Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis
Haizhong Feng, … , Hai Yan, Shi-Yuan Cheng
Haizhong Feng, … , Hai Yan, Shi-Yuan Cheng
Published July 25, 2014
Citation Information: J Clin Invest. 2014;124(9):3741-3756. https://doi.org/10.1172/JCI73093.
View: Text | PDF | Retraction
Research Article Oncology Article has an altmetric score of 5

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

  • Text
  • PDF
Abstract

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.

Authors

Haizhong Feng, Giselle Y. Lopez, Chung Kwon Kim, Angel Alvarez, Christopher G. Duncan, Ryo Nishikawa, Motoo Nagane, An-Jey A. Su, Philip E. Auron, Matthew L. Hedberg, Lin Wang, Jeffery J. Raizer, John A. Kessler, Andrew T. Parsa, Wei-Qiang Gao, Sung-Hak Kim, Mutsuko Minata, Ichiro Nakano, Jennifer R. Grandis, Roger E. McLendon, Darell D. Bigner, Hui-Kuan Lin, Frank B. Furnari, Webster K. Cavenee, Bo Hu, Hai Yan, Shi-Yuan Cheng

×

Figure 8

Coexpression of p-EGFRY1172 and p-DCBLD2Y750 correlates with poorer prognoses of gliomas or HNCs.

Options: View larger image (or click on image) Download as PowerPoint
Coexpression of p-EGFRY1172 and p-DCBLD2Y750 correlates with poorer prog...
(A) A total of 132 clinical glioma specimens, including WHO grade II–IV gliomas, were analyzed by IHC. Representative images of serial sections of a GBM tissue using anti–p-EGFRY1172, anti–p-DCBLD2Y750, anti-TRAF6, and anti–p-AKTT308 antibodies are shown. Insets: IgG controls of the same area in serial sections of these specimens. (B) Kaplan-Meier analyses of patients with high p-Y-EGFRY1172/p-DCBLD2Y750-expressing tumors (blue line) versus low p-EGFRY1172/p-DCBLD2Y750-expressing tumors (red line) in IHC analyses in A. P values were calculated by using log-rank test. Black bars indicate censored data. (C) A total of 231 clinical HNC specimens on tumor TMAs were analyzed by IHC staining. Representative images of serial sections of a HNC tissue. Insets: IgG controls of the same area in serial sections of these samples. (D) Kaplan-Meier analyses of patients with high p-EGFRY1172/p-DCBLDY750-expressing HNCs (blue line) versus low p-EGFRY1172/p-DCBLDY750-expressing HNCs (red line) in IHC analyses. P values were calculated by using log-rank test. Black bars indicate censored data. (E) A working model of EGFR/DCBLD2/TRAF6/AKT signaling in tumorigenesis. Data in A and C are representative of 2 independent experiments. Scale bars: 50 μm. Arrows in A and C indicate positive staining.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Blogged by 1
52 readers on Mendeley
See more details