title: EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis.
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
authors: H
authors: Feng
authors: Giselle Y
authors: GY
authors: Lopez
authors: Chung Kwon
authors: CK
authors: Kim
authors: Angel
authors: A
authors: Alvarez
authors: Christopher G
authors: CG
authors: Duncan
authors: Ryo
authors: R
authors: Nishikawa
authors: Motoo
authors: M
authors: Nagane
authors: An-Jey A
authors: AJ
authors: Su
authors: Philip E
authors: PE
authors: Auron
authors: Matthew L
authors: ML
authors: Hedberg
authors: Lin
authors: L
authors: Wang
authors: Jeffery J
authors: JJ
authors: Raizer
authors: John A
authors: JA
authors: Kessler
authors: Andrew T
authors: AT
authors: Parsa
authors: Wei-Qiang
authors: WQ
authors: Gao
authors: Sung-Hak
authors: SH
authors: Kim
authors: Mutsuko
authors: M
authors: Minata
authors: Ichiro
authors: I
authors: Nakano
authors: Jennifer R
authors: JR
authors: Grandis
authors: Roger E
authors: RE
authors: McLendon
authors: Darell D
authors: DD
authors: Bigner
authors: Hui-Kuan
authors: HK
authors: Lin
authors: Frank B
authors: FB
authors: Furnari
authors: Webster K
authors: WK
authors: Cavenee
authors: Bo
authors: B
authors: Hu
authors: Hai
authors: H
authors: Yan
authors: Shi-Yuan
authors: SY
authors: Cheng
mesh_terms: D001932:Brain Neoplasms / Q000209:etiology; D063646:Carcinogenesis; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000502:physiology*; D005910:Glioma / Q000209:etiology; D006258:Head and Neck Neoplasms / Q000209:etiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*
chemical_list: C436326:DCBLD2 protein, human; D008565:Membrane Proteins; D048029:TNF Receptor-Associated Factor 6; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt