Ribosomal protein S6 kinase (RSK)-2 as a central effector molecule in RON receptor tyrosine kinase mediated epithelial to mesenchymal transition induced by macrophage-stimulating protein.
Ribosomal protein S6 kinase (RSK)-2 as a central effector molecule in RON receptor tyrosine kinase mediated epithelial to mesenchymal transition induced by macrophage-stimulating protein.
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DOI：
10.1186/1476-4598-10-66
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发表时间：
2011-05-28
期刊：
影响因子：
37.3
通讯作者：
Wang MH
中科院分区：
文献类型：
--
作者：
Ma Q;Guin S;Padhye SS;Zhou YQ;Zhang RW;Wang MH
上皮间质转化（EMT）发生在癌细胞侵袭和恶性转移过程中。EMT的特征包括梭形细胞形态、上皮细胞标志物的丢失和间充质表型的获得。巨噬细胞刺激蛋白（MSP）激活罗恩受体酪氨酸激酶参与了细胞EMT过程，然而，MSP诱导EMT的主要信号决定簇尚不清楚。本研究表明，RSK 2，Ras-Erk 1/2通路的下游信号蛋白，是连接MSP激活的罗恩信号传导到完成EMT的主要分子。使用表达罗恩的MDCK细胞作为模型，进行了基于纺锤形的筛选，在各种细胞内蛋白中鉴定出RSK 2作为负责MSP诱导的EMT的潜在信号分子。MSP刺激使RSK 2与Erk 1/2解离，促进RSK 2核转位。MSP以剂量依赖性方式强烈诱导RSK 2磷酸化。这些作用依赖于罗恩和Erk 1/2磷酸化，转化生长因子（TGF）-β1（一种EMT诱导细胞因子）可显著增强这一作用。特异性RSK抑制剂SL 0101完全阻止了MSP诱导的RSK磷酸化，从而抑制了MSP诱导的纺锤体样形态和与EMT相关的细胞迁移。在几乎不表达RSK 2的HT-29癌细胞中，在MSP刺激后，强制RSK 2表达导致EMT样表型。此外，在L3.6pl胰腺癌细胞中，特异性siRNA介导的RSK 2沉默而非RSK 1沉默显著抑制MSP诱导的EMT样表型和细胞迁移。MSP诱导的RSK 2活化是将罗恩信号传导与细胞EMT程序联系起来的关键决定因素。RSK 2活性的抑制可以为阻断RON介导的癌细胞迁移和随后的侵袭提供治疗机会。
Epithelial to mesenchymal transition (EMT) occurs during cancer cell invasion and malignant metastasis. Features of EMT include spindle-like cell morphology, loss of epithelial cellular markers and gain of mesenchymal phenotype. Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein (MSP) has been implicated in cellular EMT program; however, the major signaling determinant(s) responsible for MSP-induced EMT is unknown. The study presented here demonstrates that RSK2, a downstream signaling protein of the Ras-Erk1/2 pathway, is the principal molecule that links MSP-activated RON signaling to complete EMT. Using MDCK cells expressing RON as a model, a spindle-shape based screen was conducted, which identifies RSK2 among various intracellular proteins as a potential signaling molecule responsible for MSP-induced EMT. MSP stimulation dissociated RSK2 with Erk1/2 and promoted RSK2 nuclear translocation. MSP strongly induced RSK2 phosphorylation in a dose-dependent manner. These effects relied on RON and Erk1/2 phosphorylation, which is significantly potentiated by transforming growth factor (TGF)-β1, an EMT-inducing cytokine. Specific RSK inhibitor SL0101 completely prevented MSP-induced RSK phosphorylation, which results in inhibition of MSP-induced spindle-like morphology and suppression of cell migration associated with EMT. In HT-29 cancer cells that barely express RSK2, forced RSK2 expression results in EMT-like phenotype upon MSP stimulation. Moreover, specific siRNA-mediated silencing of RSK2 but not RSK1 in L3.6pl pancreatic cancer cells significantly inhibited MSP-induced EMT-like phenotype and cell migration. MSP-induced RSK2 activation is a critical determinant linking RON signaling to cellular EMT program. Inhibition of RSK2 activity may provide a therapeutic opportunity for blocking RON-mediated cancer cell migration and subsequent invasion.
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影响因子：
11.2
作者：
Ohashi S;Natsuizaka M;Wong GS;Michaylira CZ;Grugan KD;Stairs DB;Kalabis J;Vega ME;Kalman RA;Nakagawa M;Klein-Szanto AJ;Herlyn M;Diehl JA;Rustgi AK;Nakagawa H
通讯作者：
Nakagawa H
影响因子：
11.2
作者：
Chaffer, Christine L.;Brennan, Janelle P.;Williams, Elizabeth D.
通讯作者：
Williams, Elizabeth D.
影响因子：
4.8
作者：
Lu, X;Law, BK;Moses, HL
通讯作者：
Moses, HL
DOI：
10.1073/pnas.0909333107
发表时间：
2010-01-19
影响因子：
11.1
作者：
Gjerdrum, Christine;Tiron, Crina;Lorens, James B.
通讯作者：
Lorens, James B.
影响因子：
4.7
作者：
Park, Jung Sun;Park, Ji Hye;Jung, Young Do
通讯作者：
Jung, Young Do