The RLIP76 N-terminus binds ARNO to regulate PI 3-kinase, Arf6 and Rac signaling, cell spreading and migration.
The RLIP76 N-terminus binds ARNO to regulate PI 3-kinase, Arf6 and Rac signaling, cell spreading and migration.
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DOI：
10.1016/j.bbrc.2014.10.114
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发表时间：
2014-11-28
影响因子：
3.1
通讯作者：
Goldfinger, Lawrence E.
中科院分区：
文献类型：
--
作者：
Lee, Seunghyung;Wurtzel, Jeremy G. T.;Goldfinger, Lawrence E.
RLIP 76是一种参与肿瘤生长和血管生成的多功能蛋白，是许多癌症的有希望的治疗靶点。RLIP 76含有许多蛋白质的对接位点，我们发现它与ARNO相互作用，ARNO是Arf 6的鸟嘌呤核苷酸交换因子，RLIP 76通过Arf 6调节Rac 1的激活，并以ARNO和Arf 6依赖的方式调节细胞的扩散和迁移。在这里，我们表明，ARNO与RLIP 76 N-末端结构域相互作用，该结构域是RLIP 76依赖的细胞扩散和迁移所必需的。我们确定了RLIP 76 N端的两个位点对ARNO结合和下游信号传导具有不同的影响：Ser 29/Ser 30和Ser 62。Ser 29/30突变为丙氨酸抑制ARNO相互作用，并足以阻断RLIP 76依赖性细胞扩散和迁移，以及RLIP 76依赖性Arf 6活化。相反，RLIP 76（S62 A）与ARNO相互作用并支持Arf 6活化。然而，这两组突变都阻断了Rac 1的激活。RLIP 76介导的Rac和Arf 6活化需要PI 3 K活性。S29/30 A突变抑制RLIP 76依赖的PI 3 K活化，但S62 A突变不抑制。总之，这些结果表明，ARNO与RLIP 76 N-末端的相互作用通过PI 3 K和Arf 6调节细胞铺展和运动性，而不依赖于RLIP 76对Rac的控制。
RLIP76 is a multifunctional protein involved in tumor growth and angiogenesis, and a promising therapeutic target in many cancers. RLIP76 harbors docking sites for many proteins, and we have found that it interacts with ARNO, a guanine nucleotide exchange factor for Arf6, and that RLIP76 regulates activation of Rac1 via Arf6, and regulates cell spreading and migration in an ARNO and Arf6-dependent manner. Here we show that ARNO interacts with the RLIP76 N-terminal domain, and this domain was required for RLIP76-dependent cell spreading and migration. We identified two sites in the RLIP76 N-terminus with differential effects on ARNO binding and downstream signaling: Ser29/Ser30 and Ser62. Ser29/30 mutation to Alanine inhibited ARNO interaction and was sufficient to block RLIP76-dependent cell spreading and migration, as well as RLIP76-dependent Arf6 activation. In contrast, RLIP76(S62A) interacted with ARNO and supported Arf6 activation. However, both sets of mutations blocked Rac1 activation. RLIP76-mediated Rac and Arf6 activation required PI3K activity. S29/30A mutations inhibited RLIP76-dependent PI3K activation, but S62A mutation did not. Together these results show that ARNO interaction with the RLIP76 N-terminus regulates cell spreading and motility via PI3K and Arf6, independent of RLIP76 control of Rac.
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影响因子：
3.7
作者：
Hiester KG;Santy LC
通讯作者：
Santy LC
影响因子：
14.9
作者：
Cole C;Barber JD;Barton GJ
通讯作者：
Barton GJ
DOI：
10.1016/j.str.2010.05.013
发表时间：
2010-08-11
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Fenwick RB;Campbell LJ;Rajasekar K;Prasannan S;Nietlispach D;Camonis J;Owen D;Mott HR
通讯作者：
Mott HR
影响因子：
3.3
作者：
Cohen, Lee Ann;Honda, Akira;Donaldson, Julie G.
通讯作者：
Donaldson, Julie G.
影响因子：
4.8
作者：
JULLIENFLORES, V;DORSEUIL, O;CAMONIS, JH
通讯作者：
CAMONIS, JH