Hic-5 regulates fibrillar adhesion formation to control tumor extracellular matrix remodeling through interaction with tensin1.
Hic-5 regulates fibrillar adhesion formation to control tumor extracellular matrix remodeling through interaction with tensin1.
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DOI：
10.1038/s41388-017-0074-2
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发表时间：
2018-03
期刊：
影响因子：
8
通讯作者：
Turner CE
中科院分区：
文献类型：
--
作者：
Goreczny GJ;Forsythe IJ;Turner CE
癌相关成纤维细胞（CAF）使基质细胞外基质（ECM）线性化，促进肿瘤细胞生长和转移。然而，ECM重塑的机制尚未完全了解。Hic-5（TGFβ 1 i1）是一种黏着斑支架蛋白，在体内基质ECM沉积和重塑中起重要作用。在此，我们表明，CAFs缺乏Hic-5表现出显着降低的能力，形成纤维粘连，一个专门的形式的粘着斑，促进纤连蛋白原纤维形成。HIC-5被发现通过一个新的特点与tensin 1的相互作用，以促进纤维粘附形成。此外，Hic-5的Src依赖性磷酸化促进了与tensin 1的相互作用，以阻止β1整合素内化和运输至溶酶体。Hic-5和tensin 1之间的相互作用是机械敏感的，以刚性依赖的方式促进纤维粘连形成和纤连蛋白原纤维形成。重要的是，这种Src依赖性机制在三维（3D）ECM环境中是保守的。tensin 1的免疫组化显示在体内CAFs中富集，其在Hic-5缺失后被废除。有趣的是，在基底细胞样、HER 2+和3级肿瘤患者中，Hic-5表达升高与无远处转移生存率降低相关。因此，我们已经确定了Hic-5作为一个重要的调节ECM重塑CAFs通过促进纤维粘连形成，通过一种新的相互作用与tensin 1。
The linearization of the stromal extracellular matrix (ECM) by cancer associated fibroblasts (CAFs) facilitates tumor cell growth and metastasis. However, the mechanism by which the ECM is remodeled is not fully understood. Hic-5 (TGFβ1i1), a focal adhesion scaffold protein, has previously been reported to be crucial for stromal ECM deposition and remodeling in vivo. Herein we show that CAFs lacking Hic-5 exhibit a significant reduction in the ability to form fibrillar adhesions, a specialized form of focal adhesion that promote fibronectin fibrillogenesis. Hic-5 was found to promote fibrillar adhesion formation through a newly characterized interaction with tensin1. Furthermore, Src dependent phosphorylation of Hic-5 facilitated the interaction with tensin1 to prevent β1 integrin internalization and trafficking to the lysosome. The interaction between Hic-5 and tensin1 was mechanosensitive, promoting fibrillar adhesion formation and fibronectin fibrillogenesis in a rigidity dependent fashion. Importantly, this Src dependent mechanism was conserved in three-dimensional (3D) ECM environments. Immunohistochemistry of tensin1 showed enrichment in CAFs in vivo, which was abrogated upon deletion of Hic-5. Interestingly, elevated Hic-5 expression correlates with reduced distant metastasis free survival in patients with basal-like, HER2+ and grade 3 tumors. Thus, we have identified Hic-5 as a crucial regulator of ECM remodeling in CAFs by promoting fibrillar adhesion formation through a novel interaction with tensin1.
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DOI：
10.1083/jcb.125.5.1067
发表时间：
1994-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lo SH;Janmey PA;Hartwig JH;Chen LB
通讯作者：
Chen LB
影响因子：
3.7
作者：
Deakin NO;Ballestrem C;Turner CE
通讯作者：
Turner CE
影响因子：
3.3
作者：
Deakin NO;Turner CE
通讯作者：
Turner CE
影响因子：
56.9
作者：
Cukierman, E;Pankov, R;Yamada, KM
通讯作者：
Yamada, KM
影响因子：
4.8
作者：
Fujita, H;Kamiguchi, K;Tachibana, K
通讯作者：
Tachibana, K