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Regulation of the function of EGF receptors via P_2 purinergic receptors and related cell signaling systems

通过P_2嘌呤能受体和相关细胞信号系统调节EGF受体的功能

基本信息

批准号：
04807133
负责人：
HOSOI Kazuo
金额：
$ 1.15万
依托单位：
UNIVERSITY OF TOKUSHIMA SCHOOL OF DENTISTRY (1994)Meikai University (1992-1993)
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

项目摘要

We studied how stimulation of the purinergic receptors and other receptors (bradykinin receptors) elicites the cell signalling and affects other rceptors, e.g.the EGF receptor. We used A-431 human epidermoid carcinoma cells for the present experiment since they express high level of EGF receptors in addition to P_2 purinergic receptors. The stimulation of P_2 purinergic receptors stimulated PLC activity, followed by the PKC activation and [Ca^<2+>]_i elevation. From the ligand specificity to increase [Ca^<2+>]_i, the purinergic receptors responsible for provoking such cellular activity are suggested to be the P_<2Y> or P_<2U>-type. All the nucleotides that increased [Ca^<2+>]_i also inhibited the EGF receptor high affinity bindnig indicating that the function of EGF receptors is regulated by P_2 purinergic receptors via the cellular signal transduction system. The EGF high affinity binding was also inhibited when the cells were stimulated by bradykinin. However, the inhibition by bradykinin of the EGF high affinity binding was transient. Bradykinin was shown to stimulate a phosphoprotein phosphatase (s) as well as protein kinase C.Such biphasic effects of bradykinin to phosphorylate and dephosphorylate EGF receptors imply a homeostatic control of the receptor function in regulating phopshorylation level. In addition to PLC activation, stimulation by EGF and ATP activated either DG kinase or PLD which in turn supplied PA and activated PKC/ [Ca2+]i system, all of which were found to be essential for the stimulation of PI synthesis. The present results imply the general prospect that ligand stimulation, which mobilizes second messengers and consumes their precursors, simultaneously provokes the pathway to synthesize and salvage the second messenger precursors.

我们研究了嘌呤能受体和其他受体（缓激肽受体）的刺激如何引发细胞信号传导并影响其他受体，例如EGF受体。由于A-431人表皮样癌细胞除P_2嘌呤能受体外，还表达高水平的EGF受体，故本实验选用A-431人表皮样癌细胞。P_2嘌呤能受体激活PLC活性，PKC激活，[Ca^<2+>] i升高。从配体特异性增加[Ca^<2+>]_i的角度，推测引起这种细胞活性的嘌呤能受体为P_<2Y>或P_<2U>-型。所有增加[Ca^<2+>]_i的核苷酸均抑制EGF受体的高亲和力结合，表明EGF受体的功能受P_2嘌呤受体通过细胞信号转导系统的调节。缓激肽刺激细胞后，EGF高亲和力结合也受到抑制。然而，缓激肽对EGF高亲和力结合的抑制是短暂的。缓激肽被证明刺激磷蛋白磷酸酶以及蛋白激酶C。缓激肽磷酸化和去磷酸化EGF受体的这种双相作用意味着在调节磷酸化水平中对受体功能的稳态控制。除PLC激活外，EGF和ATP刺激还激活DG激酶或PLD，进而提供PA和激活PKC/ [Ca ~（2+）]i系统，所有这些都被发现是刺激PI合成所必需的。目前的研究结果暗示了一般的前景，配体刺激，动员第二信使和消耗其前体，同时激发的途径，合成和抢救的第二信使前体。