共查询到20条相似文献,搜索用时 31 毫秒
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Shuchen Gu Michalis Kounenidakis Eva-Maria Schmidt Divija Deshpande Saad Alkahtani Saud Alarifi Michael Föller Konstantinos Alevizopoulos Florian Lang Christos Stournaras 《Cellular signalling》2013,25(1):66-73
Actin cytoskeleton reorganization initiated by testosterone conjugates through activation of membrane androgen receptors (mAR) has recently been reported in colon tumor cells. This mAR-induced actin reorganization was recognized as a critical initial event, controlling apoptosis and inhibiting cell migration. The present study addressed the molecular signaling regulating the rapid actin remodeling initiated upon testosterone-induced mAR activation in Caco2 colon tumor cells. We report early phosphorylation of the Focal Adhesion Kinase (FAK), followed by substantial early phosphorylation of mammalian target of rapamycin (mTOR), S6 kinase (p70S6K) and the actin regulating p21-activated kinase (PAK1). Pharmacological inhibition of FAK-sensitive phosphatidylinositide-3-kinase (PI-3K), a known element of mAR-signaling, fully abrogated the testosterone-induced actin reorganization and the activation of mTOR, p70S6K and PAK1. Similarly, inhibition of mTOR blocked p70S6K and PAK1 phosphorylation and actin remodeling. Pretreatment of the cells with the intracellular androgen receptor (iAR) antagonist flutamide or silencing iAR through siRNA did not influence mTOR phosphorylation and actin reorganization, indicating specific mAR-induced testosterone effects that are independent of iAR signaling. In conclusion, we demonstrate for the first time a new mAR-governed pathway involving FAK/PI-3K and mTOR/p70S6K/PAK1-cascade that regulates early actin reorganization in colon cancer cells. 相似文献
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The hippo signaling pathway in development and cancer 总被引:2,自引:0,他引:2
Pan D 《Developmental cell》2010,19(4):491-505
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Fractionation of brain extracts and functional biochemical assays identified PP2Calpha, a serine/threonine phosphatase, as the major biochemical activity inhibiting PAK1. PP2Calpha dephosphorylated PAK1 and p38, both of which were activated upon hyperosmotic shock with the same kinetics. In comparison to growth factors, hyperosmolality was a more potent activator of PAK1. Therefore we characterize the PAK signaling pathway in the hyperosmotic shock response. Endogenous PAKs were recruited to the p38 kinase complex in a phosphorylation-dependent manner. Overexpression of a PAK inhibitory peptide or dominant negative Cdc42 revealed that p38 activation was dependent on PAK and Cdc42 activities. PAK mutants deficient in binding to Cdc42 or PAK-interacting exchange factor were not activated. Using a panel of kinase inhibitors, we identified PI3K acting upstream of PAK, which correlated with PAK repression by pTEN overexpression. RNA interference knockdown of PAK expression reduced stress-induced p38 activation and conversely, PP2Calpha knockdown increased its activation. Hyperosmotic stress-induced PAK translocation away from focal adhesions to the perinuclear compartment and resulted in disassembly of focal adhesions, which are hallmarks of PAK activation. Inhibition of PAK by overexpression of PP2Calpha or the kinase inhibitory domain prevented sorbitol-induced focal adhesion dissolution. Inhibition of MAPK pathways showed that MEK-ERK signaling but not p38 is required for full PAK activation and focal adhesion turnover. We conclude that 1) PAK plays a required role in hyperosmotic signaling through the PI3K/pTEN/Cdc42/PP2Calpha/p38 pathway, and 2) PAK and PP2Calpha modulate the effects of this pathway on focal adhesion dynamics. 相似文献
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Lin Chen Haiou Liu Jing Liu Yu Zhu Le Xu Hongyong He Heng Zhang Shanshan Wang Qian Wu Weisi Liu Yidong Liu Deng Pan Shifang Ren Jiejie Xu Jianxin Gu 《PloS one》2013,8(3)
Klotho was originally characterized as an aging suppressor gene that predisposed Klotho-deficient mice to premature aging-like syndrome. Although Klotho was recently reported to exhibit tumor suppressive properties during various malignant transformations, the functional role and molecular mechanism of Klotho in hepatocarcinogenesis remains poorly understood. In our present study, immunohistochemical Klotho staining levels in a clinical follow-up of 52 hepatoma patients were significantly associated with liver cirrhosis, tumor multiplicity and venous invasion. The overall survival rate of hepatoma patients with high Klotho expression was significantly lower than those patients with low Klotho expression. Moreover, Klotho overexpression increased cellular migration, anchorage-independent growth, and anoikis resistance in hepatoma cells. Klotho overexpression elevated p21-activated kinase 1 (PAK1) expression and shRNA-mediated PAK1 knockdown and kinase activity inhibition with kinase dead mutant PAK1 K299R coexpression or allosteric inhibitor IPA3 treatment reversed anoikis resistance in Klotho-overexpressed hepatoma cells. More importantly, the pivotal significance of upregulated VEGFR2 protein levels mediated by Klotho expression was confirmed by VEGFR2 inhibitor Axitinib and blocking antibody treatment in hepatoma cells. Axitinib treatment sensitized anoikis was reversed by constitutive active mutant PAK1 T423E coexpression in Klotho-overexpressed hepatoma cells. Conversely, knockdown of Klotho reduced VEGFR2/PAK1 dependent anoikis resistance, which could be reversed by PAK1 T423E. These results revealed a novel oncogenic function of Klotho in promoting anoikis resistance via activating VEGFR2/PAK1 signaling, thus facilitating tumor migration and invasion during hepatoma progression, which could provide a putative molecular mechanism for tumor metastasis. 相似文献
