Vasodilator-stimulated phosphoprotein promotes activation of hepatic stellate cells by regulating Rab11-dependent plasma membrane targeting of transforming growth factor beta receptors.
Vasodilator-stimulated phosphoprotein promotes activation of hepatic stellate cells by regulating Rab11-dependent plasma membrane targeting of transforming growth factor beta receptors.
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血管扩张剂刺激的磷蛋白通过调节转化生长因子β受体的靶向RAB11依赖性质膜来促进肝星状细胞的激活。
DOI：
10.1002/hep.27251
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发表时间：
2015-01
期刊：
影响因子：
13.5
通讯作者：
Kang, Ningling
中科院分区：
文献类型：
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作者：
Tu, Kangsheng;Li, Jiachu;Verma, Vikas K.;Liu, Chunsheng;Billadeau, Daniel D.;Lamprecht, Georg;Xiang, Xiaoyu;Guo, Luyang;Dhanasekaran, Renumathy;Roberts, Lewis R.;Shah, Vijay H.;Kang, Ningling
肝微环境是肝转移发生和发展的关键决定因素。在TGF-β刺激下，肝星状细胞（HSC）（其是肝特异性周细胞）转分化成肿瘤相关肌成纤维细胞，其促进肿瘤在肝中的植入和生长。然而，这种HSC活化过程的调节仍然知之甚少。在本研究中，我们检测了HSC的血管舒张刺激磷蛋白（VASP）是否调节TGF-β介导的HSC活化过程和肿瘤生长。在实验性肝转移小鼠模型和癌症患者中，到达肝窦的结直肠癌细胞诱导邻近HSC中VASP和α-平滑肌肌动蛋白（α-SMA）的上调。HSC中的VASP敲低抑制了TGF-β介导的HSC的成肌纤维细胞活化、小鼠中的肿瘤植入和生长。在机制上，VASP与TGF-β受体II（TβRII）和Rab 11形成蛋白复合物，Rab 11是一种Ras样小GTdR，是再循环内体的关键调节因子。VASP敲低削弱Rab 11活性和Rab 11依赖性TβRII靶向质膜，从而使HSC对TGF-β1刺激脱敏。我们的研究表明，VASP通过调节Rab 11依赖的TβRII向质膜的再循环，对肿瘤微环境中TGF-β介导的HSC活化是必需的。因此，VASP及其在肿瘤微环境中的效应子Rab 11为减少肝脏中的肿瘤植入和转移生长提供了治疗靶点。
Liver microenvironment is a critical determinant for development and progression of liver metastasis. Under TGF-β stimulation, hepatic stellate cells (HSCs), which are liver specific pericytes, transdifferentiate into tumor associated myofibroblasts that promote tumor implantation and growth in the liver. The regulation of this HSC activation process however remains poorly understood. In this study we tested whether vasodilator-stimulated phosphoprotein (VASP) of HSCs regulated TGF-β mediated HSC activation process and tumor growth. In both an experimental liver metastasis mouse model and cancer patients, colorectal cancer cells reaching liver sinusoids induced upregulation of VASP and alpha- smooth muscle actin (α-SMA) in adjacent HSCs. VASP knockdown in HSCs inhibited TGF-β mediated myofibroblastic activation of HSCs, tumor implantation and growth in mice. Mechanistically, VASP formed protein complexes with TGF-β receptor II (TβRII) and Rab11, a Ras-like small GTPase and key regulator of recycling endosomes. VASP knockdown impaired Rab11 activity and Rab11 dependent targeting of TβRII to the plasma membrane thereby desensitizing HSCs to TGF-β1 stimulation. our study demonstrates a requirement of VASP for TGF-β mediated HSC activation in the tumor microenvironment by regulating Rab11 dependent recycling of TβRII to the plasma membrane. VASP and its effector Rab11 in the tumor microenvironment thus present therapeutic targets for reducing tumor implantation and metastatic growth in the liver.
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影响因子：
--
作者：
Vidal-Vanaclocha, Fernando
通讯作者：
Vidal-Vanaclocha, Fernando
影响因子：
6
作者：
Kang, Ningling;Yaqoob, Usman;Shah, Vijay
通讯作者：
Shah, Vijay
影响因子：
64.8
作者：
WRANA, JL;ATTISANO, L;MASSAGUE, J
通讯作者：
MASSAGUE, J
影响因子：
16.2
作者：
Ehlers, MD
通讯作者：
Ehlers, MD
DOI：
10.1083/jcb.200408165
发表时间：
2004-11-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ang AL;Taguchi T;Francis S;Fölsch H;Murrells LJ;Pypaert M;Warren G;Mellman I
通讯作者：
Mellman I