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

36 Citations (Scopus)

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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TNF Receptor-Associated Factor 6
Carcinogenesis
Phosphorylation
Head and Neck Neoplasms
Neuropilins
Neoplasms
Ubiquitin-Protein Ligases
Glioblastoma
Glioma
Tyrosine
Membrane Proteins
Cell Line

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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. / EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 9. pp. 3741-3756.
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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.",
author = "Haizhong Feng and Lopez, {Giselle Y.} and Kim, {Chung Kwon} and Angel Alvarez and Duncan, {Christopher G.} and Ryo Nishikawa and Motoo Nagane and Su, {An Jey A.} and Auron, {Philip E.} and Hedberg, {Matthew L.} and Lin Wang and Raizer, {Jeffery J.} and Kessler, {John A.} and Parsa, {Andrew T.} and Gao, {Wei Qiang} and Kim, {Sung Hak} and Mutsuko Minata and Ichiro Nakano and Grandis, {Jennifer R.} and McLendon, {Roger E.} and Bigner, {Darell D.} and Lin, {Hui Kuan} and Furnari, {Frank B.} and Cavenee, {Webster K.} and Bo Hu and Hai Yan and Cheng, {Shi Yuan}",
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Feng, H, Lopez, GY, Kim, CK, Alvarez, A, Duncan, CG, Nishikawa, R, Nagane, M, Su, AJA, Auron, PE, Hedberg, ML, Wang, L, Raizer, JJ, Kessler, JA, Parsa, AT, Gao, WQ, Kim, SH, Minata, M, Nakano, I, Grandis, JR, McLendon, RE, Bigner, DD, Lin, HK, Furnari, FB, Cavenee, WK, Hu, B, Yan, H & Cheng, SY 2014, 'EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis', Journal of Clinical Investigation, vol. 124, no. 9, pp. 3741-3756. https://doi.org/10.1172/JCI73093

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

In: Journal of Clinical Investigation, Vol. 124, No. 9, 02.09.2014, p. 3741-3756.

Research output: Contribution to journalArticle

TY - JOUR

T1 - EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis

AU - Feng, Haizhong

AU - Lopez, Giselle Y.

AU - Kim, Chung Kwon

AU - Alvarez, Angel

AU - Duncan, Christopher G.

AU - Nishikawa, Ryo

AU - Nagane, Motoo

AU - Su, An Jey A.

AU - Auron, Philip E.

AU - Hedberg, Matthew L.

AU - Wang, Lin

AU - Raizer, Jeffery J.

AU - Kessler, John A.

AU - Parsa, Andrew T.

AU - Gao, Wei Qiang

AU - Kim, Sung Hak

AU - Minata, Mutsuko

AU - Nakano, Ichiro

AU - Grandis, Jennifer R.

AU - McLendon, Roger E.

AU - Bigner, Darell D.

AU - Lin, Hui Kuan

AU - Furnari, Frank B.

AU - Cavenee, Webster K.

AU - Hu, Bo

AU - Yan, Hai

AU - Cheng, Shi Yuan

PY - 2014/9/2

Y1 - 2014/9/2

N2 - 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.

AB - 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.

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