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

dc.contributor.author

Feng, Haizhong

dc.contributor.author

Lopez, Giselle Y

dc.contributor.author

Kim, Chung Kwon

dc.contributor.author

Alvarez, Angel

dc.contributor.author

Duncan, Christopher G

dc.contributor.author

Nishikawa, Ryo

dc.contributor.author

Nagane, Motoo

dc.contributor.author

Su, An-Jey A

dc.contributor.author

Auron, Philip E

dc.contributor.author

Hedberg, Matthew L

dc.contributor.author

Wang, Lin

dc.contributor.author

Raizer, Jeffery J

dc.contributor.author

Kessler, John A

dc.contributor.author

Parsa, Andrew T

dc.contributor.author

Gao, Wei-Qiang

dc.contributor.author

Kim, Sung-Hak

dc.contributor.author

Minata, Mutsuko

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Nakano, Ichiro

dc.contributor.author

Grandis, Jennifer R

dc.contributor.author

McLendon, Roger E

dc.contributor.author

Bigner, Darell D

dc.contributor.author

Lin, Hui-Kuan

dc.contributor.author

Furnari, Frank B

dc.contributor.author

Cavenee, Webster K

dc.contributor.author

Hu, Bo

dc.contributor.author

Yan, Hai

dc.contributor.author

Cheng, Shi-Yuan

dc.date.accessioned

2019-01-02T22:36:49Z

dc.date.available

2019-01-02T22:36:49Z

dc.date.issued

2014-09

dc.date.updated

2019-01-02T22:36:46Z

dc.description.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.

dc.identifier

73093

dc.identifier.issn

0021-9738

dc.identifier.issn

1558-8238

dc.identifier.uri

https://hdl.handle.net/10161/17852

dc.language

eng

dc.publisher

American Society for Clinical Investigation

dc.relation.ispartof

The Journal of clinical investigation

dc.relation.isversionof

10.1172/jci73093

dc.subject

Cells, Cultured

dc.subject

Humans

dc.subject

Glioma

dc.subject

Head and Neck Neoplasms

dc.subject

Brain Neoplasms

dc.subject

Receptor, Epidermal Growth Factor

dc.subject

TNF Receptor-Associated Factor 6

dc.subject

Membrane Proteins

dc.subject

Signal Transduction

dc.subject

Phosphorylation

dc.subject

Proto-Oncogene Proteins c-akt

dc.subject

Carcinogenesis

dc.title

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

dc.type

Journal article

duke.contributor.orcid

Lopez, Giselle Y|0000-0001-5435-6668

duke.contributor.orcid

McLendon, Roger E|0000-0001-6682-4588

duke.contributor.orcid

Bigner, Darell D|0000-0001-5548-4899

pubs.begin-page

3741

pubs.end-page

3756

pubs.issue

9

pubs.organisational-group

School of Medicine

pubs.organisational-group

Duke

pubs.organisational-group

Duke Cancer Institute

pubs.organisational-group

Institutes and Centers

pubs.organisational-group

Pathology

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Surgery

pubs.organisational-group

Neurosurgery

pubs.organisational-group

Pharmacology & Cancer Biology

pubs.organisational-group

Basic Science Departments

pubs.publication-status

Published

pubs.volume

124

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