ERKs are the point of divergence of PKA and PKC activation by PTHrP in human skin fibroblasts
ERKs are the point of divergence of PKA and PKC activation by PTHrP in human skin fibroblasts
复制标题
DOI：
10.1007/s000180200015
复制
发表时间：
2002-12-01
影响因子：
8
通讯作者：
Maioli, E
中科院分区：
文献类型：
--
作者：
Fortino, V;Torricelli, C;Maioli, E
甲状旁腺激素相关肽(PTHrP)受体与三聚体G蛋白偶联，通过至少三种不同的转导途径在大多数靶细胞中发挥作用：Galphas介导的腺苷环酶(AC)激活、Galphaq介导的磷脂酶Cβ(PLC)激活和丝裂原激活的蛋白激酶(MAPK)激活。在这项研究中，我们研究了不同途径在人皮肤成纤维细胞增殖中的相对作用。利用化学抑制剂和信号转导激活剂，我们证明：(I)AC/cAMP和PLC/1，4，5-肌醇三磷酸/二酰甘油第二信使系统在PTHrP与其受体结合后同时被激活(Ii)PTHrP的有丝分裂反应来源于两条相互抵消的通路之间的平衡--由蛋白激酶C(PKC)介导的激活通路和由蛋白激酶A(PKA)介导的抑制通路(Iii)PTHrP的有丝分裂作用在很大程度上依赖于MAPK，其活性可由PKA和PKC共同调节。我们的结果表明，MAPK是这两种转导途径的共同靶点，同时也是它们在介导PTHrP双重和相反的有丝分裂作用方面的分歧点。
Parathyroid hormone-related peptide (PTHrP) receptors, coupled to trimeric G proteins, operate in most target cells through at least three different transduction routes: Galphas-mediated stimulation of adenylylcyclase (AC), Galphaq-mediated activation of phospholipase Cbeta (PLC) and mitogen-activated protein kinase (MAPK) activation. In this study we investigated the relative role of different pathways in human skin fibroblast proliferation. Using chemical inhibitors and activators of signal transduction, we demonstrated that: (i) AC/cAMP and PLC/1,4,5 inositol triphosphate/diacylglycerol second-messenger systems are simultaneously activated following PTHrP binding to its receptors (ii) the mitogenic response to PTHrP derives from a balance between two counteracting pathways - an activating route mediated by protein kinase C (PKC) and an inhibitory route mediated by protein kinase A (PKA) (iii) PTHrP mitogenic effects are largely dependent on MAPKs, whose activity can be modulated by both PKA and PKC. Our results indicate that MAPKs are common targets of both transduction routes and, at the same time, their point of divergence in mediating PTHrP dual and opposite mitogenic effects.