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.
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
Blood. 2016 Jan 15;
Gu S, Chan WW, Mohi G, Rosenbaum J, Sayad A, Lu Z, Virtanen C, Li S, Neel BG, Van Etten RA
Cell. 2016 Jan 14;164(1-2):293-309
Marcotte R, Sayad A, Brown KR, Sanchez-Garcia F, Reimand J, Haider M, Virtanen C, Bradner JE, Bader GD, Mills GB, Pe'er D, Moffat J, Neel BG
Proc Natl Acad Sci U S A. 2016 Jan 11;
Liu X, Zheng H, Li X, Wang S, Meyerson HJ, Yang W, Neel BG, Qu CK
J Exp Med. 2015 Dec 14;
Hatlen MA, Arora K, Vacic V, Grabowska EA, Liao W, Riley-Gillis B, Oschwald DM, Wang L, Joergens JE, Shih AH, Rapaport F, Gu S, Voza F, Asai T, Neel BG, Kharas MG, Gonen M, Levine RL, Nimer SD
Nature. 2015 Sep 2;
Hsu TY, Simon LM, Neill NJ, Marcotte R, Sayad A, Bland CS, Echeverria GV, Sun T, Kurley SJ, Tyagi S, Karlin KL, Dominguez-Vidaña R, Hartman JD, Renwick A, Scorsone K, Bernardi RJ, Skinner SO, Jain A, Orellana M, Lagisetti C, Golding I, Jung SY, Neilson...
Hum Mutat. 2015 Jul 14;
Cordeddu V, Yin JC, Gunnarsson C, Virtanen C, Drunat S, Lepri F, De Luca A, Rossi C, Ciolfi A, Pugh TJ, Bruselles A, Priest JR, Pennacchio LA, Lu Z, Danesh A, Quevedo R, Hamid A, Martinelli S, Pantaleoni F, Gnazzo M, Daniele P, Lissewski C, Bocchinfuso...
J Clin Oncol. 2015 Jun 29;
Stewart EL, Mascaux C, Pham NA, Sakashita S, Sykes J, Kim L, Yanagawa N, Allo G, Ishizawa K, Wang D, Zhu CQ, Li M, Ng C, Liu N, Pintilie M, Martin P, John T, Jurisica I, Leighl NB, Neel BG, Waddell TK, Shepherd FA, Liu G, Tsao MS



Professor, Department of Medical Biophysics, University of Toronto