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

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. McLendonDarell D. Bigner, Hui Kuan Lin, Frank B. Furnari, Webster K. Cavenee, Bo Hu*, Hai Yan, Shi Yuan Cheng

*Corresponding author for this work

Research output: Contribution to journalArticle

40 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3741-3756
Number of pages16
JournalJournal of Clinical Investigation
Volume124
Issue number9
DOIs
StatePublished - Sep 2 2014

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Feng, H., Lopez, G. Y., Kim, C. K., Alvarez, A., Duncan, C. G., Nishikawa, R., Nagane, M., Su, A. J. A., Auron, P. E., Hedberg, M. L., Wang, L., Raizer, J. J., Kessler, J. A., Parsa, A. T., Gao, W. Q., Kim, S. H., Minata, M., Nakano, I., Grandis, J. R., ... Cheng, S. Y. (2014). EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis. Journal of Clinical Investigation, 124(9), 3741-3756. https://doi.org/10.1172/JCI73093