EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis

被引：99

作者：

Feng, Haizhong ^{[1
,2
,3
]}

Lopez, Giselle Y. ^{[4
,5
]}

Kim, Chung Kwon ^{[2
,3
]}

Alvarez, Angel ^{[2
,3
]}

Duncan, Christopher G. ^{[4
,5
]}

Nishikawa, Ryo ^{[6
]}

Nagane, Motoo ^{[7
]}

Su, An-Jey A. ^{[8
]}

Auron, Philip E. ^{[8
]}

Hedberg, Matthew L. ^{[9
,10
]}

Wang, Lin ^{[9
,10
]}

Raizer, Jeffery J. ^{[2
,3
]}

Kessler, John A. ^{[2
,3
]}

Parsa, Andrew T. ^{[11
,12
]}

Gao, Wei-Qiang ^{[1
]}

Kim, Sung-Hak ^{[13
]}

Minata, Mutsuko ^{[13
]}

Nakano, Ichiro ^{[13
]}

Grandis, Jennifer R. ^{[9
,10
]}

McLendon, Roger E. ^{[4
,5
]}

Bigner, Darell D. ^{[4
,5
]}

Lin, Hui-Kuan ^{[14
]}

Furnari, Frank B. ^{[15
,16
]}

Cavenee, Webster K. ^{[15
,16
]}

Hu, Bo ^{[2
,3
]}

Yan, Hai ^{[4
,5
]}

Cheng, Shi-Yuan ^{[1
,2
,3
]}

机构：

[1] Shanghai Jiao Tong Univ, State Key Lab Oncogenes & Related Genes, Renji Med Clin Stem Cell Res Ctr X, Ren Ji Hosp,Sch Med, Shanghai 200030, Peoples R China

[2] Northwestern Univ, Dept Neurol, Feinberg Sch Med, Chicago, IL 60611 USA

[3] Northwestern Univ, Northwestern Brain Tumorr Inst, Feinberg Sch Med, Ctr Genet Med,Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA

[4] Duke Univ, Med Ctr, Pediat Brain Tumor Fdn Inst Duke, Preston Robert Tisch Brain Tumor Ctr, Durham, NC 27710 USA

[5] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA

[6] Saitama Med Univ, Int Med Ctr, Dept Neurooncol Neurosurg, Saitama, Japan

[7] Kyorin Univ, Dept Neurosurg, Tokyo, Japan

[8] Duquesne Univ, Dept Biol Sci, Pittsburgh, PA 15219 USA

[9] Univ Pittsburgh, Sch Med, Dept Otolaryngol, Pittsburgh, PA USA

[10] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA

[11] Northwestern Univ, Dept Neurol Surg, Feinberg Sch Med, Chicago, IL 60611 USA

[12] Northwestern Univ, Northwestern Brain Tumor Inst, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA

[13] Ohio State Univ, Dept Neurol Surg, James Comprehens Canc Ctr, Columbus, OH 43210 USA

[14] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[15] Ludwig Inst Canc Res, La Jolla, CA USA

[16] UCSD, Sch Med, La Jolla, CA USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2014年 / 124卷 / 09期

基金：

中国国家自然科学基金;

关键词：

CELL-PROLIFERATION; CANCER; GROWTH; MUTANT; ACTIVATION; GENE; UBIQUITINATION; ANGIOGENESIS; EXPRESSION; INHIBITOR;

D O I：

10.1172/JCI73093

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

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.

引用

页码：3741 / 3756

页数：16

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