Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression
Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression
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DOI：
10.1074/jbc.m411985200
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发表时间：
2005-03-25
影响因子：
4.8
通讯作者：
Peyrollier, K
中科院分区：
文献类型：
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作者：
Bourguignon, LYW;Gilad, E;Peyrollier, K
在本研究中，我们在SK-OV-3.ipl人卵巢癌细胞中研究了透明质酸(HA)-CD44与Rho GTPase CDc42的结合伙伴之一IQGAP1的相互作用。免疫学和生化分析表明，IQGAP1(分子质量约190 kDa)在SK-OV-3.ipl细胞中表达，IQGAP1与CDc42以GTP依赖的方式直接相互作用。透明质酸刺激SK-OV-3.ipl细胞后，IQGAP1和CDC42均与CD44发生物理连接。此外，HA-CD44诱导的CDC42-IQGAP1复合体通过与F-肌动蛋白密切相关来调节细胞骨架功能，从而导致卵巢肿瘤细胞的迁移。此外，透明质酸与CD44的结合促进了ERK2与IQGAP1分子的结合，从而刺激了ERK2的磷酸化和激酶活性。然后，激活的ERK2增加了ELK-1和雌激素受体-α(ERα)的磷酸化，导致ELK-1和雌激素反应元件介导的转录上调。IQGAP1的下调(通过用IQGAP1特异的小干扰RNA处理细胞)不仅阻断了IQGAP1与CD44、CDC42、F-肌动蛋白和ERK2的关联，而且还抑制了HA-CD44诱导的细胞骨架功能、ERK2信号(如ERK2磷酸化/活性、ERK2介导的ELK-1/ERα磷酸化和ELK-1/ERα特异性转录激活)和肿瘤细胞迁移。综上所述，这些发现表明，在卵巢癌进展过程中，HA-CD44与IQGAP1的相互作用通过调节CDC42细胞骨架功能、介导ELK-1特异性转录激活以及协调膜受体(CD44)和核激素受体(ERα)信号通路之间的“串扰”而发挥信号整合作用。
In this study, we have examined the interaction of hyaluronan (HA)-CD44 with IQGAP1 (one of the binding partners for the Rho GTPase Cdc42) in SK-OV-3.ipl human ovarian tumor cells. Immunological and biochemical analyses indicated that IQGAP1 (molecular mass of similar to 190 kDa) is expressed in SK-OV-3.ipl cells and that IQGAP1 interacts directly with Cdc42 in a GTP-dependent manner. Both IQGAP1 and Cdc42 were physically linked to CD44 in SK-OV-3.ipl cells following HA stimulation. Furthermore, the HA-CD44-induced Cdc42-IQGAP1 complex regulated cytoskeletal function via a close association with F-actin that led to ovarian tumor cell migration. In addition, the binding of HA to CD44 promoted the association of ERK2 with the IQGAP1 molecule, which stimulated both ERK2 phosphorylation and kinase activity. The activated ERK2 then increased the phosphorylation of both Elk-1 and estrogen receptor-alpha (ER alpha), resulting in Elk-1- and estrogen-responsive element-mediated transcriptional up-regulation. Down-regulation of IQGAP1 (by treating cells with IQGAP1-specific small interfering RNAs) not only blocked IQGAP1 association with CD44, Cdc42, F-actin, and ERK2 but also abrogated HA-CD44-induced cytoskeletal function, ERK2 signaling (e.g. ERK2 phosphorylation/activity, ERK2-mediated Elk-1/ER alpha phosphorylation, and Elk-1/ER alpha-specific transcriptional activation), and tumor cell migration. Taken together, these findings indicate that HA-CD44 interaction with IQGAP1 serves as a signal integrator by modulating Cdc42 cytoskeletal function, mediating Elk-1-specific transcriptional activation, and coordinating "cross-talk" between a membrane receptor ( CD44) and a nuclear hormone receptor (ER alpha) signaling pathway during ovarian cancer progression.