Transforming growth factor beta induces clustering of HER2 and integrins by activating Src-focal adhesion kinase and receptor association to the cytoskeleton.
Transforming growth factor beta induces clustering of HER2 and integrins by activating Src-focal adhesion kinase and receptor association to the cytoskeleton.
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DOI：
10.1158/0008-5472.can-08-2649
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发表时间：
2009-01-15
期刊：
影响因子：
11.2
通讯作者：
Arteaga CL
中科院分区：
文献类型：
--
作者：
Wang SE;Xiang B;Zent R;Quaranta V;Pozzi A;Arteaga CL
有人提出，整合素和生长因子受体信号如ErbB2 （HER2）之间的串扰是激活下游效应物和ErbB2介导的乳腺肿瘤发生所必需的。本研究表明，在HER2过表达的乳腺上皮细胞中，转化生长因子β (TGF-β)诱导HER2和整合素α6、β1和β4依赖于局灶黏附激酶（FAK）的聚集，而不改变HER2受体的总水平和表面水平。这种作用是由配体诱导的EGFR激活和随后的Src和FAK磷酸化介导的。我们之前报道过TGF-β通过TNF-α转换酶（TACE/ADAM17）磷酸化的机制上调EGFR配体脱落。通过siRNA敲低TACE、FAK或整合素α6，或通过特异性抑制剂抑制EGFR或Src，可消除TGF-β诱导的受体聚集和向PI3K-Akt的信号传导。最后，Src-FAK的抑制逆转了TGF-β诱导的HER2过表达乳腺癌细胞对治疗性HER2抑制剂曲妥珠单抗的耐药性。综上所述，这些数据表明，TGF-β通过激活Src-FAK，整合ErbB受体和整合素信号，诱导乳腺癌进展过程中的细胞迁移和存活。
It has been proposed that cross-talk between integrin and growth factor receptor signaling such as ErbB2 (HER2) is required for activation of downstream effectors and ErbB2-mediated mammary tumorigenesis. Here we show that transforming growth factor β (TGF-β) induced focal adhesion kinase (FAK)-dependent clustering of HER2 and integrin α6, β1 and β4 in HER2-overexpressing mammary epithelial cells without altering the total and surface levels of HER2 receptors. This effect was mediated by ligand-induced EGFR activation and the subsequent phosphorylation of Src and FAK. We have previously reported that TGF-β upregulates EGFR ligand shedding through a mechanism involving the phosphorylation of TNF-α converting enzyme (TACE/ADAM17). Knock down of TACE, FAK or integrin α6 by siRNA or inhibition of EGFR or Src by specific inhibitors abrogated TGF-β-induced receptor clustering and signaling to PI3K-Akt. Finally, inhibition of Src-FAK reversed TGF-β-induced resistance to the therapeutic HER2 inhibitor trastuzumab in HER2-overexpressing breast cancer cells. Taken together, these data suggest that, by activating Src-FAK, TGF-β integrates ErbB receptor and integrin signaling to induce cell migration and survival during breast cancer progression.