SSeCKS/Gravin/AKAP12 metastasis suppressor inhibits podosome formation via RhoA- and Cdc42-dependent pathways
SSeCKS/Gravin/AKAP12 metastasis suppressor inhibits podosome formation via RhoA- and Cdc42-dependent pathways
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DOI：
10.1158/1541-7786.mcr-05-0252
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发表时间：
2006-03-01
影响因子：
5.2
通讯作者：
Gao, LQ
中科院分区：
文献类型：
--
作者：
Gelman, IH;Gao, LQ
Podosomes是一种知之甚少的富含肌动蛋白的结构，特别是在癌细胞系或v-Src转化细胞中发现的，被认为有助于肿瘤转移中涉及的一些侵袭性特性。富集的Tks 5/Fish蛋白，一个v-Src底物，是需要形成的podosomes。我们先前表明，四环素调节的Src抑制的C激酶底物（SSeCKS，也称为Gravin/AKAP 12）的再表达抑制了NIH 3 T3中v-Src诱导的致癌生长的变量，与正常肌动蛋白细胞骨架结构和细胞形态的诱导相关，但与细胞中Src磷酸化活性的总体抑制无关。在这里，我们表明，SSeCKS在生理水平上的再表达抑制了podosome的形成，与Matrigel侵袭性的降低相关，而对总细胞酪氨酸磷酸化或Tks 5/Fish的磷酸化没有影响。RhoA和Cdc 42的活化形式能够挽救再表达SSeCKS的v-Src细胞中的足体形成，并且这与SSeCKS抑制RhoA和Cdc 42活性水平> 5倍的能力相关。有趣的是，尽管激活的Rac I对足体形成几乎没有影响，但它可以与激活的RhoA合作逆转SSeCKS诱导的细胞扁平化。这些数据表明，v-Src诱导的Tks 5酪氨酸磷酸化是不足以在没有RhoA和/或Cdc 42介导的细胞骨架重塑的情况下形成足状体。此外，他们加强了SSeCKS通过重建肌动蛋白为基础的细胞骨架结构抑制Src诱导的肿瘤发生的概念。
Podosomes are poorly understood actin-rich structures notably found in cancer cell lines or in v-Src-transformed cells that are thought to facilitate some of the invasive properties involved in tumor metastasis. The enrichment of the Tks5/Fish protein, a v-Src substrate, is required for formation of podosomes. We showed previously that the tetracycline-regulated reexpression of the Src-suppressed C kinase substrate (SSeCKS, also known as Gravin/AKAP12) inhibited variables of v-Src-induced oncogenic growth in NIH3T3, correlating with the induction of normal actin cytoskeletal structures and cell morphology but not with gross inhibition of Src phosphorylation activity in the cell. Here, we show that SSeCKS reexpression at physiologic levels suppresses podosome formation, correlating with decreases in Matrigel invasiveness, whereas there is no effect on total cellular tyrosine phosphorylation or on the phosphorylation of Tks5/Fish. Activated forms of RhoA and Cdc42 were capable of rescuing podosome formation in v-Src cells reexpressing SSeCKS, and this correlated with the ability of SSeCKS to inhibit RhoA and Cdc42 activity levels by > 5-fold. Interestingly, although activated Rac I had little effect on podosome formation, it could partner with activated RhoA to reverse the cell flattening induced by SSeCKS. These data suggest that v-Src-induced Tks5 tyrosine phosphorylation is insufficient for podosome formation in the absence of RhoA- and/or Cdc42-mediated cytoskeletal remodeling. Additionally, they strengthen the notion that SSeCKS suppresses Src-induced oncogenesis by reestablishing actin-based cytoskeletal architecture.