P-Rex1 participates in Neuregulin-ErbB signal transduction and its expression correlates with patient outcome in breast cancer
P-Rex1 participates in Neuregulin-ErbB signal transduction and its expression correlates with patient outcome in breast cancer
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DOI：
10.1038/onc.2010.489
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发表时间：
2011-03-01
期刊：
影响因子：
8
通讯作者：
Pandiella, A.
中科院分区：
文献类型：
--
作者：
Montero, J. C.;Seoane, S.;Pandiella, A.
神经调节蛋白及其受体，ErbB/Her受体酪氨酸激酶亚家族，在动物生理学中起着关键作用，在癌症中经常发生它们的失控。在这里，我们报道了鸟嘌呤核苷酸交换因子，磷脂酰肌醇3，4，5-三磷酸依赖的RAC交换器1(P-REx1)，作为ErbB/Her受体信号转导的一个新的中介。P-REx1以前被描述为一种调节RAC功能的磷脂酰肌醇3-激酶和Gβ-γ激活蛋白。我们定义了ErbB/HER受体如何调节P-REx1功能，包括抑制残基的去磷酸化和P-Rex激活残基的磷酸化。激活P-REx1的这种磷酸化/去磷酸化循环所产生的净平衡有利于RAC的激活。分子和生物学研究表明，P-REx1磷酸化调控乳腺癌细胞的增殖，P-REx1基因敲除影响癌细胞的迁移或侵袭能力，以及体内致瘤潜能。此外，随着我们发现乳腺癌中P-Rex1的高表达与患者预后不良之间的相关性，P-Rex1靶向可能与癌症的治疗相关。Oncogene(2011)30,1059-1071；doi：10.1038/onc.2010.489；2010年11月1日在线发布
The Neuregulins and their receptors, the ErbB/HER subfamily of receptor tyrosine kinases, have critical roles in animal physiology, and their deregulation is frequent in cancer. Here we report the identification of the guanine nucleotide exchange factor, phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger 1 (P-Rex1), as a novel mediator in signalling by ErbB/HER receptors. P-Rex1 was formerly described as a phosphoinositide 3-kinase and G beta gamma activated protein that regulates Rac function. We define how ErbB/HER receptors regulate P-Rex1 function, which involves dephosphorylation of inhibitory residues, and phosphorylation of activating residues of P-Rex. The net balance resulting from activation of this phosphorylation/dephosphorylation cycle of P-Rex1 favours Rac activation. Molecular and biological studies indicated that P-Rex1 phosphorylation regulated the proliferation of breast cancer cells, and P-Rex1 knockdown affected their migration or invasiveness, as well as their in vivo tumourigenic potential. Moreover, as we found correlation between high P-Rex1 expression and poor patient outcome in breast cancer, P-Rex1 targeting may be therapeutically relevant in cancer. Oncogene (2011) 30, 1059-1071; doi:10.1038/onc.2010.489; published online 1 November 2010