Integrins activate trimeric G proteins via the nonreceptor protein GIV/Girdin.
Integrins activate trimeric G proteins via the nonreceptor protein GIV/Girdin.
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DOI：
10.1083/jcb.201506041
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发表时间：
2015-09-28
期刊：
影响因子：
--
通讯作者：
Garcia-Marcos M
中科院分区：
文献类型：
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作者：
Leyme A;Marivin A;Perez-Gutierrez L;Nguyen LT;Garcia-Marcos M
GIV/Girdin是一种非受体GEF，它直接将整合素与三聚体G蛋白的激活联系起来，从而促进癌细胞获得非侵袭性特征。通过整合素和G蛋白偶联受体的信号转导是控制细胞行为的关键。传统上认为，这两类受体在响应细胞外信号时触发不同且独立的信号级联反应。在这里，我们报道了一种新的整合素信号传导机制，该机制需要非受体鸟嘌呤核苷酸交换因子（GEF） GIV（也称为Girdin）（一种转移相关蛋白）激活三聚体G蛋白Gαi。我们证明，GIV增强了整合素依赖性细胞对细胞外基质刺激的反应，使肿瘤细胞更具侵袭性。这些反应包括肌动蛋白细胞骨架的重塑和pi3k依赖的信号传导，导致趋向性和侵袭性增强。我们发现，GIV及其底物Gαi3都被招募到活性整合素复合物中，并且经过工程改造表达缺乏gef的GIV的肿瘤细胞无法通过Gβγ-PI3K轴将整合素信号转导为非侵入性反应。我们的发现描述了一种新的机制，通过这种机制，整合素信号在转移过程中被重新连接，从而导致肿瘤侵袭性增加。
GIV/Girdin, a nonreceptor GEF, directly links integrins to activation of trimeric G proteins to promote the acquisition of proinvasive traits in cancer cells. Signal transduction via integrins and G protein–coupled receptors is critical to control cell behavior. These two receptor classes have been traditionally believed to trigger distinct and independent signaling cascades in response to extracellular cues. Here, we report a novel mechanism of integrin signaling that requires activation of the trimeric G protein Gαi by the nonreceptor guanine nucleotide exchange factor (GEF) GIV (also known as Girdin), a metastasis-associated protein. We demonstrate that GIV enhances integrin-dependent cell responses upon extracellular matrix stimulation and makes tumor cells more invasive. These responses include remodeling of the actin cytoskeleton and PI3K-dependent signaling, resulting in enhanced haptotaxis and invasion. We show that both GIV and its substrate Gαi3 are recruited to active integrin complexes and that tumor cells engineered to express GEF-deficient GIV fail to transduce integrin signals into proinvasive responses via a Gβγ-PI3K axis. Our discoveries delineate a novel mechanism by which integrin signaling is rewired during metastasis to result in increased tumor invasiveness.