Somatostatin receptor 1 (SSTR1)-mediated inhibition of cell proliferation correlates with the activation of the MAP kinase cascade: role of the phosphotyrosine phosphatase SHP-2
Somatostatin receptor 1 (SSTR1)-mediated inhibition of cell proliferation correlates with the activation of the MAP kinase cascade: role of the phosphotyrosine phosphatase SHP-2
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DOI：
10.1016/s0928-4257(00)00214-x
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发表时间：
2000-05-01
影响因子：
--
通讯作者：
Stork, PJS
中科院分区：
文献类型：
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作者：
Florio, T;Thellung, S;Stork, PJS
有丝分裂原活化蛋白（MAP）激酶级联是激素和生长因子对细胞生长的主要调节因子之一。然而，尽管这种细胞内途径的激活通常被认为是细胞增殖的介质，但在许多细胞类型中，MAP激酶（也称为细胞外信号调节激酶; ERK）活性的增加可能导致细胞生长停滞，这取决于刺激的长度或强度。在这篇综述中，我们研究了最近的数据，生长抑素对MAP激酶级联反应的影响，通过其主要受体亚型之一，生长抑素受体1（SSTR 1），稳定表达在CHO-KI细胞。生长抑素抑制碱性成纤维细胞生长因子（bFGF）对CHO-SSTR 1细胞的增殖作用。然而，在这些细胞中，生长抑素强烈激活MAP激酶和增强bFGF诱导的ERK刺激。我们表明，ERK通过SSTR 1的激活是由百日咳毒素敏感的G蛋白的py亚基介导的，需要小G蛋白Pas和丝氨酸/苏氨酸激酶Raf-1。此外，磷脂酰肌醇-3激酶和胞质酪氨酸激酶c-src参与了SSTR 1激活ERK的信号转导过程，并与蛋白酪氨酸磷酸酶（PTP）SHP-2有关。以前的研究表明，生长抑素刺激PTP活性介导生长抑素的生长抑制作用，在CHO-SSTR 1细胞。因此，SSTR 1激活SHP-2可能介导生长抑素的抗增殖活性。反过来，SHP-2可以调节ERK上游激酶的活性，这些激酶需要酪氨酸去磷酸化才能被激活，例如c-src。最后，生长抑素和bFGF之间的协同作用，在ERK的激活的结果在一个增加的表达的细胞周期蛋白依赖性激酶抑制剂p2（cip 1/WAF 1）作为生长抑素的抗增殖活性的分子效应。(C)2000 Elsevier Science Ltd.由Editions scientifiques et medicales Elsevier SAS出版。
The mitogen activated protein (MAP) kinase cascade represents one of the major regulator of cell growth by hormones and growth factors. However, although the activation of this intracellular pathway has been often regarded as mediator of cell proliferation, in many cell types the increase in MAP kinase (also called extra-cellular signal regulated kinase; ERK) activity may result in cell growth arrest, depending on the length or the intensity of the stimulation. In this review we examine recent data concerning the effects of somatostatin on the MAP kinase cascade through one of its major receptor subtype, the somatostatin receptor 1 (SSTR1), stably expressed in CHO-KI cells. Somatostatin inhibits the proliferative effects of basic FGF (bFGF) in CHO-SSTR1 cell line. However, in these cells, somatostatin robustly activates the MAP kinase and augments bFGF-induced stimulation of ERK. We show that the activation of ERK via SSTR1 is mediated by the py subunit of a pertussis toxin-sensitive G-protein and requires both the small G protein Pas and the serine/threonine kinase Raf-1. Moreover the phosphatidyl inositol-3kinase and the cytosolic tyrosine kinase c-src participate in the signal transduction regulated by SSTR1 to activate ERK, as well as it is involved the protein tyrosine phosphatase (PTP) SHP-2. Previous studies have suggested that somatostatin-stimulated PTP activity mediates the growth inhibitory actions of somatostatin, in CHO-SSTR1 cells. Thus, the activation of SHP-2 by SSTR1 may mediate the antiproliferative activity of somatostatin. SHP-2 may, in turn, regulate the activity of kinases upstream of ERK that require tyrosine dephosphorylation to be activated, such as c-src. Finally, the synergism between somatostatin and bFGF in the activation of ERK results in an increased expression of the cyclin-dependent kinase inhibitor p2(cip1/WAF1) as molecular effector of the antiproliferative activity of somatostatin. (C) 2000 Elsevier Science Ltd. Published by Editions scientifiques et medicales Elsevier SAS.