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Anaplastic thyroid cancer (ATC) is one of the most lethal and aggressive human malignancies, with no effective treatment currently available. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. TAZ is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal TAZ expression in ATC remains to be characterized. In the present study, we identified USP26, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of TAZ in ATC. USP26 was shown to interact with, deubiquitylate, and stabilize TAZ in a deubiquitylation activity-dependent manner. USP26 depletion significantly decreased ATC cell proliferation, migration, and invasion. The effects induced by USP26 depletion could be rescued by further TAZ overexpression. Depletion of USP26 decreased the TAZ protein level and the expression of TAZ/TEAD target genes in ATC, including CTGF, ANKRD1, and CYR61. In general, our findings establish a previously undocumented catalytic role for USP26 as a deubiquitinating enzyme of TAZ and provides a possible target for the therapy of ATC.Subject terms: Cancer, Oncogenes 相似文献
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Trakul N Menard RE Schade GR Qian Z Rosner MR 《The Journal of biological chemistry》2005,280(26):24931-24940
Raf kinase inhibitory protein (RKIP; also known as phosphatidylethanolamine-binding protein or PEBP) is a modulator of the Raf/MAPK signaling cascade and a suppressor of metastatic cancer. Here, we show that RKIP inhibits MAPK by regulating Raf-1 activation; specifically, RKIP acts subsequent to Raf-1 membrane recruitment, prevents association of Raf-1 and p21-activated kinase (PAK), and blocks phosphorylation of the Raf-1 kinase domain by PAK and Src family kinases. Mutation of the PAK and Src phosphorylation sites on Raf-1 to aspartate, a phosphate mimic, prevented RKIP association with or inhibition of Raf-1 signaling. Interestingly, although RKIP can interact with B-Raf, RKIP depletion had no effect on activation of B-Raf. Because c-Raf-1 and B-Raf are both required for maximal MAPK stimulation by epidermal growth factor in neuronal and epithelial cell lines, we determined whether RKIP significantly affects MAPK signaling. In fact, RKIP depletion increased not only the amplitude but also the sensitivity of MAPK and DNA synthesis to epidermal growth factor stimulation by up to an order of magnitude. These results indicate that selective modulation of c-Raf-1 but not B-Raf activation by RKIP can limit the dynamic range of the MAPK signaling response to growth factors and may play a critical role in growth and development. 相似文献
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Hippo通路是一种在进化中形成的保守的蛋白激酶级联通路,它与发育中器官的大小和肿瘤的形成有关。Hippo通路的中枢是从肿瘤抑制子Hippo到原癌蛋白YAP/TAZ的激酶级联反应。YAP/TAZ是Hippo通路下游的主要的效应分子,它们广泛表达于多种组织器官中。在哺乳动物细胞中,Hippo通路激酶级联反应通过对YAP/TAZ磷酸化作用,促使其从细胞核转入细胞质中,从而抑制了YAP/TAZ的功能作用。TEAD家族转录子被鉴定为YAP/TAZ发挥生物学功能的重要调节因子。YAP/TAZ的失调引起的相关的基因的表达改变,将会影响细胞的增殖,分化,以及凋亡,从而会影响器官的大小以及肿瘤的形成。本文综述Hippo通路的最新进展,重点关注的是该通路中的YAP/TAZ调控的缺失对发育缺陷和肿瘤的影响。这将为我们研究再生医学,组织工程技术,肿瘤的干预防治提供新的思路与策略。 相似文献
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哺乳动物肺对于血液与外部环境之间的气体交换至关重要。而肺相关的疾病是现代人死亡的主要原因之一。肺的发育、再生和相关疾病的研究对临床治疗具有重要的指导作用。研究发现,Hippo信号通路参与细胞增殖与分化的调控、器官大小的控制,以及机械力的感应和传递。Hippo信号通路中的核心转录调控分子YAP/TAZ在肺部的多种细胞中均有表达,其表达及定位的变化在肺发育与再生中发挥着重要的调控作用。本文主要介绍了Hippo信号通路在肺生长发育中的功能及其与肺纤维化、肺癌的关系,并从肺泡力学和肺泡相关免疫两个角度对Hippo信号通路潜在的功能进行了展望。 相似文献
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Tong Liu Yang Li Hui Gu Ge Zhu Jiabin Li Liu Cao Feng Li 《The Journal of biological chemistry》2013,288(5):3359-3369
The androgen receptor (AR) signaling pathway plays a crucial role in the development and growth of prostate malignancies. Regulation of AR homeostasis in prostate tumorigenesis has not yet been fully characterized. In this study, we demonstrate that p21-activated kinase 6 (PAK6) inhibits prostate tumorigenesis by regulating AR homeostasis. First, we demonstrated that in normal prostate epithelium, AR co-localizes with PAK6 in the cytoplasm and translocates into the nucleus in malignant prostate. Furthermore, AR phosphorylation at Ser-578 by PAK6 promotes AR-E3 ligase murine double minute-2 (Mdm2) association, causing AR degradation upon androgen stimuli. We also showed that PAK6 phosphorylates Mdm2 on Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation. Moreover, we found that Thr-158 collaborates with Ser-186 for AR-Mdm2 association and AR ubiquitin-mediated degradation as it facilitates PAK6-mediated AR homeostasis. PAK6 knockdown promotes prostate tumor growth in vivo. Interestingly, we found a strong inverse correlation between PAK6 and AR expression in the cytoplasm of prostate cancer cells. These observations indicate that PAK6 may be important for the maintenance of androgen-induced AR signaling homeostasis and in prostate malignancy, as well as being a possible new therapeutic target for AR-positive and hormone-sensitive prostate cancer. 相似文献
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