Association with the SRC family tyrosyl kinase LYN triggers a conformational change in the catalytic region of human cAMP-specific phosphodiesterase HSPDE4A4B - Consequences for rolipram inhibition

The cAMP-specific phosphodiesterase (PDE) HSPDE 4A4B(pde46) selectively bou nd SH3 domains of SRC family tyrosyl kinases. Such an interaction profoundl y changed the inhibition of PDE4 activity caused by the PDE4-selective inhi bitor rolipram and mimicked the enhanced rolipram inhibition seen for parti culate, compared with cytosolic pde46 expressed in COS7 cells. Particulate pde46 co-localized with LYN kinase in COS7 cells. The unique N-terminal and LR2 regions of pde46 contained the sites for SH3 binding. Altered rolipram inhibition was triggered by SH3 domain interaction with the LR2 region. Pu rified LYN SH3 and human PDE4A LR2 could be co immunoprecipitated, indicati ng a direct interaction. Protein kinase A-phosphorylated pde46 remained abl e to bind LYN SH3, pde46 was found to be associated with SRC kinase in the cytosol of COS1 cells, leading to aberrant kinetics of rolipram inhibition. It is suggested that pde46 may be associated with SRC family tyrosyl kinas es in intact cells and that the ensuing SH3 domain interaction with the LR2 region of pde46 alters the conformation of the PDE catalytic unit, as dete cted by altered rolipram inhibition. Interaction between pde46 and SRC fami ly tyrosyl kinases highlights a potentially novel regulatory system and poi nt of signaling system cross-talk.