CIB1 contributes to oncogenic signalling by Ras via modulating the subcellular localisation of sphingosine kinase 1.
CIB1 contributes to oncogenic signalling by Ras via modulating the subcellular localisation of sphingosine kinase 1.
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DOI：
10.1038/onc.2016.428
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发表时间：
2017-05-04
期刊：
影响因子：
8
通讯作者：
Pitson SM
中科院分区：
文献类型：
--
作者：
Zhu W;Gliddon BL;Jarman KE;Moretti PAB;Tin T;Parise LV;Woodcock JM;Powell JA;Ruszkiewicz A;Pitman MR;Pitson SM
CIB 1（钙和整合素结合蛋白1）是一种具有许多相互作用伴侣的小细胞内蛋白，因此参与了各种细胞功能。最近的研究揭示了CIB 1在调节癌细胞存活和血管生成中的新作用，尽管所涉及的机制在很大程度上尚未确定。在研究CIB 1的致癌功能时，我们最初发现CIB 1在多种癌症中广泛上调，这种上调通常与KRas的致癌突变相关。与此一致，我们发现细胞中致癌KRas和HRas的异位表达导致CIB 1表达升高。我们先前描述了CIB 1的Ca 2 +-肉豆蔻酰开关功能，以及其促进激动剂诱导的鞘氨醇激酶1（SK 1）质膜定位的能力，已知SK 1在该位置引发致癌信号传导。因此，我们研究了这可能在肿瘤发生中发挥的作用。与这些发现一致，我们在此证明CIB 1自身的过表达足以驱动SK 1定位于质膜并增强SK 1的膜相关酶活性及其致癌信号传导。我们随后证明，CIB 1水平升高导致完全的肿瘤转化，在某种程度上依赖于SK 1。与我们先前的发现一致，即SK 1是Ras致癌信号传导的下游介质，我们发现靶向CIB 1也抑制了致癌Ras诱导的细胞的肿瘤生长，这表明CIB 1具有重要的促肿瘤作用。因此，我们首次证明了CIB 1在肿瘤转化中的作用，并揭示了Ras和SK 1促进致癌信号传导的新机制。
CIB1 (calcium and integrin binding protein 1) is a small intracellular protein with numerous interacting partners, and hence has been implicated in various cellular functions. Recent studies have revealed emerging roles of CIB1 in regulating cancer cell survival and angiogenesis, although the mechanisms involved have remained largely undefined. In investigating the oncogenic function of CIB1, we initially found that CIB1 is widely up-regulated across a diverse range of cancers, with this up-regulation frequently correlating with oncogenic mutations of KRas. Consistent with this, we found that ectopic expression of oncogenic KRas and HRas in cells resulted in elevated CIB1 expression. We previously described the Ca2+-myristoyl switch function of CIB1, and its ability to facilitate agonist-induced plasma membrane localisation of sphingosine kinase 1 (SK1), a location where SK1 is known to elicit oncogenic signalling. Thus, we examined the role this may play in oncogenesis. Consistent with these findings, we demonstrated here that over-expression of CIB1 by itself is sufficient to drive localisation of SK1 to the plasma membrane and enhance the membrane associated enzymatic activity of SK1, as well as its oncogenic signalling. We subsequently demonstrated that elevated levels of CIB1 resulted in full neoplastic transformation, in a manner dependent on SK1. In agreement with our previous findings that SK1 is a downstream mediator of oncogenic signalling by Ras, we found that targeting CIB1 also inhibited neoplastic growth of cells induced by oncogenic Ras, suggesting an important pro-tumorigenic role for CIB1. Thus, we have demonstrated for the first time a role for CIB1 in neoplastic transformation, and revealed a novel mechanism facilitating oncogenic signalling by Ras and SK1.