Yang Chengfeng, Liu Ying, Lemmon Mark A, Kazanietz Marcelo G
Department of Pharmacology, University of Pennsylvania School of Medicine, 816 Biomedical Research Building II/III, 421 Curie Blvd., Philadelphia, PA 19104-6160, USA.
Mol Cell Biol. 2006 Feb;26(3):831-42. doi: 10.1128/MCB.26.3.831-842.2006.
Heregulins are a family of ligands for the ErbB3/ErbB4 receptors that play important roles in breast cancer cell proliferation and tumorigenesis. Limited information is available on the contribution of Rho GTPases to heregulin-mediated signaling. In breast cancer cells, heregulin beta1 (HRG) causes a strong activation of Rac; however, it does so with striking differences in kinetics compared to epidermal growth factor, which signals through ErbB1 (epidermal growth factor receptor [EGFR]). Using specific ErbB receptor inhibitors and depletion of receptors by RNA interference (RNAi), we established that, surprisingly, activation of Rac by HRG is mediated not only by ErbB3 and ErbB2 but also by transactivation of EGFR, and it is independent of ErbB4. Similar receptor requirements are observed for HRG-induced actin cytoskeleton reorganization and mitogenic activity via extracellular signal-regulated kinase (ERK). HRG-induced Rac activation was phosphatidylinositol 3-kinase dependent and Src independent. Furthermore, inactivation of Rac by expression of the Rac GTPase-activating protein beta2-chimerin inhibited HRG-induced ERK activation, mitogenicity, and migration in breast cancer cells. HRG mitogenic activity was also impaired by depletion of Rac1 using RNAi. Our studies established that Rac is a critical mediator of HRG mitogenic signaling in breast cancer cells and highlight additional levels of complexity for ErbB receptor coupling to downstream effectors that control aberrant proliferation and transformation.
Heregulins是ErbB3/ErbB4受体的配体家族，在乳腺癌细胞增殖和肿瘤发生中起重要作用。关于Rho GTPases对Heregulin介导信号传导的贡献的信息有限。在乳腺癌细胞中，Heregulin beta1（HRG）可导致Rac的强烈激活；然而，与通过ErbB1（表皮生长因子受体[EGFR]）发出信号的表皮生长因子相比，其激活动力学存在显著差异。使用特异性ErbB受体抑制剂和通过RNA干扰（RNAi）使受体缺失，我们惊奇地发现，HRG对Rac的激活不仅由ErbB3和ErbB2介导，还由EGFR的反式激活介导，且与ErbB4无关。对于HRG诱导的通过细胞外信号调节激酶（ERK）的肌动蛋白细胞骨架重组和促有丝分裂活性，也观察到类似的受体需求。HRG诱导的Rac激活依赖于磷脂酰肌醇3激酶，且不依赖于Src。此外，通过表达Rac GTPase激活蛋白β2-嵌合蛋白使Rac失活，可抑制HRG诱导的乳腺癌细胞中的ERK激活、促有丝分裂性和迁移。使用RNAi使Rac1缺失也会损害HRG的促有丝分裂活性。我们的研究表明，Rac是乳腺癌细胞中HRG促有丝分裂信号传导的关键介质，并突出了ErbB受体与控制异常增殖和转化的下游效应器偶联的额外复杂程度。
