Regulation of tyrosine hydroxylase by stress‐activated protein kinases

• Published in: Journal of neurochemistry 2002-11, Vol.83 (4), p.775-783
• Main Authors: Toska, Karen, Kleppe, Rune, Armstrong, Christopher G., Morrice, Nick A., Cohen, Philip, Haavik, Jan
• Format: Article
• Language: English
• Subjects: 14-3-3 Proteins; Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Binding Sites; Biological and medical sciences; Chromatography, High Pressure Liquid; Circular Dichroism; Cyclic AMP-Dependent Protein Kinases - chemistry; Enzyme Activation - physiology; Enzyme Stability - physiology; Fundamental and applied biological sciences. Psychology; Humans; Intracellular Signaling Peptides and Proteins; Kinetics; Mitogen-Activated Protein Kinase 1 - chemistry; MSK1; Other biological molecules; Phosphorylation; PRAK; Protein Binding - physiology; Protein-Serine-Threonine Kinases - chemistry; Ribosomal Protein S6 Kinases, 90-kDa - chemistry; stress‐activated protein kinases; Substrate Specificity - physiology; Surface Plasmon Resonance; Temperature; Terpenes, steroids. Hormones; Tyrosine 3-Monooxygenase - chemistry; tyrosine hydroxylase
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2002.01172.x

Recombinant human tyrosine hydroxylase (hTH1) was found to be phosphorylated by mitogen and stress‐activated protein kinase 1 (MSK1) at Ser40 and by p38 regulated/activated kinase (PRAK) on Ser19. Phosphorylation by MSK1 induced an increase in Vmax and a decrease in Km for 6‐(R)‐5,6,7,8‐tetrahydrobiopterin (BH4), while these kinetic parameters were unaffected as a result of phosphorylation by PRAK. Phosphorylation of both Ser40 and Ser19 induced a high‐affinity binding of 14‐3‐3 proteins, but only the interaction of 14‐3‐3 with Ser19 increased the hTH1 activity. The 14‐3‐3 proteins also inhibited the rate of dephosphorylation of Ser19 and Ser40 by 82 and 36%, respectively. The phosphorylation of hTH1 on Ser19 caused a threefold increase in the rate of phosphorylation of Ser40. These studies provide new insights into the possible roles of stress‐activated protein kinases in the regulation of catecholamine biosynthesis.