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Vol. 302, Issue 1, 111-118, July 2002
Laboratory of Membrane Biology, Neuroscience Center, Massachusetts
General Hospital, Charlestown, Massachusetts (M.S.F., E.S., K.J.S.);
and Laboratory of Molecular and Cellular Neuroscience, Rockefeller
University, New York, New York (A.C.N.)
Elevated cAMP in NRK-52E and L6 cells causes a marked reduction in the
phosphorylation of numerous phosphoproteins, as detected initially with
phosphoserine-specific antibodies. Here, we show that elevation of cAMP
in NRK cells by forskolin/3-isobutyl-1-methylxanthine (IBMX) treatment
decreased phosphorylation of substrates for different protein kinases,
pointing to a common protein phosphatase as a target for cAMP-dependent
regulation. Forskolin/IBMX treatment completely dephosphorylated a
selective protein phosphatase 2A (PP2A) substrate, elongation factor-2
(EF-2), at its Ca2+ calmodulin-dependent kinase site, and
decreased phosphorylation of substrates for cyclin-dependent kinases,
including retinoblastoma (Rb) protein. As reported before,
forskolin/IBMX also decreased phosphorylation of a protein kinase C
substrate, the Na,K-ATPase. The cAMP-stimulated dephosphorylation was
blocked by the protein phosphatases 1 (PP1) and PP2A inhibitor okadaic
acid at concentrations selective for PP2A but was not blocked by
tautomycin at concentrations selective for PP1. The data implicate PP2A
as a cAMP-activated phosphatase. Contrary to expectation, we found
evidence that cAMP-dependent activation of PP2A did not depend on
protein kinase A (PKA). Pretreatment of cells with the PKA inhibitor
H89 abolished PKA activity measured in cell extracts and significantly
decreased cAMP-activated phosphorylation of a known PKA substrate,
ARPP-19, in cells, but failed to block the cAMP-stimulated
dephosphorylation of EF-2, Rb, and other proteins. This novel pathway
of PP2A activation, acting on the time scale of minutes, represents yet
another example of a cAMP-mediated, PKA-independent signaling
mechanism. Because PP2A is active toward a variety of endogenous
substrates, cAMP-stimulated dephosphorylation may have complicated the
interpretation of many prior studies.
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