Gas6 anti-apoptotic signaling requires NF-κB activation
Gas6 anti-apoptotic signaling requires NF-κB activation
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DOI：
10.1074/jbc.m104457200
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发表时间：
2001-08-24
影响因子：
4.8
通讯作者：
Schneider, C
中科院分区：
文献类型：
--
作者：
Demarchi, F;Verardo, R;Schneider, C
生长停滞特异性6基因产物Gas 6是与蛋白S相关的生长和存活因子。Gas 6是AxI受体酪氨酸激酶的配体;与其受体结合后，Gas 6激活磷脂酰肌醇3-OH激酶（PI 3 K）及其下游靶点S6 K和Akt。Gas 6抗凋亡信号传导先前显示需要功能性PI 3 K和Akt，并且涉及血清饥饿的NIH 3 T3细胞中的Bad磷酸化。在这里，我们证明Gas 6诱导核NF-κ B结合活性的快速和短暂增加，与NF-κ B应答启动子的转录激活和Bcl-x（L）蛋白水平的增加相耦合。Gas 6存活功能在缺乏p65/RelA的细胞和用显性负性I κ B转染的NIH 3 T3细胞中受损，表明NF-κ B活化在促进该系统中的存活中起核心作用。此外，NF-κ B活化可以被显性负性Akt和渥曼青霉素（一种PI 3 K抑制剂）阻断，因此表明NF-κ B活化是相对于PI 3 K和Akt的下游事件，如已经描述的其他生长因子。此外，我们表明，糖原合成酶激酶3，这是在响应Gas 6磷酸化，可以在活细胞中与NFKB 1/p105物理关联，并可以在体外磷酸化它。此外，Gas 6处理与p105蛋白水平的降低相结合。总之，这些数据表明NF-κ B和糖原合成酶激酶3参与Gas 6抗凋亡信号传导，并揭示了这些生存途径之间可能的联系。
The growth arrest-specific 6 gene product Gas6 is a growth and survival factor related to protein S. Gas6 is the ligand of AxI receptor tyrosine kinase; upon binding to its receptor Gas6 activates the phosphatidylinositol 3-OH kinase (PI3K) and its downstream targets S6K and Akt. Gas6 anti-apoptotic signaling was previously shown to require functional PI3K and Akt and to involve Bad phosphorylation in serum-starved NIH 3T3 cells. Here we demonstrate that Gas6 induces a rapid and transient increase in nuclear NF-kappaB binding activity coupled to transcription activation from NF-kappaB-responsive promoters and increase in Bcl-x(L) protein level. Gas6 survival function is impaired in cells lacking p65/RelA and in NIH 3T3 cells transfected with a dominant negative I kappaB, indicating that NF-kappaB activation plays a central role in promoting survival in this system. Moreover, NF-kappaB activation can be blocked by a dominant negative Akt and by wortmannin, an inhibitor of PI3K, thus suggesting that NF-kappaB activation is a downstream event with respect to PI3K and Akt, as already described for other growth factors. In addition, we show that glycogen synthase kinase 3, which is phosphorylated in response to Gas6, can physically associate with NFKB1/p105 in living cells and can phosphorylate it in vitro. Furthermore, Gas6 treatment is coupled to a decrease in p105 protein level. Altogether these data suggest the involvement of NF-kappaB and glycogen synthase kinase 3 in Gas6 anti-apoptotic signaling and unveil a possible link between these survival pathways.