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GEN-SHENG FENG, PH.D.
Adjunct Professor
Signal Transduction
858.795.5265 (phone)
858.795.5274 (fax)
gfeng@burnham.org
RESEARCH FOCUS, BIOGRAPHY, PUBLICATIONS
Research Focus
Research in Dr. Feng’s lab is centered on two major areas. One focus is the dissection of molecular signaling mechanism in embryonic stem cells (ESCs). Previous work in this lab has led to the identification of a crucial role for Shp2, an SH2-containing cytoplasmic tyrosine phosphatase, in promoting differentiation of ESCs. Current work is focused on understanding how Shp2 modulates signaling pathways for the determination of stem cell self-renewal versus differentiation using both mouse and human ESCs. This group is also investigating the molecular signals in directing the commitment, maintenance and differentiation of adult stem cells, such as neural stem cells (NSCs) and hematopoietic stem cells (HSCs), using cell type-specific gene knockout mouse models created in the lab.
The second focus is on the molecular basis for metabolic disorders such as obesity and diabetes. Recent results obtained by this lab lead to fresh views on leptin signaling in the hypothalamus for control of energy balance and hepatic insulin signaling for glucose homeostasis, through generation and characterization of mice deficient for Shp2 in the brain or Gab1 in the liver. Current efforts are devoted to understanding the mechanisms of leptin resistance in obese mouse models/human subjects and of insulin resistance in type II diabetes, using combined genetic/biochemical approaches. The long-term goal of this work is to identify novel pharmaceutical targets for treatment of obesity/diabetes, the disease of the 21st century.
Biography
Gen-Sheng Feng earned his Ph.D. in Molecular Biology from Indiana University Bloomington in 1990. He received postdoctoral training in the area of signal transduction at the Hospital for Sick Children and Mount Sinai Hospital, Toronto, Canada. In 1994, he was appointed as an assistant professor in Biochemistry and Molecular Biology at Indiana University School of Medicine in 1994, and was promoted to associate professor in 1999. Dr. Feng was recruited to the Burnham Institute for Medical Research in 2000.
Selected Publications
Feng GS, CC Hui and T Pawson. SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science 259: 1607, 1993.
You M, LM Flick, DH Yu, and GS Feng. Modulation of the NF-kappaB pathway by Shp-2 tyrosine phosphatase in IL-6 induction by IL-1 or TNF. J Exp Med 193: 101, 2001.
Shen R, YB Ouyang, CK Qu, A Alonso, L Sperzel, T Mustelin, MH Kaplan, and GS Feng. Grap negatively regulates TCR-elicited lymphocyte proliferation and interleukin-2 induction. Mol Cell Biol 22: 3230, 2002.
Chan RJ, SA Johnson, Y Li, MC Yoder and GS Feng. A definitive role of Shp-2 tyrosine phosphatase in mediating embryonic stem cell differentiation and hematopoiesis. Blood 102, 2074, 2003.
Zhang EE, E Chapeau, K Hagihara and GS Feng. Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc Natl Acad Sci USA 101, 16064, 2004.
Bard-Chapeau E, AL Hevener, S Long, EE Zhang, JM Olefsky and GS Feng. Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action. Nature Medicine May issue, 2005 (advanced online pub: Apr. 10, 2005).
List of Publications via PubMed
(NIH National Library of Medicine)
RESEARCH REPORT
TYROSINE PHOSPHATASES, SCAFFOLD/ADAPTER PROTEINS AND CYTOPLASMIC SIGNALING
(Download report as PDF)The focus of our research program is centered on understanding the dynamic interaction between phosphatases and kinases in the control of intracellular signal relay for cell growth, differentiation, migration and death, using broad approaches from genetic analysis of conditional mouse knockouts to biochemical dissection of multi-protein complexes.
Shp-2 tyrosine phosphatase with two SH2 domains
Shp-2 is a widely expressed cytoplasmic tyrosine phosphatase with two
SH2 domains. We have generated a targeted mutant Shp-2 allele with a
deletion of 65 amino acids in the SH2-N domain, and homozygous mutant
mice die at mid-gestation with multiple defects in the mesodermal
patterning and formation of posterior structures. By in vitro ES cell
differentiation assay and chimeric animal analysis, we have
demonstrated a stringent requirement of Shp-2 for the development of
hematopoietic stem/progenitor cells. Using Shp-2 mutant fibroblast
cells as a model system, we were able to show for the first time that a
tyrosine phosphatase has opposite effects in mediating the activation
of Erk and Jnk MAP kinases, and that Shp-2 acts to promote cell
spreading and migration, by working in concert with Fak tyrosine
kinase. It seems very likely that Shp-2 acts to integrate or coordinate
signals from integrins and receptors for growth factors and cytokines.
We are currently in the process of generating tissue-specific Shp-2
knockouts using the Cre-LoxP system, to examine its physiological roles
in various cell types.
Gab1 and Gab2, PH domain-containing scaffold proteins
Scaffold proteins apparently serve as platforms in cytoplasmic signal
relay downstream of cell surface receptors. We have recently identified
a novel member of this family, Gab2 that contains a PH domain,
potential phosphotyrosine sites for SH2 proteins and proline-rich
motifs for SH3 engagement. Interestingly, we have found that Gab1 and
Gab2, two molecules closely related in structure, have opposite effects
in coupling cytoplasmic-nuclear signaling, which allows us to propose
an intriguing model that these molecules act to target the same set of
SH2-enzymes to different specific substrates in cells. For example, we
have obtained very promising evidence that Gab1 appears to orchestrate
the interaction of Shp-2 tyrosine phosphatase with its putative
substrate, p90, in mediating EGF-stimulated Erk activation.
Grap, a SH3-SH2-SH3 adapter protein in lymphocyte signaling
Grap, a molecule we identified recently, possesses the same structural
architecture of SH3-SH2-SH3 domains as Grb2, but is expressed
predominantly in thymus and spleen. This small adaptor molecule appears
to couple signals from receptor and cytoplasmic tyrosine kinases to the
Ras pathway in lymphoid cells. We have disrupted the mouse Grap gene in
ES cells and have generated Grap knockout mice. Homozygous mutant
animals are viable. We are now in the process of examining lymphocyte
development and functions in mutant animals and our results point to a
unique function of Grap in lymphocyte signaling as a negative effector.
