The CXCR4-Dependent LASP1-Ago2 Interaction in Triple-Negative Breast Cancer.
The CXCR4-Dependent LASP1-Ago2 Interaction in Triple-Negative Breast Cancer.
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DOI：
10.3390/cancers12092455
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发表时间：
2020-08-29
期刊：
影响因子：
5.2
通讯作者：
Raman D
中科院分区：
文献类型：
--
作者：
Tilley AMC;Howard CM;Sridharan S;Subramaniyan B;Bearss NR;Alkhalili S;Raman D
CXCR 4与三阴性乳腺癌转移密切相关。LASP 1以前被发现是CXCR 4依赖性肿瘤细胞侵袭所必需的。在这里，我们的目的是了解LASP 1如何在这个对转移至关重要的过程中发挥如此强大的作用。我们发现Ago 2，一个主调节蛋白，与LASP 1在响应CXCR 4活性。此外，我们发现，这种关联是负责影响由Ago 2调节的蛋白质的表达。CXCR 4-LASP 1轴是乳腺癌转移领域的新兴靶点。C-X-C趋化因子受体4型（CXCR 4）在被其同源配体CXCL 12激活时介导定向细胞迁移。LIM和SH 3蛋白1（LASP 1）是CXCR 4信号通路中的关键节点，因为其缺陷阻断CXCR 4依赖性基质胶侵袭。当CXCR 4被激活时，LASP 1促进肿瘤细胞这种侵袭能力的机制尚不清楚。我们以前的蛋白质组学工作揭示了RNA干扰（RNAi）机制的几个组成部分是潜在的LASP 1相互作用蛋白。在这里，我们报告了argonaute 2（Ago 2），一种在RNAi中具有中心参与的蛋白质，与三阴性乳腺癌（TNBC）细胞中的LASP 1相关。我们证明LASP 1与Ago 2以CXCL 12依赖性方式内源性共免疫沉淀，并通过邻近连接试验进一步证实了这种相互作用。此外，这种关联对CXCR 4是特异性的，因为它可以被CXCR 4拮抗剂AMD 3465消除。通过GST-下拉方法，我们确定LASP 1通过其LIM和SH 3结构域直接与Ago 2结合，并且这种结合由LASP 1的S146和Y171磷酸化位点决定。此外，LASP 1的磷酸化状态影响肿瘤抑制microRNA（miRNA）Let-7a引导的Ago 2活性。发现Let-7a的几种内源性靶标的水平发生改变，包括C-C趋化因子受体7型（CCR 7），其是参与淋巴结转移的另一种关键趋化因子受体。我们的研究结果表明LASP 1-Ago 2模块在塑造RNAi景观中的新作用，在功能上影响癌细胞的侵袭能力。
CXCR4 is critically involved in triple-negative breast cancer metastasis. LASP1 was previously found to be necessary for CXCR4-dependent tumor cell invasion. Here we aimed to understand how LASP1 can have such a powerful role this process that is critical to metastasis. We found Ago2, a master regulator protein, to associate with LASP1 in response to CXCR4 activity. Furthermore, we found that this association was responsible for affecting the expression of proteins regulated by Ago2. The CXCR4-LASP1 axis is an emerging target in the field of breast cancer metastasis. C-X-C chemokine receptor type 4 (CXCR4) mediates directed cell migration when activated by its cognate ligand CXCL12. LIM and SH3 Protein 1 (LASP1) is a critical node in the CXCR4 signaling pathway, as its deficiency blocks CXCR4-dependent Matrigel invasion. The mechanism by which LASP1 facilitates this invasive ability of tumor cells when CXCR4 is activated is unknown. Our previous proteomics work had revealed several components of the RNA interference (RNAi) machinery as being potential LASP1 interacting proteins. Here we report that argonaute 2 (Ago2), a protein with central involvement in RNAi, associates with LASP1 in triple-negative breast cancer (TNBC) cells. We demonstrate that LASP1 co-immunoprecipitates with Ago2 endogenously in a CXCL12-dependent manner, with further confirmation of this interaction by proximity ligation assay. Furthermore, this association is specific to CXCR4 as it can be abrogated by the CXCR4 antagonist, AMD3465. By GST-pulldown approach, we identify that LASP1 directly binds to Ago2 through its LIM and SH3 domains, and that this binding is dictated by the S146 and Y171 phosphorylation sites of LASP1. Additionally, the phosphorylation status of LASP1 affected tumor suppressor microRNA (miRNA) Let-7a-guided Ago2 activity. Levels of several endogenous targets of Let-7a were found to be altered including C-C chemokine receptor type 7 (CCR7), which is another critical chemokine receptor involved in metastasis to lymph nodes. Our results suggest a novel role for the LASP1-Ago2 module in shaping the RNAi landscape, functionally impacting the invasive ability of cancer cells.
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影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
4.7
作者：
Butt E;Raman D
通讯作者：
Raman D
影响因子：
64.5
作者：
Diederichs, Sven;Haber, Daniel A.
通讯作者：
Haber, Daniel A.
影响因子：
50.3
作者：
Allinen, M;Beroukhim, R;Polyak, K
通讯作者：
Polyak, K
ER α 的缺失通过下调纽蛋白诱导乳腺癌细胞的阿米巴样迁移
影响因子：
16.6
作者：
Gao Y;Wang Z;Hao Q;Li W;Xu Y;Zhang J;Zhang W;Wang S;Liu S;Li M;Xue X;Zhang W;Zhang C;Zhang Y
通讯作者：
Zhang Y