Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The Journal of clinical investigation, 2014-09, Vol.124 (9), p.3741-3756

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2014

Quelle

Open access e-journals list

Beschreibungen/Notizen

• 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.