The interaction between caveolin-1 and Rho-GTPases promotes metastasis by controlling the expression of alpha5-integrin and the activation of Src, Ras and Erk.
The interaction between caveolin-1 and Rho-GTPases promotes metastasis by controlling the expression of alpha5-integrin and the activation of Src, Ras and Erk.
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DOI：
10.1038/onc.2011.288
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发表时间：
2012-02-16
期刊：
影响因子：
8
通讯作者：
Mak, T. W.
中科院分区：
文献类型：
--
作者：
Arpaia, E.;Blaser, H.;Quintela-Fandino, M.;Duncan, G.;Leong, H. S.;Ablack, A.;Nambiar, S. C.;Lind, E. F.;Silvester, J.;Fleming, C. K.;Rufini, A.;Tusche, M. W.;Bruestle, A.;Ohashi, P. S.;Lewis, J. D.;Mak, T. W.
含有小窝蛋白结合结构域（CBD）的蛋白质，例如Rho-GTPases，可以通过其小窝蛋白支架结构域与小窝蛋白-1（Cav 1）相互作用。Rho-GTP酶是p130 Cas的重要调节因子，p130 Cas对正常细胞迁移和Src激酶介导的癌细胞转移都至关重要。然而，尽管Rho-GTP酶（特别是RhoC）和Cav 1与癌症进展和转移有关，但其潜在的分子机制在很大程度上是未知的。为了研究Cav 1-Rho-GT3相互作用在转移中的功能，我们通过过表达CBD破坏了黑素瘤和乳腺上皮肿瘤细胞中Cav 1-Rho-GT3的结合，并检查了RhoC在转移性癌细胞中的功能丧失。过表达CBD或缺乏RhoC的癌细胞p130 Cas磷酸化和Rac 1活化减少，导致体外迁移和侵袭抑制。Src的活性及其下游靶点FAK、Pyk 2、Ras和细胞外信号调节激酶（Erk）1/2的活化也受到损害。在CBD表达细胞和缺乏RhoC的细胞中观察到α5-整联蛋白表达的减少，α 5-整联蛋白表达是与纤连蛋白结合并因此细胞迁移和存活所需的。由于这些缺陷，表达CBD的黑色素瘤细胞在受体小鼠中转移的能力降低，并且在鸡胚胎的次级部位中的外渗和存活受损。我们的数据表明Cav 1和Rho-GTP酶（最可能是RhoC而不是RhoA）之间的相互作用通过刺激α5-整合素表达和调节Src依赖的p130 Cas/Rac 1、FAK/Pyk 2和Ras/Erk 1/2信号级联的激活来促进转移。
Proteins containing a caveolin-binding domain (CBD), such as the Rho-GTPases, can interact with caveolin-1 (Cav1) through its caveolin scaffold domain. Rho-GTPases are important regulators of p130Cas, which is crucial for both normal cell migration and Src kinase-mediated metastasis of cancer cells. However, although Rho-GTPases (particularly RhoC) and Cav1 have been linked to cancer progression and metastasis, the underlying molecular mechanisms are largely unknown. To investigate the function of Cav1–Rho-GTPase interaction in metastasis, we disrupted Cav1–Rho-GTPase binding in melanoma and mammary epithelial tumor cells by overexpressing CBD, and examined the loss-of-function of RhoC in metastatic cancer cells. Cancer cells overexpressing CBD or lacking RhoC had reduced p130Cas phosphorylation and Rac1 activation, resulting in an inhibition of migration and invasion in vitro. The activity of Src and the activation of its downstream targets FAK, Pyk2, Ras and extracellular signal-regulated kinase (Erk)1/2 were also impaired. A reduction in α5-integrin expression, which is required for binding to fibronectin and thus cell migration and survival, was observed in CBD-expressing cells and cells lacking RhoC. As a result of these defects, CBD-expressing melanoma cells had a reduced ability to metastasize in recipient mice, and impaired extravasation and survival in secondary sites in chicken embryos. Our data indicate that interaction between Cav1 and Rho-GTPases (most likely RhoC but not RhoA) promotes metastasis by stimulating α5-integrin expression and regulating the Src-dependent activation of p130Cas/Rac1, FAK/Pyk2 and Ras/Erk1/2 signaling cascades.
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影响因子：
64.8
作者：
Clark, EA;Golub, TR;Hynes, RO
通讯作者：
Hynes, RO
DOI：
10.1083/jcb.200709019
发表时间：
2008-03-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Goetz JG;Joshi B;Lajoie P;Strugnell SS;Scudamore T;Kojic LD;Nabi IR
通讯作者：
Nabi IR
Caveolin-1和活化的AKT/MTOR途径的结合表达预测，临床上受限制的肾细胞癌中无病生存率降低。
影响因子：
8.8
作者：
Campbell, L.;Jasani, B.;Edwards, K.;Gumbleton, M.;Griffiths, D. F. R.
通讯作者：
Griffiths, D. F. R.
影响因子：
56.9
作者：
Bonni, A;Brunet, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
4.8
作者：
Couet, J;Li, SW;Lisanti, MP
通讯作者：
Lisanti, MP