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

The extracellular receptor stimulated kinase ERK2 (P42(MAPK))-phosphorylate d human cAMP-specific phosphodiesterase PDE4D3 at Ser579 and profoundly red uced (similar to 75%) its activity. These effects could be reversed by the action of protein phosphatase PP1. The inhibitory state of PDE4D3, engender ed by ERK2 phosphorylation, was mimicked by the Ser579-->Asp mutant form of PDE4D3, In COS1 cells transfected to express PDE4D3, challenge with epider mal 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 F442 A cells with EGF led to the PD98059-ablatable inhibition of endogenous PDE4 D3 and PDE4D5 activities. EGF challenge of COS1 cells transfected to expres s PDE4D3 increased cAMP levels through a process ablated by PD98059. The ac tivity of the Ser579-->Asp mutant form of PDE4D3 was increased by PKA phosp horylation. The transient form of the EGF-induced inhibition of PDE4D3 is t hus 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 cros s-talk between the cAMP and ERK signalling pathways whereby cell stimuli th at lead to ERK2 activation may modulate cAMP signalling.