Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase
Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase
复制标题
DOI：
10.1042/bj3250449
复制
发表时间：
1997-07-15
影响因子：
4.1
通讯作者：
Nahmias, C
中科院分区：
文献类型：
--
作者：
Bedecs, K;Elbaz, N;Nahmias, C
血管紧张素II 2型（AT（2））受体通过尚不明确的细胞内信号通路参与细胞增殖抑制以及细胞凋亡和神经元分化。本研究检测AT（2）受体刺激对生长因子诱导的导致丝裂原活化蛋白（MAP）激酶活化的途径的影响。在N1 E-115神经母细胞瘤细胞中，AT（2）受体抑制由血清以及表皮生长因子诱导的MAP激酶的活性。血管紧张素II（Ang II）的抑制作用是快速和短暂的，并且影响该酶的ERK 1和ERK 2（胞外信号相关蛋白激酶）亚型。AT（2）介导的MAP激酶失活对百日咳毒素或冈田酸不敏感，但涉及钒酸敏感的蛋白酪氨酸磷酸酶（PTP）。MAP激酶磷酸酶-1（MKP-1）的表达在AT（2）受体激活后没有显著改变，并且对放线菌素D不敏感也排除了其他MKP的转录诱导作为AT（2）介导的MAP激酶失活的可能机制。此外，我们还报道了在表达重组人AT（2）受体的N1 E-115细胞和中国仓鼠卵巢细胞中，Ang Ⅱ迅速刺激SHP-1的催化活性，SHP-1是一种可溶性PTP，与细胞因子和生长因子受体信号传导的终止有关。因此，这些发现证明了七螺旋AT（2）受体和受体酪氨酸激酶之间的功能性负串扰，并表明SHP-1酪氨酸磷酸酶是AT（2）受体信号通路的早期转导子。
Angiotensin II type 2 (AT(2)) receptors are involved in the inhibition of cell proliferation as well as in apoptosis and neuronal differentiation, through intracellular signalling pathways that remain poorly defined. The present study examines the effect of AT(2)-receptor stimulation on growth-factor-induced pathways leading to the activation of mitogen-activated protein (MAP) kinases. In N1E-115 neuroblastoma cells, AT(2) receptors inhibit the activity of MAP kinases induced by serum as well as by epidermal growth factor, The inhibitory effect of angiotensin II (Ang II) is rapid and transient, and affects both ERK1 and ERK2 (extracellular signal-related protein kinase) isoforms of the enzyme. AT(2)-mediated MAP kinase inactivation is not sensitive to pertussis toxin or okadaic acid, but involves a vanadate-sensitive protein tyrosine phosphatase (PTP). Expression of MAP kinase phosphatase-l (MKP-1) is not significantly modified upon AT(2)-receptor activation, and insensitivity to actinomycin D also rules out transcriptional induction of other MKPs as a possible mechanism for AT(2)-mediated inactivation of MAP kinases. In addition, eve report here that both in N1E-115 cells and in Chinese hamster ovary cells expressing recombinant human AT(2) receptors, Ang II rapidly stimulates the catalytic activity of SHP-1, a soluble PTP that has been implicated in termination of signalling by cytokine and growth-factor receptors. These findings thus demonstrate functional negative cross-talk between heptahelical AT(2) receptors and receptor tyrosine kinases, and suggest that SHP-1 tyrosine phosphatase is an early transducer of the AT(2) receptor signalling pathway.