Benjamin G Neel

Benjamin G Neel, MD, PhD

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
    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.
Leukemia. 2017 Aug 14;:
Gu S, Sayad A, Chan G, Yang W, Lu Z, Virtanen C, Van Etten RA, Neel BG
Nat Commun. 2017 May 26;8:15518
Yin JC, Platt MJ, Tian X, Wu X, Backx PH, Simpson JA, Araki T, Neel BG
Cell Rep. 2017 Mar 21;18(12):2932-2942
Zhang X, Dong Z, Zhang C, Ung CY, He S, Tao T, Oliveira AM, Meves A, Ji B, Look AT, Li H, Neel BG, Zhu S
Cell Rep. 2017 Mar 07;18(10):2343-2358
Medrano M, Communal L, Brown KR, Iwanicki M, Normand J, Paterson J, Sircoulomb F, Krzyzanowski P, Novak M, Doodnauth SA, Saiz FS, Cullis J, Al-Awar R, Neel BG, McPherson J, Drapkin R, Ailles L, Mes-Massons AM, Rottapel R
Proteomics. 2017 Feb 07;:
Tong J, Helmy M, Cavalli FM, Jin L, St-Germain J, Karisch R, Taylor P, Minden MD, Taylor MD, Neel BG, Bader GD, Moran MF
Mol Cell. 2016 Dec 21;:
Yao Z, Darowski K, St-Denis N, Wong V, Offensperger F, Villedieu A, Amin S, Malty R, Aoki H, Guo H, Xu Y, Iorio C, Kotlyar M, Emili A, Jurisica I, Neel BG, Babu M, Gingras AC, Stagljar I
Nature. 2016 Oct 26;:
Chan G, Neel BG
Cancer Cell. 2016 Aug 8;30(2):194-6
Ran H, Tsutsumi R, Araki T, Neel BG
Nat Cell Biol. 2016 Jun 20;
Banh RS, Iorio C, Marcotte R, Xu Y, Cojocari D, Rahman AA, Pawling J, Zhang W, Sinha A, Rose CM, Isasa M, Zhang S, Wu R, Virtanen C, Hitomi T, Habu T, Sidhu SS, Koizumi A, Wilkins SE, Kislinger T, Gygi SP, Schofield CJ, Dennis JW, Wouters BG, Neel BG
J Biol Chem. 2016 May 18;
Fang Z, Marshall CB, Yin JC, Mazhab-Jafari MT, Gasmi-Seabrook GM, Smith MJ, Nishikawa T, Xu Y, Neel BG, Ikura M

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Professor, Department of Medical Biophysics, University of Toronto