Mutations in the protein kinase BRAF have been found in ~70% of human melanoma. In preliminary studies, I have found that oncogenic BRAF V600E suppresses the activities ofthe tumor suppressor LKBl and its downstream kinase AMPK through indirect phosphorylation on LKBl. Moreover, this inhibition is critical for the proliferation of melanoma cells with BRAF V600E mutation. The goal of this proposal is to fiilly understand the regulation of LKBl and AMPK by BRAF signaling, examine its relevance in melanoma pathogenesis and explore its therapeutic implication. This proposal will define the molecular mechanism underlying the inhibition of LKBl- AMPK activity by BRAF V600E signaling, will investigate whether this inhibitory signaling mechanism is critical for melanoma cell proliferation, and tumor growth in mouse xenograft models, will examine the potential correlation between the active state of AMPK and ERK in human melanoma, will evaluate the effects of combined treatment of AMPK activators and MEK inhibitors on melanoma cell proliferation and xenograft tumor growth, and finally will characterize critical downstream signaling proteins of AMPK in melanoma. CANDIDATE: Bin Zheng received his Ph.D. in molecular pathology in 2002 from UC San Diego and postdoctoral trainings in the laboratory of Lewis Cantley at Harvard Medical School. His scientific advisory committee includes Cory Abate-Shen, Richard Baer, Meenhard Herlyn and Ramon Parsons, who are experts in cancer biology, cancer signaling and melanoma. The advisory committee and the vibrant scientific environment at the Columbia University Medical Center will facilitate Dr. Zheng in achieving his scientific and career goals.
Melanoma is one of the most common and aggressive cancers, with ~60,000 new cases in the US in 2007. The goal of this research is to understand the regulation ofthe metabolic sensing LKB1-AMPK pathway by BRAF, one ofthe most frequently mutated genes in melanoma. This research will provide the molecular basis for future targeted therapies for melanoma.
|Yuan, Ping; Ito, Koichi; Perez-Lorenzo, Rolando et al. (2013) Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci U S A 110:18226-31|
|Shen, Che-Hung; Yuan, Ping; Perez-Lorenzo, Rolando et al. (2013) Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. Mol Cell 52:161-72|
|Wu, Ning; Zheng, Bin; Shaywitz, Adam et al. (2013) AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol Cell 49:1167-75|
|Mack, Hildegard I D; Zheng, Bin; Asara, John M et al. (2012) AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization. Autophagy 8:1197-214|
|Perez-Lorenzo, Rolando; Zheng, Bin (2012) Targeted inhibition of BRAF kinase: opportunities and challenges for therapeutics in melanoma. Biosci Rep 32:25-33|
|Amato, Stephen; Liu, Xiuxin; Zheng, Bin et al. (2011) AMP-activated protein kinase regulates neuronal polarization by interfering with PI 3-kinase localization. Science 332:247-51|
|Tsou, Peiling; Zheng, Bin; Hsu, Chia-Hsien et al. (2011) A fluorescent reporter of AMPK activity and cellular energy stress. Cell Metab 13:476-86|