Prolactin-stimulated activation of ERK1/2 mitogen-activated protein kinases is controlled by PI3-kinase/Rac/PAK signaling pathway in breast cancer cells.
Prolactin-stimulated activation of ERK1/2 mitogen-activated protein kinases is controlled by PI3-kinase/Rac/PAK signaling pathway in breast cancer cells.
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DOI：
10.1016/j.cellsig.2011.06.014
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发表时间：
2011-11
影响因子：
4.8
通讯作者：
Kiyatkin A
中科院分区：
文献类型：
--
作者：
Aksamitiene E;Achanta S;Kolch W;Kholodenko BN;Hoek JB;Kiyatkin A
有强有力的证据表明，催乳素 (PRL) 信号的失调有助于乳腺癌的发病机制和化疗耐药性。因此，了解催乳素受体（PRL-R）激活触发的不同信号转导途径之间的串扰对于阐明转移性乳腺癌的发病机制至关重要。在这项研究中，我们对各种信号中间体进行了序贯抑制分析，以检查 PRL 信号网络内蛋白质相互作用的层次结构，并评估 PRL-R 下游多个信号分支对 T47D 和 MCF-7 人乳腺癌细胞中细胞外信号调节激酶 ERK1 和 ERK2 激活的相对贡献。蛋白质磷酸化/激活模式的定量测量表明，PRL 同时激活 Src 家族激酶 (SFK) 和 JAK/STAT、磷酸肌醇 3 (PI3) 激酶/Akt 和 MAPK 信号通路。对 SFK/FAK、JAK2/STAT5、PI3-kinase/PDK1/Akt、Rac/PAK 或 Ras 调节回路的特异性阻断或 siRNA 介导的抑制表明：（1）PI3-kinase/Akt 途径是 PRL 刺激后 MAPK/ERK 信号级联激活所必需的； (2) PI3激酶介导的c-Raf-MEK1/2-ERK1/2级联激活独立于STAT、Akt和PKC的信号下游，但需要JAK2、SFK和FAK活性； (3)激活的PRL-R主要利用PI3激酶依赖性Rac/PAK途径而不是经典的Shc/Grb2/SOS/Ras途径来启动和维持ERK1/2信号传导。通过互连不同的信号通路，PLR 可以增强乳腺癌细胞的增殖、存活、迁移和侵袭性。
There is strong evidence that deregulation of prolactin (PRL) signaling contributes to pathogenesis and chemoresistance of breast cancer. Therefore, understanding cross-talk between distinct signal transduction pathways triggered by activation of the prolactin receptor (PRL-R), is essential for elucidating the pathogenesis of metastatic breast cancer. In this study, we applied a sequential inhibitory analysis of various signaling intermediates to examine the hierarchy of protein interactions within the PRL signaling network and to evaluate the relative contributions of multiple signaling branches downstream of PRL-R to the activation of the extracellular signal-regulated kinases ERK1 and ERK2 in T47D and MCF-7 human breast cancer cells. Quantitative measurements of the phosphorylation/activation patterns of proteins showed that PRL simultaneously activated Src family kinases (SFKs) and the JAK/STAT, phosphoinositide-3 (PI3)-kinase/Akt and MAPK signaling pathways. The specific blockade or siRNA-mediated suppression of SFK/FAK, JAK2/STAT5, PI3-kinase/PDK1/Akt, Rac/PAK or Ras regulatory circuits revealed that (1) the PI3-kinase/Akt pathway is required for activation of the MAPK/ERK signaling cascade upon PRL stimulation; (2) PI3-kinase-mediated activation of the c-Raf-MEK1/2-ERK1/2 cascade occurs independent of signaling dowstream of STATs, Akt and PKC, but requires JAK2, SFKs and FAK activities; (3) activated PRL-R mainly utilizes the PI3-kinase-dependent Rac/PAK pathway rather than the canonical Shc/Grb2/SOS/Ras route to initiate and sustain ERK1/2 signaling. By interconnecting diverse signaling pathways PLR may enhance proliferation, survival, migration and invasiveness of breast cancer cells.
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影响因子：
4.8
作者：
Aksamitiene E;Kholodenko BN;Kolch W;Hoek JB;Kiyatkin A
通讯作者：
Kiyatkin A
影响因子：
3.4
作者：
Gill, S;Peston, D;Shousha, S
通讯作者：
Shousha, S
影响因子：
4.8
作者：
ERWIN, RA;KIRKEN, RA;RUI, H
通讯作者：
RUI, H
影响因子：
4.8
作者：
Chen, HC;Appeddu, PA;Guan, JL
通讯作者：
Guan, JL
影响因子：
4.1
作者：
Gabarra-Niecko, V;Keely, PJ;Schaller, MD
通讯作者：
Schaller, MD