Inducible RGS2 is a cross-talk regulator for parathyroid hormone signaling in rat osteoblast-like UMR106 cells.
Parathyroid hormone (PTH) activates dual signal transduction systems via Galphas and Galphaq proteins. We now report a novel mechanism by which "cross-talk" may occur between the Galphas and Galphaq signaling pathways. RGS2 (Regulator of G protein Signaling 2) mRNA was rapidly and transiently increased only by PTH analogs (PTH1-84, 1-34, 1-31, and PTHrP) that activated the Galphas-mediated cAMP/PKA signaling pathway, whereas activation of the Galphaq-mediated Ca(2+)/PKC signaling pathway by PTH3-34 had no effect on RGS2 expression. Treatment of UMR106 cells with nonPTH activators of the cAMP/PKA signaling pathway such as cholera toxin, forskolin, 8-Br-cAMP, and dibutyryl-cAMP also significantly elevated RGS2 mRNA levels, while activator of the Galphaq pathway PMA did not. Pretreatment using the Galphas signaling pathway inhibitors SQ22536 and H89 significantly blocked PTH-induced RGS2 expression, but the Galphaq signaling pathway inhibitor bisindolylmaleimide I had no effect. Therefore, RGS2 expression is governed solely by the Galphas signaling pathway. Additionally, we demonstrate for the first time that RGS2 binds to both Galphas and Galphaq subunits in their transition state (GDP/AlF(-4)-bound) forms, suggesting that RGS2 has the potential to act as a bridge between the cAMP/PKA and Ca(2+)/PKC pathways, and that it may act as a cross-talk regulator for these two PTH signaling pathways.
Ko
J K
JK
Cancer Research Institute, Seoul National University College of Medicine, 28 Yungun-dong, Chongno-ku, Seoul 110-744, Korea. jaeguri@chollian.net
Choi
K H
KH
Kim
I S
IS
Jung
E K
EK
Park
D H
DH
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D020710:RGS Proteins / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004791:Enzyme Inhibitors; D010281:Parathyroid Hormone; D020710:RGS Proteins; C105345:Rgs2 protein, mouse; D005576:Colforsin; D002772:Cholera Toxin; D000242:Cyclic AMP; D013755:Tetradecanoylphorbol Acetate