Cyclic AMP and protein kinase A stimulate Cdc42: role of A(2) adenosine receptors in human mast cells.

Feoktistov I, Goldstein AE, Biaggioni I
Mol Pharmacol. 2000 58 (5): 903-10

PMID: 11040036 · DOI:10.1124/mol.58.5.903

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 A(2A) and the low-affinity A(2B) subtypes of adenosine receptors known to increase intracellular cAMP levels. We found that both subtypes of A(2) 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.

MeSH Terms (11)

Adenosine cdc42 GTP-Binding Protein Cells, Cultured Cyclic AMP Cyclic AMP-Dependent Protein Kinases Humans Mast Cells Phosphorylation Receptor, Adenosine A2A Receptor, Adenosine A2B Receptors, Purinergic P1

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