GIV/Girdin (Gα-interacting, Vesicle-associated Protein/Girdin) Creates a Positive Feedback Loop That Potentiates Outside-in Integrin Signaling in Cancer Cells
GIV/Girdin (Gα-interacting, Vesicle-associated Protein/Girdin) Creates a Positive Feedback Loop That Potentiates Outside-in Integrin Signaling in Cancer Cells
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DOI：
10.1074/jbc.m115.691550
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发表时间：
2016-04-08
影响因子：
4.8
通讯作者：
Garcia-Marcos, Mikel
中科院分区：
文献类型：
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作者：
Leyme, Anthony;Marivin, Arthur;Garcia-Marcos, Mikel
酪氨酸激酶粘着斑激酶（FAK）在细胞外基质刺激时的活化启动整联蛋白由外向内信号传导。FAK直接募集到活性整合素，这增强了其激酶活性并触发下游信号传导，如PI 3 K的活化。我们最近描述了G相互作用的囊泡相关蛋白（GIV），一种在转移性癌症中上调的蛋白质，也是由外向内整合素信号传导所必需的。更具体地说，我们发现GIV是一种非受体鸟嘌呤核苷酸交换因子，其响应于整合素刺激而激活三聚体G蛋白，以增强PI 3 K信号传导和肿瘤细胞迁移。相比之下，先前的报道已经确定，GIV参与响应于生长因子刺激的基于磷酸酪氨酸（Tyr（P））的信号传导;即，在Tyr-1764和Tyr-1798处的GIV磷酸化募集并激活PI 3 K。在这里，我们表明，GIV在Tyr-1764/Tyr-1798处的磷酸化也是增强PI 3 K-Akt信号传导和肿瘤细胞迁移响应于整合素刺激所必需的，表明GIV在Tyr（P）依赖性整合素信号传导中起作用。出乎意料的是，我们发现FAK（整合素Tyr（P）信号级联的上游组分）的激活在GIV耗尽的细胞中减弱，表明GIV是建立增强整合素-FAK信号传导的正反馈环所必需的。从机制上讲，我们证明FAK的这种反馈激活依赖于鸟嘌呤核苷酸交换因子和Tyr（P）GIV信号传导以及它们的会聚点PI 3 K。总之，我们的研究结果提供了新的机制的见解，如何GIV促进癌细胞的行为，作为一个信号放大平台，在三聚体G蛋白和酪氨酸（P）信号的十字路口。
Activation of the tyrosine kinase focal adhesion kinase (FAK) upon cell stimulation by the extracellular matrix initiates integrin outside-in signaling. FAK is directly recruited to active integrins, which enhances its kinase activity and triggers downstream signaling like activation of PI3K. We recently described that G-interacting, vesicle-associated protein (GIV), a protein up-regulated in metastatic cancers, is also required for outside-in integrin signaling. More specifically, we found that GIV is a non-receptor guanine nucleotide exchange factor that activates trimeric G proteins in response to integrin stimulation to enhance PI3K signaling and tumor cell migration. In contrast, previous reports have established that GIV is involved in phosphotyrosine (Tyr(P))-based signaling in response to growth factor stimulation; i.e. GIV phosphorylation at Tyr-1764 and Tyr-1798 recruits and activates PI3K. Here we show that phosphorylation of GIV at Tyr-1764/Tyr-1798 is also required to enhance PI3K-Akt signaling and tumor cell migration in response to integrin stimulation, indicating that GIV functions in Tyr(P)-dependent integrin signaling. Unexpectedly, we found that activation of FAK, an upstream component of the integrin Tyr(P) signaling cascade, was diminished in GIV-depleted cells, suggesting that GIV is required to establish a positive feedback loop that enhances integrin-FAK signaling. Mechanistically, we demonstrate that this feedback activation of FAK depends on both guanine nucleotide exchange factor and Tyr(P) GIV signaling as well as on their convergence point, PI3K. Taken together, our results provide novel mechanistic insights into how GIV promotes proinvasive cancer cell behavior by working as a signal-amplifying platform at the crossroads of trimeric G protein and Tyr(P) signaling.