Cyclic Nucleotide Dependent Dephosphorylation of Regulator of G-Protein Signaling 18 in Human Platelets
Figure 6
Model of the regulation of the RGS18 complex in platelets.
In resting platelets RGS18 is attached to the scaffold protein spinophilin which also binds PP1, and the tyrosine phosphatase SHP-1 (not shown). In addition, RGS18 binds 14-3-3 via phosphorylated S218 of RGS18 (top). Platelet activation by thrombin, thromboxane A2, or ADP leads to the phosphorylation of S49 and increased 14-3-3 binding. Thrombin also induces the detachment of spinophilin together with PP1, which might prevent dephosphorylation of the 14-3-3 binding sites pS49 and pS218. 14-3-3 reduces the function of RGS18 resulting in facilitated Gq signaling which contributes to platelet activation. In contrast, activation of cAMP- and cGMP-dependent protein kinases by prostacyclin (PGI2) or nitric oxide (NO) leads to the phosphorylation of RGS18 on serine 216 (pS216). S216 phosphorylation might activate PP1 leading to dephosphorylation of both 14-3-3 binding sites, S49 and S218, and detachment of 14-3-3. Removal of 14-3-3 activates RGS18 to turn off Gq signaling thus contributing to platelet inhibition.