Signal Transduction in Health and Disease
Our laboratory studies cell signaling in normal development and disease. We have a particular emphasis on members of the protein-tyrosine phosphatase (PTP) superfamily (especially SHP2 and PTP1B) and on the RAS/ERK pathway and its role in RASopathies (a family of germ line disorders caused by RAS/ERK pathway mutations) and cancer. We also have a substantial program in breast cancer functional genomics and in the identification and characterization of high grade serous ovarian cancer (SOC) tumor initiating cells. We employ a wide range of cell biological, biochemical and mouse and human (hESC/iPSC) genetic approaches to study these questions.
Current work is aimed at using mass spectrometry to identify SHP2 substrates in normal cell signaling and in SHP2-induced myeloproliferative disease/leukemia, elucidating the molecular basis for SHP2 and PTP1B requirements in breast cancer. We are determining key substrates of the RAS/ERK pathway that are differentially phosphorylated in normal cells and cells from mouse models of RASopathies of cancer, respectively, determining why different RAS/ERK pathway mutations confer distinct RASopathy phenotypes. Finally, we are identifying novel targets for breast cancer using lentiviral shRNA dropout screening and large scale integrative genomic analysis, and defining the nature of SOC tumor initiating cells from patients and mouse models of this disease.
List of Key Publications:Link to Pubmed Publications
- Wu, X., Simpson, J., Hong, JH., Kim, KH., Thavarajah NK., Backx, PB., Neel, BG. Araki, T., Modulating MEK-ERK pathway ameliorates disease phenotypes in a mouse model of Noonan syndrome-associated Raf1 mutation. J Clin Invest, Mar 1 2011; 121(3):1009-25 Epub Feb 21 2011 – PMID 21339642.
- Stewart, JM., Shaw PA., Gedye C., Bernardini MQ., Neel BG.*, Ailles LE., Phenotypic heterogeneity and instability of human ovarian tumor-initiating cells. Proc Natl Acad Sci USA. Apr 19 2011; 108(16):6468-73 Epub Mar 30 2011-PMID 21451132.
- Karisch,R., Fernandez,M., Taylor,P., Virtanen,C., St-Germain,J.R., Jin,L.L., Harris,I.S., Mori,J., Mak,T.W., Senis,Y.A., Östman, A., Moran,M.F., Neel,BG. Global proteomic assessment of the classical protein-tyrosine phosphatome and “redoxome”. Cell, Volume 146, Issue 5, 826-840, 2 September 2011 - PMID: 21884940.
- Marcotte, R., Brown, KR., Suarez, F., Sayad, A., Karamboulas, K., Krzyzanowski, PM., Sircoulomb, F., Medrano, M., Fedyshyn, Y., Koh, JLY., van Dyk, D., Fedyshyn, B., Luhova, M., Brito, GC., Vizeacoumar, FJ., Vizeacoumar, FS., Datti, A., Kasimer, D., Buzina, A., Mero, P., Misquitta, C., Normand, J., Haider, M., Ketela, M., Wrana, JL., Rottapel, R., Neel, BG., Moffat, J., Essential gene profiles in breast, pancreas and ovarian cancer cells. Cancer Discovery February 2012 2:172-189; Epub December 29, 2011 PMID: 22585861.
- Robert Banh
- Anderson Chang
- Yang Xu
- Connie Yin