Blockade of epidermal growth factor- or heregulin-dependent ErbB2 activation with the anti-ErbB2 monoclonal antibody 2C4 has divergent downstream signaling and growth effects
Blockade of epidermal growth factor- or heregulin-dependent ErbB2 activation with the anti-ErbB2 monoclonal antibody 2C4 has divergent downstream signaling and growth effects
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DOI：
10.1158/0008-5472.can-03-3106
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发表时间：
2004-04-01
期刊：
影响因子：
11.2
通讯作者：
Brattain, MG
中科院分区：
文献类型：
--
作者：
Jackson, JG;Clair, PS;Brattain, MG
由于异源二聚化和多种刺激配体，ErbB受体系统既多样又灵活，这被证明对癌细胞的异常信号传导特别有利。然而，特定受体如何有助于产生导致异常生长调节的灵活性的具体机制尚未得到很好的描述。我们比较了结肠癌细胞对表皮生长因子（EGF）和调蛋白刺激的反应中ErbB 2的利用。抗ErbB 2单克隆抗体2C 4阻断调蛋白刺激的ErbB 2和ErbB 3磷酸化;丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇3 '-激酶（PI 3 K）和Akt的活化;增殖;和锚定非依赖性生长。2C 4阻断EGF介导的ErbB 2磷酸化，抑制PI 3 K/Akt和锚定非依赖性生长，但不影响ErbB 1或MAPK。免疫沉淀显示，ErbB 3和Grb 2相关的结合剂（Gab）1磷酸化，并与PI 3 K活性heregulin治疗后，Gab 1和Gab 2，但不是ErbB 3，磷酸化，并与PI 3 K活性EGF治疗后。这些数据显示，单克隆抗体2C 4抑制调蛋白信号传导的所有方面以及锚定非依赖性和单层生长。此外，我们确定ErbB 2作为EGF信号转导的Gab 1/Gab 2-PI 3 K-Akt途径和锚定非依赖性生长的关键组分，但EGF刺激MAPK和单层生长可以有效地发生而没有ErbB 2的贡献。
Due to heterodimerization and a variety of stimulating ligands, the ErbB receptor system is both diverse and flexible, which proves particularly advantageous to the aberrant signaling of cancer cells. However, specific mechanisms of how a particular receptor contributes to generating the flexibility that leads to aberrant growth regulation have not been well described. We compared the utilization of ErbB2 in response to epidermal growth factor (EGF) and heregulin stimulation in colon carcinoma cells. Anti-ErbB2 monoclonal antibody 2C4 blocked heregulin-stimulated phosphorylation of ErbB2 and ErbB3; activation of mitogen-activated protein kinase (MAPK), phosphatidylinositol 3'-kinase (PI3K), and Akt; proliferation; and anchorage-independent growth. 2C4 blocked EGF-mediated phosphorylation of ErbB2 and inhibited PI3K/Akt and anchorage-independent growth but did not affect ErbB1 or MAPK. Immunoprecipitations showed that ErbB3 and Grb2-associated binder (Gab) 1 were phosphorylated and associated with PI3K activity after heregulin treatment and that Gab1 and Gab2, but not ErbB3, were phosphorylated and associated with PI3K activity after EGF treatment. These data show that monoclonal antibody 2C4 inhibited all aspects of heregulin signaling as well as anchorage-independent and monolayer growth. Furthermore, we identify ErbB2 as a critical component of EGF signaling to the Gab1/Gab2-PI3K-Akt pathway and anchorage-independent growth, but EGF stimulation of MAPK and monolayer growth can occur efficiently without the contribution of ErbB2.