Activation and targeting of mitogen-activated protein kinases by G-protein-coupled receptors
Activation and targeting of mitogen-activated protein kinases by G-protein-coupled receptors
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DOI：
10.1139/y02-045
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发表时间：
2002-05-01
影响因子：
2.1
通讯作者：
Luttrell, LM
中科院分区：
文献类型：
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作者：
Luttrell, LM
在过去的十年中，许多G蛋白偶联受体（GPCR）产生控制细胞分化和生长的信号，包括Ras家族GTP酶的刺激和促分裂原活化蛋白（MAP）激酶途径的活化已经变得显而易见。GPCR用于控制MAP激酶活性的机制在受体和细胞类型之间不同，但大致属于以下三类之一：由经典G蛋白效应物启动的信号，例如，蛋白激酶（PK）A和PKC，由GPCR和经典受体酪氨酸激酶之间的串扰引发的信号，例如，表皮生长因子（EGF）受体的“反式激活”，以及由β-抑制蛋白和MAP激酶级联的组分之间的直接相互作用引发的信号，例如，β-抑制蛋白“支架”。虽然这些途径中的每一种都会导致细胞MAP激酶活性增加，但新出现的数据表明它们在功能上并不冗余。通过PKC依赖性途径和EGF受体反式激活发生的MAP激酶激活导致激酶的核转位并刺激细胞增殖，而通过β-抑制蛋白支架的MAP激酶激活主要增加胞质激酶活性。通过控制MAP激酶活性在细胞内的空间和时间分布，GPCR刺激的MAP激酶活化的结果可以由它们被活化的机制决定。
Over the past decade, it has become apparent that many G-protein-coupled receptors (GPCRs) generate signals that control cellular differentiation and growth, including stimulation of Ras family GTPases and activation of mitogen-activated protein (MAP) kinase pathways. The mechanisms that GPCRs use to control the activity of MAP kinases vary between receptor and cell type but fall broadly into one of three categories: signals initiated by classical G protein effectors, e.g., protein kinase (PK)A and PKC, signals initiated by cross-talk between GPCRs and classical receptor tyrosine kinases, e.g., "transactivation" of epidermal growth factor (EGF) receptors, and signals initiated by direct interaction between beta-arrestins and components of the MAP kinase cascade, e.g., beta-arrestin "scaffolds". While each of these pathways results in increased cellular MAP kinase activity, emerging data suggest that they are not functionally redundant. MAP kinase activation occurring via PKC-dependent pathways and EGF receptor transactivation leads to nuclear translocation of the kinase and stimulates cell proliferation, while MAP kinase activation via beta-arrestin scaffolds primarily increases cytosolic kinase activity. By controlling the spatial and temporal distribution of MAP kinase activity within the cell, the consequences of GPCR-stimulated MAP kinase activation may be determined by the mechanism by which they are activated.