表皮生长因子受体（EGFR）磷酸化肿瘤源性 EGFRvIII，驱动胶质母细胞瘤中 STAT3/5 的激活和进展。
EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma.
机构信息
Department of Neurology, University of California, San Francisco, 1450 Third Street, MC0520, San Francisco, CA 94158-9001, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 Third Street, MC0520, San Francisco, CA 94158-9001, USA.
出版信息
Cancer Cell. 2013 Oct 14;24(4):438-49. doi: 10.1016/j.ccr.2013.09.004.
EGFRvIII, a frequently occurring mutation in primary glioblastoma, results in a protein product that cannot bind ligand, but signals constitutively. Deducing how EGFRvIII causes transformation has been difficult because of autocrine and paracrine loops triggered by EGFRvIII alone or in heterodimers with wild-type EGFR. Here, we document coexpression of EGFR and EGFRvIII in primary human glioblastoma that drives transformation and tumorigenesis in a cell-intrinsic manner. We demonstrate enhancement of downstream STAT signaling triggered by EGFR-catalyzed phosphorylation of EGFRvIII, implicating EGFRvIII as a substrate for EGFR. Subsequent phosphorylation of STAT3 requires nuclear entry of EGFRvIII and formation of an EGFRvIII-STAT3 nuclear complex. Our findings clarify specific oncogenic signaling relationships between EGFR and EGFRvIII in glioblastoma.
EGFRvIII 是原发性脑胶质瘤中经常发生的突变，导致不能结合配体但持续发出信号的蛋白质产物。由于 EGFRvIII 单独或与野生型 EGFR 形成异二聚体触发的自分泌和旁分泌环，推断 EGFRvIII 如何引起转化一直很困难。在这里，我们记录了 EGFR 和 EGFRvIII 在原发性人脑胶质瘤中的共表达，这些胶质瘤以细胞内在的方式驱动转化和肿瘤发生。我们证明了由 EGFR 催化的 EGFRvIII 磷酸化触发的下游 STAT 信号的增强，这暗示 EGFRvIII 是 EGFR 的底物。STAT3 的后续磷酸化需要 EGFRvIII 的核内进入和 EGFRvIII-STAT3 核复合物的形成。我们的发现阐明了脑胶质瘤中 EGFR 和 EGFRvIII 之间特定的致癌信号关系。
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