Keywords: signal transduction, tyrosine phosphatases, scaffolding adapters, mouse models of signaling abnormalities and human disease, insulin and leptin signalling, glucose homeostasis, breast carcinogenesis, leukemogenesis, cancer stem cells, leukemia stem cells |
The Neel laboratory studies cell signaling, with a particular emphasis on protein-tyrosine phosphatases (PTPs). We also have a developing interest in normal and tumor stem cell signaling. The roles of the SH2 domain-containing phosphatase Shp2 and its binding proteins in several human diseases are a major focus.
Shp2 is expressed ubiquitously and is a positive signal transducer, required for Ras/Erk activation downstream of most receptor tyrosine kinases, cyotkine receptors, and integrins. Shp2 is required for a variety of developmental processes, including the survival of trophoblast stem cells, As a consequence of loss of the latter function, Shp2-null embryos die peri-implantation. In the absence of an appropriate phosphotyrosyl peptide, Shp2 is inactive, because the N-SH2 domain is inserted into the catalytic cleft of the phosphatase (PTP) domain. We showed earlier that mutations in the SH2/PTP interface can yield ''activated mutants''. Analogous mutations in humans cause 50% of cases of the autosomal dominant disorder Noonan Syndrome (NS), while somatic mutations cause some leukemias/myeloproliferative disorders (MPD).
Interestingly, another autosomal dominant disorder, LEOPARD syndrome, also is caused by Shp2 mutations, but surprisingly, we showed recently that such mutations are catalytically inactive/impaired and act as dominant negative mutants in transfection assays. We have generated an allelic series of inducible and stable NS and leukemia mutant knock-in mutants, as well as inducible Shp2 knockout mice and cell lines.
Current work is aimed at elucidating key Shp2 substrates using both candidate and unbiased proteomic approaches, delineating its role in specific tissues using the inducible knockouts, determining the cellular and molecular basis of how Shp2 mutations cause NS and hematopoietic disease, and generating mouse models of NS.
We have also recently identified another major NS gene, and are studying the biochemical and cellular effects of these mutations, as well as the potential involvement of this gene in human tumors.
Finally, we are testing the effects of specific oncogene/tumor suppressor gene mutations on prospectively purified mammary stem and progenitor cell populations, and attempting to identify/purify and culture cancer stem cells from several types of solid tumors.
- Yang W, Klaman L, Chen B, Araki T, Harada H, Thomas SM, George EL, Neel BG. An Shp2/SFK/Ras/Erk signaling pathway controls trophoblast stem cell survival. Dev. Cell, 2006;10:317-27.
- Bentires-Alj M, Gil SG, Chan R, Wang ZC, Imanaka N, Harris L, Richardson A, Neel BG, Gu H. Casual role of the scaffolding adapter Gab2 in breast cancer. Nature Medicine 2006, 12:114-121.
- Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG. PTPN11 (SHP2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006; 281:6785-92.
- Keilhack H, David FS, McGregor M, Cantley LC, Neel BG. Diverse biochemical properties
of Shp2 mutants: Implications for disease phenotypes. J Biol Chem; 2005; 280:30984-93.
- Mohi MG, Williams IR, Dearolf CR, Chan G, Kutok JL, Cohen S, Morgan K, Boulton C, Shigematsu H, Keilhack H, et al.: Prognostic, therapeutic and mechnistic implications of mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer Cell 2005, 7:1-14.
- Bentires-Alj M, Paez JG, David FS, Keilhack H, Halmos B, Naoki K, Maris JM, Richardson
A, Bardelli A, Sugarbaker DJ, Richards WG, Du J, Girard L, Minna JD, Loh ML, Fisher DE, Velculescu VE, Vogelstein B, Meyerson M, Sellers WR and Neel BG. Activating mutations of the Noonan Syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 2004, 64:8816-8820.
- Araki T, Mohi MG, Ismat FA, Bronson RT, Williams IR, Kutok JL, Pao LI, Gilliland DG, Epstein
JA and Neel BG. Murine Model of Noonan Syndrome Reveals Cell Type and Gene Dosage Dependent Effects of PTPN11 Mutation. Nature Medicine, 2004 10:849-57.
- Zhang SQ, Yang W, Kontaridis MI, Bivona TG, Wen G, Araki T, Thompson JA, Schraven BL, Philips MR and Neel BG. Shp2 Regulates Src Family Kinase Activity and Ras/Erk Activation by Controlling Csk Recruitment. Mol Cell 2004. 13:341-55.
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