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.
Blood. 2018 Nov 14;:
Nagy Z, Vögtle T, Geer MJ, Mori J, Heising S, Di Nunzio G, Gareus R, Tarakhovsky A, Weiss A, Neel BG, Desanti GE, Mazharian A, Senis YA
Cancer Res. 2018 Oct 08;:
Xu Y, Taylor P, Andrade J, Ueberheide B, Shuch B, Glazer PM, Bindra RS, Moran MF, Linehan WM, Neel BG
FEBS Open Bio. 2018 Sep;8(9):1405-1411
Tsutsumi R, Ran H, Neel BG
Cancer Discov. 2018 Jul 25;:
Fedele C, Ran H, Diskin B, Wei W, Jen J, Geer MJ, Araki K, Ozerdem U, Simeone DM, Miller G, Neel BG, Tang KH
Trends Cell Biol. 2018 Apr 30;:
Cimmino L, Neel BG, Aifantis I
Hum Mol Genet. 2018 Apr 12;:
Tajan M, Pernin-Grandjean J, Beton N, Gennero I, Capilla F, Neel BG, Araki T, Valet P, Tauber M, Salles JP, Yart A, Edouard T
Bone Res. 2018;6:12
Zuo C, Wang L, Kamalesh RM, Bowen ME, Moore DC, Dooner MS, Reginato AM, Wu Q, Schorl C, Song Y, Warman ML, Neel BG, Ehrlich MG, Yang W
Sci Signal. 2018 Mar 20;11(522):
Zheng H, Yu WM, Waclaw RR, Kontaridis MI, Neel BG, Qu CK
Am J Pathol. 2018 Feb 16;:
Cybulska P, Stewart JM, Sayad A, Virtanen C, Shaw PA, Clarke B, Stickle N, Bernardini MQ, Neel BG
Proc Natl Acad Sci U S A. 2017 Dec 27;:
Peled M, Tocheva AS, Sandigursky S, Nayak S, Philips EA, Nichols KE, Strazza M, Azoulay-Alfaguter I, Askenazi M, Neel BG, Pelzek AJ, Ueberheide B, Mor A



Professor, Department of Medical Biophysics, University of Toronto