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J Biol Chem, Vol. 273, Issue 34, 21616-21622, August 21, 1998

Phosphorylation of GTP Cyclohydrolase I and Modulation of Its Activity in Rodent Mast Cells
GTP CYCLOHYDROLASE I HYPERPHOSPHORYLATION IS COUPLED TO HIGH AFFINITY IgE RECEPTOR SIGNALING AND INVOLVES PROTEIN KINASE C

Christian Hesslinger, Elisabeth Kremmer^¶, Lothar Hültner, Marius Ueffing, and Irmgard Ziegler

From the  GSF-Institut für Klinische Molekularbiologie und Tumorgenetik, the ^¶ GSF-Institut für Immunologie, and the  GSF-Institut für Experimentelle Hämatologie, D-81377 München, Germany

GTP cyclohydrolase I controls the de novo pathway for the synthesis of tetrahydrobiopterin, which is the essential cofactor for tryptophan 5-monooxygenase and thus, for serotonin production. In mouse bone marrow-derived mast cells, the kit ligand selectively up-regulates GTP cyclohydrolase I activity (Ziegler, I., Hültner, L., Egger, D., Kempkes, B., Mailhammer, R., Gillis, S., and Rödl, W. (1993) J. Biol. Chem. 268, 12544-12551). Immunoblot analysis now confirms that this long term enhancement is caused by increased expression of the enzyme. Furthermore we show that GTP cyclohydrolase I is subject to modification at the post-translational level. In vivo labeling with [³²P]orthophosphate demonstrates that in primary mast cells and in transfected RBL-2H3 cells overexpressing GTP cyclohydrolase I, the enzyme exists in a phosphorylated form. Antigen binding to the high affinity receptor for IgE triggers an additional and transient phosphorylation of GTP cyclohydrolase I with a concomitant rise in its activity, and in consequence, cellular tetrahydrobiopterin levels increase. These events culminate 8 min after stimulation and can be mimicked by phorbol ester. The hyperphosphorylation is greatly reduced by the protein kinase C inhibitor Ro-31-8220. In vitro phosphorylation studies indicate that GTP cyclohydrolase I is a substrate for both casein kinase II and protein kinase C.

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