Photo of Bin Zheng,  PhD

Bin Zheng, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 724-9958


bin.zheng@cbrc2.mgh.harvard.edu

Bin Zheng, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Assistant Professor, Dermatology, Harvard Medical School
  • Assistant Biologist, Dermatology, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Our laboratory is interested in deciphering the molecular mechanisms of metabolic signaling in cancer, with special emphasis on melanoma, and translating these basic research findings into potential personalized targeted therapies. The focus of our current research is on the LKB1-AMPK signaling pathway, which couples energy metabolism to cell growth, proliferation and survival. AMPK (AMP-activated protein kinase) is a Ser/Thr protein kinase thatserves as a cellular energy sensor. The activity of AMPK is regulated by the AMP/ATP ratio and by upstream activating kinases, including the tumor suppressor LKB1. Metformin, one of the most prescribed drugs for treating type II diabetes, has been shown to target the LKB1-AMPK pathway and is currently being evaluated for the treatment of cancer in clinical trials. Understanding the complex LKB1-AMPK signaling circuitries underlying tumorigenesis will contribute to the development of effective therapeutic strategies.

Our current research directions include:

1) Identification of novel substrates of AMPK and characterization of their roles in cancer biology. We are using a combination of bioinformatics, proteomics and metabolomics approaches to uncover critical AMPK substrates relevant to cancer biology, especially those involved in cancer cell metabolism and EMT (Epithelial Mesenchymal Transition).

2) Down-regulation of LKB1 and AMPK in Cancer. The LKB1-AMPK pathway serves as an "energy brake" to suppress cell growth and proliferation under energy stress conditions. Cancer cells need to inactivate this pathway in order to gain a growth advantage over normal cells. We are studying various mechanisms by which the LKB1-AMPK "energy brake" is "overridden" in cancer.

3) Cross-talk between LKB1-AMPK and RAF-MEK-ERK signaling pathways. RAF signaling pathway is one of the other most important signaling pathways in cancer. We have recently discovered that this pathway is tightly linked to the LKB1-AMPK pathway. Currently we are continuing to investigate the biochemical mechanism by which these two pathways interact and regulate each other's functions. Moreover, we are assessing the therapeuticpotential of combining drugs targeting both of these pathways (metformin and RAF/MEK inhibitors) in melanoma treatment using various preclinical models, such as xenograft and genetically engineered mouse models.

Publications

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  • Zheng B, Fisher DE. Metabolic vulnerability in melanoma: a ME2 (me too) story. J Invest Dermatol 2015; 135:657-9. PubMed
  • Yuan P, Ito K, Perez-Lorenzo R, Del Guzzo C, Lee JH, Shen CH, Bosenberg MW, McMahon M, Cantley LC, Zheng B. Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci U S A 2013. PubMed
  • Shen CH, Yuan P, Perez-Lorenzo R, Zhang Y, Lee SX, Ou Y, Asara JM, Cantley LC, Zheng B. Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. Mol Cell 2013. PubMed
  • Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C, Bellinger G, Shen CH, Wen J, Asara J, McGraw TE, Kahn BB, Cantley LC. AMPK-Dependent Degradation of TXNIP upon Energy Stress Leads to Enhanced Glucose Uptake via GLUT1. Mol Cell 2013; 49:1167-75. PubMed
  • Mack HI, Zheng B, Asara J, Thomas SM. AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization. Autophagy 2012; 8:1197-214. PubMed
  • Dagon Y, Hur E, Zheng B, Wellenstein K, Cantley LC, Kahn BB. p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin's effect on food intake. Cell Metab 2012; 16:104-12. PubMed
  • Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 2011; 13:376-88. PubMed
  • Tsou P, Zheng B, Hsu CH, Sasaki AT, Cantley LC. A Fluorescent Reporter of AMPK Activity and Cellular Energy Stress. Cell Metab 2011; 13:476-86. PubMed
  • Zheng B,Jeong JH,Asara JM,Yuan YY,Granter SR,Chin L,Cantley LC. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell 2009; 33:237-47. PubMed