EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis
EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis
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DCBLD2 的 EGFR 磷酸化招募 TRAF6 并刺激 AKT 促进的肿瘤发生
DOI：
10.1172/jci73093
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发表时间：
2014-09-01
影响因子：
15.9
通讯作者：
Cheng, Shi-Yuan
中科院分区：
文献类型：
--
作者：
Feng, Haizhong;Lopez, Giselle Y.;Cheng, Shi-Yuan
人类癌症中EGFR的异常激活通过刺激AKT信号传导促进肿瘤发生。在这里，我们确定了盘状神经纤毛蛋白样膜蛋白DCBLD 2在胶质母细胞瘤和头颈癌（HNC）的临床标本中上调，并且是EGFR刺激的肿瘤发生所必需的。在多种癌细胞系中，EGFR激活DCBLD 2的酪氨酸750（Y750）磷酸化，其位于最近鉴定的TNF受体相关因子6（TRAF6）结合基序内。因此，DCBLD2 Y750的磷酸化募集TRAF6，导致TRAF6 E3泛素连接酶活性增加，随后激活AKT，从而增强EGFR驱动的肿瘤发生。此外，对神经胶质瘤和HNC患者样本的评价揭示了EGFR活化、DCBLD2磷酸化和不良预后之间的关联。总之，我们的研究结果揭示了DCBLD2作为致癌EGFR信号传导的信号中继以促进肿瘤发生的途径，并表明DCBLD2和TRAF6是与EGFR活化相关的人类癌症的潜在治疗靶点。
Aberrant activation of EGFR in human cancers promotes tumorigenesis through stimulation of AKT signaling. Here, we determined that the discoidina neuropilin-like membrane protein DCBLD2 is upregulated in clinical specimens of glioblastomas and head and neck cancers (HNCs) and is required for EGFR-stimulated tumorigenesis. In multiple cancer cell lines, EGFR activated phosphorylation of tyrosine 750 (Y750) of DCBLD2, which is located within a recently identified binding motif for TNF receptor-associated factor 6 (TRAF6). Consequently, phosphorylation of DCBLD2 Y750 recruited TRAF6, leading to increased TRAF6 E3 ubiquitin ligase activity and subsequent activation of AKT, thereby enhancing EGFR-driven tumorigenesis. Moreover, evaluation of patient samples of gliomas and HNCs revealed an association among EGFR activation, DCBLD2 phosphorylation, and poor prognoses. Together, our findings uncover a pathway in which DCBLD2 functions as a signal relay for oncogenic EGFR signaling to promote tumorigenesis and suggest DCBLD2 and TRAF6 as potential therapeutic targets for human cancers that are associated with EGFR activation.