et al, 1999), SCH51866 (7.…”