Heregulin-mediated ErbB2-ERK signaling activates hyaluronan synthases leading to CD44-dependent ovarian tumor cell growth and migration
Heregulin-mediated ErbB2-ERK signaling activates hyaluronan synthases leading to CD44-dependent ovarian tumor cell growth and migration
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DOI：
10.1074/jbc.m610054200
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发表时间：
2007-07-06
影响因子：
4.8
通讯作者：
Peyrollier, Karine
中科院分区：
文献类型：
--
作者：
Bourguignon, Lilly Y. W.;Gilad, Eli;Peyrollier, Karine
Heregulin （HRG）诱导的细胞反应是由酪氨酸激酶受体ErbB家族介导的。在这项研究中，我们研究了HRG激活ErbB2，细胞外信号调节激酶（ERK）信号，以及它们在调节人卵巢肿瘤细胞（SK-OV-3）透明质酸合成酶（HAS）活性中的作用。ipl细胞)。免疫学和生化分析表明，SK-OV-3中均表达ErbB2、ErbB3和ErbB4。HRG刺激后，ErbB4（而不是ErbB3）与ErbB2存在物理联系。此外，我们的数据表明hrg诱导的ErbB2（。）ErbB4复合物刺激ErbB2酪氨酸激酶，从而诱导ERK磷酸化和激酶活性。然后，活化的ERK增加了HAS1、HAS2和HAS3的磷酸化。因此，所有三种HAS同工酶被激活，导致透明质酸（HA）的产生。由于hrg介导的HAS同质酶磷酸化/激活可以被AG825 （ErbB2抑制剂）或噻唑烷二酮化合物（ERK阻滞剂）有效阻断，我们得出结论，ErbB2-ERK信号和HAS同质酶磷酸化/HA产生在SK-OV-3中功能偶联。ipl细胞。HRG还以ErbB2-ERK信号依赖的方式促进HA-和cd44依赖性的致癌事件（例如CD44-Cdc42关联、p21活化的激酶1活化和p21活化的激酶1-丝蛋白复合物形成）和肿瘤细胞特异性行为。最后，我们发现下调HAS同工酶表达（通过转染HAS1/HAS2/ has3特异性小干扰rna）不仅抑制hrg介导的HAS磷酸化/活化和HA产生，还会损害cd44特异性Cdc42-PAK1/丝蛋白信号传导、细胞骨架激活和肿瘤细胞行为。综上所述，这些发现清楚地表明HRG激活ErbB2-ERK信号调节HAS磷酸化/激活和HA产生，导致cd44介导的致癌事件和卵巢癌进展。
Heregulin (HRG)-induced cell responses are mediated by the ErbB family of tyrosine kinase receptors. In this study we have investigated HRG activation of ErbB2, extracellular signal-regulated kinase (ERK) signaling, and their role in regulating hyaluronan synthase (HAS) activity in human ovarian tumor cells (SK-OV-3.ipl cells). Immunological and biochemical analyses indicate that ErbB2, ErbB3, and ErbB4 are all expressed in SK-OV-3.ipl cells and that ErbB4 (but not ErbB3) is physically linked to ErbB2 following HRG stimulation. Furthermore, our data indicate that the HRG-induced ErbB2(.)ErbB4 complexes stimulate ErbB2 tyrosine kinase, which induces both ERK phosphorylation and kinase activity. The activated ERK then increases the phosphorylation of HAS1, HAS2, and HAS3. Consequently, all three HAS isozymes are activated resulting in hyaluronan (HA) production. Because HRG-mediated HAS isozyme phosphorylation/activation can be effectively blocked by either AG825 (an ErbB2 inhibitor) or thiazolidinedione compound (an ERK blocker), we conclude that ErbB2-ERK signaling and HAS isozyme phosphorylation/HA production are functionally coupled in SK-OV-3.ipl cells. HRG also promotes HA- and CD44-dependent oncogenic events (e. g. CD44-Cdc42 association, p21-activated kinase 1 activation, and p21-activated kinase 1-filamin complex formation) and tumor cell-specific behaviors in an ErbB2-ERK signaling-dependent manner. Finally, we have found that the down-regulation of HAS isozyme expression (by transfecting cells with HAS1/HAS2/HAS3-specific small interfering RNAs) not only inhibits HRG-mediated HAS phosphorylation/ activation and HA production but also impairs CD44-specific Cdc42-PAK1/filamin signaling, cytoskeleton activation and tumor cell behaviors. Taken together, these findings clearly indicate that HRG activation of ErbB2-ERK signaling modulates HAS phosphorylation/activation and HA production leading to CD44-mediated oncogenic events and ovarian cancer progression.