Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation of EGFR growth signals in head and neck squamous cancer cells
Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation of EGFR growth signals in head and neck squamous cancer cells
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DOI：
10.1096/fj.08-112771
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发表时间：
2009-02-01
期刊：
影响因子：
4.8
通讯作者：
Li, Lu-Yuan
中科院分区：
文献类型：
--
作者：
Zou, Huafei;Thomas, Sufi M.;Li, Lu-Yuan
表皮生长因子受体（EGFR）是许多癌症中激活的癌基因。它可以被G蛋白偶联受体（GPCR）的配体反式激活。我们在这里表明，一种新的基因，人菱形家族-1（RHBDF 1），这是最近报道的上皮癌细胞的生长在文化和异种移植肿瘤中发挥了关键作用，参与GPCR介导的EGFR反式激活的调制。RHBDF 1蛋白主要定位于内质网。用siRNA沉默头颈部鳞癌细胞系1483细胞中的RHBDF 1基因导致抑制胃泌素释放肽（GRP）诱导的EGFR和EGFR依赖性信号蛋白p44/42 MAPK和AKT的磷酸化，伴随着抑制GRP诱导的细胞存活、增殖和侵袭。然而，EGFR信号通路本身保持完整，因为细胞对外源性EGF保持反应。此外，RHBDF 1基因沉默破坏GRP刺激的EGFR配体TGF-α的分泌，但不破坏潜伏TGF-α的产生，而RHBDF 1的工程过表达显著加速TGF-α的分泌。这些发现与RHBDF 1在GPCR配体刺激过程中起关键作用，导致潜在EGFR配体活化的观点一致。- 邹，H.，托马斯，S. M.，Yan，Z.- W.，Grandis，J.R.，沃格特，A.，李湖，澳-地Y.人菱形蛋白家族-1基因RHBDF 1参与GPCR介导的头颈部鳞癌细胞EGFR生长信号的反式激活FASEB J. 23，425-432（2009）
Epidermal growth factor receptor (EGFR) is an activated oncogene in many cancers. It can be transactivated by ligands of G protein-coupled receptors (GPCRs). We show here that a novel gene, human rhomboid family-1 (RHBDF1), which was recently reported to have a pivotal role in epithelial cancer cell growth in culture and in xenograft tumors, participates in the modulation of GPCR-mediated EGFR transactivation. The RHBDF1 protein localizes mainly in the endoplasmic reticulum. Silencing the RHBDF1 gene in head and neck squamous cancer cell line 1483 cells with siRNA causes an inhibition of gastrin-releasing peptide (GRP) -induced phosphorylation of EGFR and EGFR-dependent signaling proteins p44/42 MAPK and AKT, accompanied by an inhibition of GRP-induced survival, proliferation, and invasion of the cells. The EGFR signaling pathway itself remains intact, however, as the cells remain responsive to exogenous EGF. In addition, RHBDF1 gene silencing disrupts GRP-stimulated secretion of EGFR ligand TGF-alpha, but not the production of latent TGF-alpha, whereas engineered overexpression of RHBDF1 markedly accelerates the secretion of TGF-alpha. These findings are consistent with the view that RHBDF1 is critically involved in a GPCR ligand-stimulated process leading to the activation of latent EGFR ligands. - Zou, H., Thomas, S. M., Yan, Z.-W., Grandis, J. R., Vogt, A., Li, L.-Y. Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation of EGFR growth signals in head and neck squamous cancer cells. FASEB J. 23, 425-432 (2009)