PHOTOSENSITIZED INHIBITION OF GROWTH FACTOR-REGULATED PROTEIN-KINASES BY HYPERICIN
PHOTOSENSITIZED INHIBITION OF GROWTH FACTOR-REGULATED PROTEIN-KINASES BY HYPERICIN
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DOI：
10.1016/0006-2952(95)00097-j
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发表时间：
1995-05-26
影响因子：
5.8
通讯作者：
DEWITTE, P
中科院分区：
文献类型：
--
作者：
AGOSTINIS, P;VANDENBOGAERDE, A;DEWITTE, P
石楠王座金丝桃素引起光敏抑制参与生长因子信号通路的蛋白激酶。纳米浓度的金丝桃素可抑制表皮生长因子受体和胰岛素受体的蛋白酪氨酸激酶活性（PTR），而对胞质蛋白酪氨酸激酶Lyn、Fgr、TPK-IIB和CSK无效。金丝桃素的光敏抑制并不局限于受体ptks，因为丝氨酸/苏氨酸蛋白激酶（蛋白激酶CK-2、蛋白激酶C和丝裂原活化激酶）也对抑制非常敏感（蛋白激酶CK-2的IC50值= 6 nM）。比较金丝桃素介导的对表皮生长因子受体PTK和蛋白激酶CK-2的抑制作用发现，这种抑制是不可逆的，严格依赖于荧光照射酶抑制剂复合物，可能是由自由基中间体的形成介导的（I型机制）。虽然金丝桃素选择性抑制酶的确切分子基础尚不清楚，但我们的研究结果表明，远亲蛋白激酶仍然可以共享与金丝桃素相互作用的共同反应结构域。
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 (PTR) 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.