An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism.
An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism.
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一种通过调节磷酸肌醇代谢促进侵袭和转移的ARF GT3模块。
DOI：
10.1038/s41467-021-21847-4
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发表时间：
2021-03-12
影响因子：
16.6
通讯作者：
Bryant DM
中科院分区：
文献类型：
--
作者：
Nacke M;Sandilands E;Nikolatou K;Román-Fernández Á;Mason S;Patel R;Lilla S;Yelland T;Galbraith LCA;Freckmann EC;McGarry L;Morton JP;Shanks E;Leung HY;Markert E;Ismail S;Zanivan S;Blyth K;Bryant DM
支持细胞生长和侵袭的信号通路使用重叠的成分，但相互排斥的细胞反应如何发生尚不清楚。在这里，我们报告了三维培养分析的发展，以分别量化生长和侵袭。我们发现IQSEC 1（一种ARF GTP交换因子）的替代变体通过控制磷酸肌醇代谢作为开关促进侵袭超过生长。所有IQSEC 1变体均激活ARF 5和ARF 6依赖性PIP 5激酶，以促进PI（3，4，5）P3-AKT信号传导和生长。相比之下，选择的促侵入IQSEC 1变体促进PI（3，4，5）P3产生以形成侵入驱动突起。IQSEC 1的抑制减弱体外侵袭和体内转移。在许多肿瘤类型中诱导促侵袭性IQSEC 1变体和升高的IQSEC 1表达，并与较高级别的转移性癌症、PI（3，4，5）P3信号传导激活相关，并预测多种癌症的长期不良结局。因此，IQSEC 1调节的磷酸肌醇代谢是一个开关，以诱导入侵超过生长，以响应相同的外部信号。靶向IQSEC 1作为该开关的中央调节器可能代表了阻止转移的治疗脆弱性。支持细胞生长和侵袭的信号通路使用重叠的成分，但相互排斥的反应如何发生尚不清楚。在这里，作者表明ARF GT3交换因子IQSEC 1的替代亚型指导磷酸肌醇代谢来控制这种转换。
The signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive cellular responses occur is unclear. Here, we report development of 3-Dimensional culture analyses to separately quantify growth and invasion. We identify that alternate variants of IQSEC1, an ARF GTPase Exchange Factor, act as switches to promote invasion over growth by controlling phosphoinositide metabolism. All IQSEC1 variants activate ARF5- and ARF6-dependent PIP5-kinase to promote PI(3,4,5)P3-AKT signalling and growth. In contrast, select pro-invasive IQSEC1 variants promote PI(3,4,5)P3 production to form invasion-driving protrusions. Inhibition of IQSEC1 attenuates invasion in vitro and metastasis in vivo. Induction of pro-invasive IQSEC1 variants and elevated IQSEC1 expression occurs in a number of tumour types and is associated with higher-grade metastatic cancer, activation of PI(3,4,5)P3 signalling, and predicts long-term poor outcome across multiple cancers. IQSEC1-regulated phosphoinositide metabolism therefore is a switch to induce invasion over growth in response to the same external signal. Targeting IQSEC1 as the central regulator of this switch may represent a therapeutic vulnerability to stop metastasis. The signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive responses occur is unclear. Here, the authors show that alternate isoforms of the ARF GTPase exchange factor IQSEC1 direct phosphoinositide metabolism to control this switch.
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影响因子：
3.7
作者：
Hashimoto A;Hashimoto S;Ando R;Noda K;Ogawa E;Kotani H;Hirose M;Menju T;Morishige M;Manabe T;Toda Y;Ishida S;Sabe H
通讯作者：
Sabe H
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
9.8
作者：
Beemiller P;Hoppe AD;Swanson JA
通讯作者：
Swanson JA
影响因子：
4.5
作者：
Dunphy, Jillian L.;Ye, Keqiang;Casanova, James E.
通讯作者：
Casanova, James E.
影响因子：
21.3
作者：
Joffre, Carine;Barrow, Rachel;Kermorgant, Stephanie
通讯作者：
Kermorgant, Stephanie