The candidate tumor suppressor SASH1 interacts with the actin cytoskeleton and stimulates cell-matrix adhesion
The candidate tumor suppressor SASH1 interacts with the actin cytoskeleton and stimulates cell-matrix adhesion
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DOI：
10.1016/j.biocel.2011.07.012
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发表时间：
2011-11-01
影响因子：
4
通讯作者：
Janssen, Klaus-Peter
中科院分区：
文献类型：
--
作者：
Martini, Melanie;Gnann, Alexandra;Janssen, Klaus-Peter
SASH1是信号适配器蛋白sly家族的一员，是乳腺癌和结肠癌的候选肿瘤抑制因子。SASH1表达降低与肿瘤侵袭性生长、转移形成和不良预后相关。然而，SASH1的生物学作用在很大程度上仍然未知。为了揭示SASH1的功能，我们分析了内源性SASH1的细胞内定位，并产生了SASH1结构突变体。SASH1定位于上皮细胞的细胞核和细胞质。此外，SASH1在板足和膜褶中富集，与肌动蛋白细胞骨架共分布。此外，我们证明了SASH1与癌蛋白的一种新的相互作用，癌蛋白是板足中肌动蛋白聚合的一种已知调节剂。SASH1表达增强，丝状肌动蛋白含量显著增加，导致细胞突起，细胞形状拉长。这种活性被定位到SASH1的中心，进化上保守的区域。此外，SASH1的表达抑制细胞迁移，导致细胞对纤维连接蛋白和层粘连蛋白的粘附增加，而内源性SASH1的敲除导致细胞-基质粘附显著降低。综上所述，我们的发现首次揭示了SASH1通过调节癌细胞的粘附和迁移行为在肿瘤形成中的机制作用。(C) 2011 Elsevier Ltd.版权所有。
SASH1, a member of the SLY-family of signal adapter proteins, is a candidate tumor suppressor in breast and colon cancer. Reduced expression of SASH1 is correlated with aggressive tumor growth, metastasis formation, and inferior prognosis. However, the biological role of SASH1 remains largely unknown. To unravel the function of SASH1, we have analyzed the intracellular localization of endogenous SASH1, and have generated structural SASH1 mutants. SASH1 localized to the nucleus as well as to the cytoplasm in epithelial cells. In addition, SASH1 was enriched in lamellipodia and membrane ruffles, where it co-distributed with the actin cytoskeleton. Moreover, we demonstrate a novel interaction of SASH1 with the oncoprotein cortactin, a known regulator of actin polymerization in lamellipodia. Enhanced SASH1 expression significantly increased the content of filamentous actin, leading to the formation of cell protrusions and elongated cell shape. This activity was mapped to the central, evolutionarily conserved domain of SASH1. Furthermore, expression of SASH1 inhibited cell migration and lead to increased cell adhesion to fibronectin and laminin, whereas knock-down of endogenous SASH1 resulted in significantly reduced cell-matrix adhesion. Taken together, our findings unravel for the first time a mechanistic role for SASH1 in tumor formation by regulating the adhesive and migratory behaviour of cancer cells. (C) 2011 Elsevier Ltd. All rights reserved.