PROLACTIN ACTIVATES RAS VIA SIGNALING PROTEINS SHC, GROWTH-FACTOR RECEPTOR-BOUND-2, AND SON-OF-SEVENLESS
PROLACTIN ACTIVATES RAS VIA SIGNALING PROTEINS SHC, GROWTH-FACTOR RECEPTOR-BOUND-2, AND SON-OF-SEVENLESS
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DOI：
10.1210/en.136.8.3512
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发表时间：
1995-08-01
期刊：
影响因子：
4.8
通讯作者：
RUI, H
中科院分区：
文献类型：
--
作者：
ERWIN, RA;KIRKEN, RA;RUI, H
识别PRL所使用的信号转导通路对于理解PRL受体在生长和分化过程中的作用是必不可少的。PRL受体活化的早期细胞介质包括Janus激酶（JAK）和SRC家族的酪氨酸激酶，通过酪氨酸磷酸化的信号转导子和转录激活子进行快速核信号传导。在本研究中，我们提供了PRL诱导的Ras激活的第一个证明，Ras是一种致癌蛋白，支持从膜到核的替代信号通路。在大鼠Nb 2-SP淋巴瘤细胞中，PRL刺激Ras，其GTP结合状态增加2.0倍（P < 0.01）。这种激活与显著的酪氨酸磷酸化和增加的52千道尔顿形式的SHC的膜结合有关。此外，PRL诱导SHC与生长因子受体结合2和鸟嘌呤-核苷酸交换因子son的结合，这是生长因子受体激活Ras的常用方法。相比之下，没有明显的调节PRL的Ras通过VAV或p120 Ras-鸟苷三磷酸酶激活蛋白被检测到，基于PRL诱导的酪氨酸磷酸化的情况下，这些蛋白质。总的来说，这些结果提供了PRL受体相关酪氨酸激酶的激活和随后的丝氨酸/苏氨酸激酶Raf-1的刺激之间的分子桥梁，Raf-1是一种已建立的Ras靶点，最近显示在Nb 2细胞中被PRL激活。我们的结论是，PRL是能够激活Ras通过招聘的信号蛋白SHC，生长因子受体结合2，和儿子的sevenless在Nb 2细胞。此外，PRL诱导的酪氨酸磷酸化的SHC在两个三个PRL响应的人乳腺癌细胞系，表明SHC介导的Ras激活是一种常用的信号策略，由PRL。
Identification of the signal transduction pathways used by PRL is essential for understanding the role of PRL receptors in growth and differentiation processes. Early cellular mediators of PRL receptor activation include tyrosine kinases of the Janus kinase (JAK) and SRC families, with rapid nuclear signaling via tyrosine phosphorylated signal transducers and activators of transcription. In the present study we provide the first demonstration of PRL-induced activation of Ras, an oncogenic protein that supports an alternative signaling route from the membrane to the nucleus. PRL stimulated Ras in rat Nb2-SP lymphoma cells, as detected by a 2.0-fold increase in the GTP-bound state of the molecule (P < 0.01). This activation was associated with marked tyrosine phosphorylation and increased membrane association of the 52-kilodalton form of SHC. Moreover, PRL induced binding of SHC to growth factor receptor bound 2 and the guanine-nucleotide exchange factor son of sevenless, a common method used by growth factor receptors to activate Ras. In contrast, no apparent regulation by PRL of Ras via VAV or p120 Ras-guanosine triphosphatase-activating protein was detected, based upon an absence of PRL-inducible tyrosine phosphorylation of these proteins. Collectively, these results provide a molecular bridge between activation of PRL receptor-associated tyrosine kinases and subsequent stimulation of the serine/threonine kinase Raf-1, an established Ras target that was recently shown to be activated by PRL in Nb2 cells. We conclude that PRL is able to activate Ras via recruitment of the signaling proteins SHC, growth factor receptor bound 2, and son of sevenless in Nb2 cells. Moreover, PRL induced tyrosine phosphorylation of SHC in two of three PRL-responsive human breast cancer cell lines, suggesting that SHC-mediated Ras activation is a commonly used signaling strategy by PRL.