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Vol. 58, Issue 5, 903-910, November 2000
Divisions of Cardiology (I.F., A.E.G.) and Clinical Pharmacology
(I.B.), Departments of Medicine (I.F., A.E.G., I.B.) and Pharmacology
(I.F., I.B.), Vanderbilt University, Nashville, Tennessee
The functional activity of Cdc42 is known to be regulated by proteins
that control its GDP/GTP-bound state. However, there is still limited
information on how Cdc42 is controlled by G-protein-coupled receptors. Adenosine receptors belong to the G-protein-coupled receptor family of cell surface receptors. Human HMC-1 mast cells express the high-affinity A2A and the low-affinity
A2B subtypes of adenosine receptors known to increase
intracellular cAMP levels. We found that both subtypes of
A2 adenosine receptors activate Cdc42 in HMC-1 cells.
Furthermore, stimulation of adenylate cyclase with forskolin, or
loading of HMC-1 with the cell-permeable cAMP analog 8-Br-cAMP,
activated Cdc42. Stimulation of Cdc42 by cAMP was also observed in
CHO-K1 and COS-7 cells. Protein kinase A (PKA)-mediated phosphorylation
is likely involved in cAMP-dependent Cdc42 activation, because
transient expression of the PKA catalytic subunit in COS-7 cells
activated Cdc42. Inhibition of protein phosphatases 1 and 2A with
calyculin A potentiated the effects of
5'-N-ethylcarboxamidoadenosine and 8-Br-cAMP, whereas
the selective PKA inhibitor H-89 reversed the activation of Cdc42. We
demonstrated that Cdc42 is a poor substrate for PKA phosphorylation in
vitro and in intact cells. Our data suggest that PKA does not
phosphorylate Cdc42 directly. Instead, the proteins that modulate the
GDP/GTP-bound state of Cdc42 may be the primary targets of PKA phosphorylation.
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