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磷酸化的小窝蛋白-1支架结构域可抑制粘着斑中的力波动并促进癌细胞迁移。

The phospho-caveolin-1 scaffolding domain dampens force fluctuations in focal adhesions and promotes cancer cell migration.

作者信息

Meng Fanrui, Saxena Sandeep, Liu Youtao, Joshi Bharat, Wong Timothy H, Shankar Jay, Foster Leonard J, Bernatchez Pascal, Nabi Ivan R

机构信息

Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

Department of Biochemistry and Molecular Biology and Michael Smith Labs, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

出版信息

Mol Biol Cell. 2017 Aug 1;28(16):2190-2201. doi: 10.1091/mbc.E17-05-0278. Epub 2017 Jun 7.

DOI:10.1091/mbc.E17-05-0278
PMID:28592633
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5531735/
Abstract

Caveolin-1 (Cav1), a major Src kinase substrate phosphorylated on tyrosine-14 (Y14), contains the highly conserved membrane-proximal caveolin scaffolding domain (CSD; amino acids 82-101). Here we show, using CSD mutants (F92A/V94A) and membrane-permeable CSD-competing peptides, that Src kinase-dependent pY14Cav1 regulation of focal adhesion protein stabilization, focal adhesion tension, and cancer cell migration is CSD dependent. Quantitative proteomic analysis of Cav1-GST (amino acids 1-101) pull downs showed sixfold-increased binding of vinculin and, to a lesser extent, α-actinin, talin, and filamin, to phosphomimetic Cav1Y14D relative to nonphosphorylatable Cav1Y14F. Consistently, pY14Cav1 enhanced CSD-dependent vinculin tension in focal adhesions, dampening force fluctuation and synchronously stabilizing cellular focal adhesions in a high-tension mode, paralleling effects of actin stabilization. This identifies pY14Cav1 as a molecular regulator of focal adhesion tension and suggests that functional interaction between Cav1 Y14 phosphorylation and the CSD promotes focal adhesion traction and, thereby, cancer cell motility.

摘要

小窝蛋白-1（Cav1）是一种主要的Src激酶底物，在酪氨酸-14（Y14）位点发生磷酸化，包含高度保守的膜近端小窝蛋白支架结构域（CSD；氨基酸82-101）。在此我们利用CSD突变体（F92A/V94A）和膜渗透性CSD竞争肽表明，Src激酶依赖性的pY14Cav1对粘着斑蛋白稳定性、粘着斑张力和癌细胞迁移的调节是依赖于CSD的。对Cav1-GST（氨基酸1-101）下拉产物进行的定量蛋白质组学分析显示，与不可磷酸化的Cav1Y14F相比，磷酸模拟物Cav1Y14D与纽蛋白的结合增加了6倍，与α-辅肌动蛋白、踝蛋白和细丝蛋白的结合程度较低。一致地，pY14Cav1增强了粘着斑中CSD依赖性的纽蛋白张力，抑制了力的波动，并以高张力模式同步稳定细胞粘着斑，这与肌动蛋白稳定的作用相似。这确定了pY14Cav1是粘着斑张力的分子调节因子，并表明Cav1 Y14磷酸化与CSD之间的功能相互作用促进了粘着斑牵引，从而促进了癌细胞的运动。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/460585b614b9/2190fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/f68b284f86b6/2190fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/9b78b0945209/2190fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/d4e9fc260760/2190fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/22a0484bcf93/2190fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/76eb80f905bc/2190fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/e175e41a88fe/2190fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/1f57a87538ab/2190fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/460585b614b9/2190fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/f68b284f86b6/2190fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/9b78b0945209/2190fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/d4e9fc260760/2190fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/22a0484bcf93/2190fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/76eb80f905bc/2190fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/e175e41a88fe/2190fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/1f57a87538ab/2190fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35ca/5531735/460585b614b9/2190fig8.jpg

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