EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis.
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2014-09
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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.
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Feng, Haizhong, Giselle Y Lopez, Chung Kwon Kim, Angel Alvarez, Christopher G Duncan, Ryo Nishikawa, Motoo Nagane, An-Jey A Su, et al. (2014). EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis. The Journal of clinical investigation, 124(9). pp. 3741–3756. 10.1172/jci73093 Retrieved from https://hdl.handle.net/10161/17852.
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Scholars@Duke
Giselle Yvette López
I am a physician scientist with a clinical focus on neuropathology, and a research interest in brain tumors. Originally from Maryland, I completed my undergraduate training at the University of Maryland, completing degrees in Physiology and Neurobiology as well as Spanish Language and Literature. I subsequently came to Duke for my MD and PhD, and discovered a passion for brain tumor research, and quickly realized that this was my life's calling. Clinically, I specialize in neuropathology. While I have active projects and collaborations on many kinds of brain tumors, my lab's primary focus is oligodendroglioma, a kind of infiltrative brain tumor that impacts adults. Our goal is to identify new ways to treat these tumors and improve the lives of patients with oligodendrogliomas and other kinds of brain tumors. By blending together computational approaches with wet lab approaches, we use the strengths inherent in different research modalities to excel in identifying unexplored pathways and thinking outside the box to identify new ways to target this brain tumor. We do this through research in an inclusive, multidisciplinary lab environment that strives for excellence in research while creating well-rounded, thriving scientists ready for the next step in their careers.
Research Opportunities
We currently have opportunities in the laboratory for one-year projects (ideal for post-bac fellows or third year med student research experiences). These projects are centered on identifying and testing novel therapeutic approaches for oligodendroglioma using in vitro and in vivo model systems. Please reach out if you are interested and would like to hear more about my mentoring philosophy, lab culture, and opportunities to be at the cutting edge of science.
Roger Edwin McLendon
Brain tumors are diagnosed in more than 20,000 Americans annually. The most malignant neoplasm, glioblastoma, is also the most common. Similarly, brain tumors constitute the most common solid neoplasm in children and include astrocytomas of the cerebellum, brain stem and cerebrum as well as medulloblastomas of the cerebellum. My colleagues and I have endeavored to translate the bench discoveries of genetic mutations and aberrant protein expressions found in brain tumors to better understand the processes involved in the etiology, pathogenesis, and treatment of brain tumors. Using the resources of the Preston Robert Brain Tumor Biorepository at Duke, our team, consisting of Henry Friedman, Allan Friedman, and Hai Yan and lead by Darell Bigner, have helped to identify mutations in Isocitrate Dehydrogenase (IDH1 and IDH2) as a marker of good prognosis in gliomas of adults. This test is now offered at Duke as a clinical test. Working with the Molecular Pathology Laboratory at Duke, we have also brought testing for TERT promoter region mutations as another major test for classifying gliomas in adults. Our collaboration with the Toronto Sick Kids Hospital has resulted in prognostic testing for childhood medulloblastomas, primitive neuroectodermal tumors, and ependymomas at Duke.
Hui-Kuan Lin
The research interest in Dr. Lin lab is to understand oncogenic networks between oncogenes and tumor suppressor genes, dissect the regulatory mechanisms underlying the crosstalk between ageing and cancer, to unravel the role of posttranslational modifications (PTMs) such as ubiquitination and metabolism in diverse molecular and biological processes important for cancer progression and metastasis, cancer stem regulation, cancer immunity and drug resistance by using biochemical and molecular approaches along with and genetic mouse models, and finally to develop small molecule inhibitors and antibodies targeting critical oncogenic signaling and metabolic vulnerabilities for cancer treatment. His research goals aim to not only reveal fundamental insights and concepts for cancer biology and cancer immunity, but also develop novel paradigms and therapeutic strategies for targeting human cancer and overcoming drug resistance.
Research interests include:
- Crosstalk between oncogenic and tumor suppressor networks
- Posttranslational modifications in signaling and cancer
- Cancer progression and metastasis
- Biology of normal and cancer stem cells
- Metabolism in cancer and ageing
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