Gas6-Axl Signaling Induces SRF/MRTF-A Gene Transcription via MICAL2.
Gas6-Axl Signaling Induces SRF/MRTF-A Gene Transcription via MICAL2.
复制标题
作者：
MICAL 2是一种肌动蛋白调节蛋白，通过氧化还原修饰肌动蛋白发挥功能。核定位的MICAL 2触发核肌动蛋白的分解，其随后导致肌动蛋白结合转录辅助调节因子肌红蛋白相关转录因子-A（MRTF-A）的核保留，其导致血清反应因子（SRF）/MRTF-A依赖性基因转录的激活。在这项研究中，我们发现分泌的信号蛋白GAS 6（生长停滞特异性6）及其同源受体Axl，一种跨膜酪氨酸激酶，也诱导SRF/MRTF-A及其下游靶基因的激活。我们发现，血清诱导的SRF/MRTF-A依赖的基因表达可以被阻断，在一定程度上，通过抑制Axl信号。此外，我们发现Gas 6/Axl诱导的SRF/MRTF-A依赖性转录依赖于MICAL 2。Gas 6/Axl促进细胞侵袭，其被MICAL 2敲低阻断，表明MICAL 2促进Gas 6/Axl途径的细胞骨架效应。我们发现Gas/6/Axl信号促进MICAL 2的核定位，这可能有助于Gas 6/SRF增强SRF/MRTF-A依赖的基因转录的能力。本文所述的Gas 6/Axl-MICAL 2信号传导途径的生理学意义得到了MICAL 2与Axl和Gas 6之间跨广泛的不同癌症的显著基因表达相关性以及这些基因和已知的SRF/MRTF-A靶转录物的共表达的支持。总的来说，这些数据揭示了Gas 6/Axl和SRF/MRTF-A依赖性基因转录之间的新联系，并将MICAL 2作为Gas 6/Axl信号传导途径的新型效应物。
MICAL2 is an actin-regulatory protein that functions through redox modification of actin. Nuclear localized MICAL2 triggers the disassembly of nuclear actin, which subsequently leads to nuclear retention of the actin-binding transcriptional coregulator myocardin-related transcription factor-A (MRTF-A), which leads to the activation of serum response factor (SRF)/MRTF-A-dependent gene transcription. In this study, we show that the secreted signaling protein GAS6 (growth-arrest specific 6) and its cognate receptor Axl, a transmembrane tyrosine kinase, also induce the activation of SRF/MRTF-A and their downstream target genes. We find that serum-induced SRF/MRTF-A-dependent gene expression can be blocked, in part, by the inhibition of Axl signaling. Furthermore, we find that Gas6/Axl-induced SRF/MRTF-A-dependent transcription is dependent on MICAL2. Gas6/Axl promotes cell invasion, which is blocked by MICAL2 knockdown, suggesting that MICAL2 promotes cytoskeletal effects of the Gas6/Axl pathway. We find that Gas/6/Axl signaling promotes the nuclear localization of MICAL2, which may contribute to the ability of Gas6/SRF to augment SRF/MRTF-A-dependent gene transcription. The physiological significance of the Gas6/Axl-MICAL2 signaling pathway described here is supported by the marked gene expression correlation across a broad array of different cancers between MICAL2 and Axl and Gas6, as well as the coexpression of these genes and the known SRF/MRTF-A target transcripts. Overall, these data reveal a new link between Gas6/Axl and SRF/MRTF-A-dependent gene transcription and link MICAL2 as a novel effector of the Gas6/Axl signaling pathway.
登录
查看更多内容
影响因子：
--
作者：
Mariotti S;Barravecchia I;Vindigni C;Pucci A;Balsamo M;Libro R;Senchenko V;Dmitriev A;Jacchetti E;Cecchini M;Roviello F;Lai M;Broccoli V;Andreazzoli M;Mazzanti CM;Angeloni D
通讯作者：
Angeloni D
影响因子：
5.3
作者：
MANFIOLETTI, G;BRANCOLINI, C;SCHNEIDER, C
通讯作者：
SCHNEIDER, C
影响因子：
3.7
作者：
Hayashi K;Watanabe B;Nakagawa Y;Minami S;Morita T
通讯作者：
Morita T
影响因子：
5.3
作者：
MIWA, T;KEDES, L
通讯作者：
KEDES, L
影响因子：
2.7
作者：
Wang, Dong;Bi, Lixin;Li, Xiaoli
通讯作者：
Li, Xiaoli