title: Photosensitized inhibition of growth factor-regulated protein kinases by hypericin.
abstract: The naphthodianthrone hypericin causes a photosensitized inhibition of protein kinases involved in growth factor signalling pathways. Nanomolar concentrations of hypericin inhibit the protein tyrosine kinase activities (PTK) of the epidermal growth factor receptor and the insulin receptor, while being ineffective towards the cytosolic protein tyrosine kinases Lyn, Fgr, TPK-IIB and CSK. Photosensitized inhibition by hypericin is not restricted to receptor-PTKs since the Ser/Thr protein kinases (protein kinase CK-2, protein kinase C and mitogen-activated kinase) are also extremely sensitive to inhibition (IC50 value for protein kinase CK-2 = 6 nM). A comparison of the hypericin-mediated inhibition of the epidermal growth factor-receptor PTK and protein kinase CK-2 revealed that the inhibition is irreversible, strictly dependent upon irradiation of the enzyme-inhibitor complex with fluorescent light and likely mediated by the formation of radical intermediates (type I mechanism). Although the exact molecular basis for the selectivity of enzyme inhibition by hypericin remains unknown, our results suggest that distantly related protein kinases could still share common reactive domains for the interaction with hypericin.
authors.affiliation: Afdeling Biochemie, Faculteit der Geneeskunde, Katholieke Universiteit Leuven, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Agostinis
authors.forename: A
authors.initials: A
authors.lastname: Vandenbogaerde
authors.forename: A
authors.initials: A
authors.lastname: Donella-Deana
authors.forename: L A
authors.initials: LA
authors.lastname: Pinna
authors.forename: K T
authors.initials: KT
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Goris
authors.forename: W
authors.initials: W
authors.lastname: Merlevede
authors.forename: J R
authors.initials: JR
authors.lastname: Vandenheede
authors.forename: P
authors.initials: P
authors.lastname: De Witte
mesh_terms: D000595:Amino Acid Sequence; D000873:Anthracenes; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D047388:Casein Kinases; D003600:Cytosol / Q000201:enzymology; D066246:ErbB Receptors / Q000737:chemistry; D006133:Growth Substances / Q000494:pharmacology; D007700:Kinetics; D008027:Light; D008969:Molecular Sequence Data; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D017319:Photosensitizing Agents / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011972:Receptor, Insulin / Q000737:chemistry
chemical_list: D000873:Anthracenes; D006133:Growth Substances; D017319:Photosensitizing Agents; D047428:Protein Kinase Inhibitors; D010569:Perylene; C004965:hypericin; D066246:ErbB Receptors; D011972:Receptor, Insulin; D047388:Casein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases