Ferguson, Shawn Michael - Yale University

个人简介

The goal of research in my lab is to understand how the status of lysosomes is sensed and how lysosomal function is regulated to meet cellular demands. The basic building blocks (amino acids, sugars, lipids and nucleotides) released by degradation of lysosomal substrates represent important sources of energy during starvation and of material for new macromolecule synthesis to support cell growth and/or remodeling. Conversely, lysosomes are critical for the turnover and clearance from cells of damaged organelles and protein aggregates. The importance of maintaining optimal lysosomal function is illustrated by contributions of lysosome dysfunction to human neurodegenerative diseases including Alzheimer’s disease, Frontotemporal Dementia, Parkinson’s disease and lysosomal storage disorders such as Batten’s disease. Furthermore, the role played by lysosomes in sensing cellular energy and nutrient levels and transducing this information into signals controlling growth represents a potential therapeutic target in cancer. With this growing appreciation of the roles played by lysosomes in health and disease, we ultimately seek to address the following fundamental questions: (A) How do cells sense and regulate the status of their lysosomes? (B) How is lysosomal function altered in disease states? (C) Can lysosomal function be modulated for therapeutic purposes? To address these questions we combine live cell imaging to monitor the dynamic recruitment of proteins to lysosomes with proteomic approaches to define the molecular basis for this recruitment and high-throughput siRNA screening to identify new mechanisms controlling lysosomal homeostasis. Insights obtained through these strategies will contribute to answering fundamental cell biological questions concerning organelle homeostasis and are expected to be of direct relevance to human health. PhD Vanderbilt University (2004) MS University of Ottawa (1999) BS University of Ottawa (1997)

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Beyond indigestion: emerging roles for lysosome-based signaling in human disease. Ferguson, S.M. 2015. Beyond indigestion: emerging roles for lysosome-based signaling in human disease. Curr Opin Cell Biol. 35:59-68. Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. Petit, C.S., Roczniak-Ferguson, A., Ferguson, S.M. Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J Cell Biol., 30;202(7):1107-112, 2013. PMID: 24081491. The Transcription Factor TFEB links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis. Roczniak-Ferguson, A., Petit, C.S., Qian, S., Ky, J., Angarola, B., Froehlich, F., Walther, T.C., Ferguson, S.M. The Transcription Factor TFEB links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis. Science Signaling, Jun 12;5(228): ra42, 2012. C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling. Amick J, Roczniak-Ferguson A, Ferguson SM. Mol Biol Cell. 2016 Oct 15;27(20):3040-3051. Epub 2016 Aug 24. C9orf72: At the intersection of lysosome cell biology and neurodegenerative disease. Amick J, Ferguson SM. C9orf72: At the intersection of lysosome cell biology and neurodegenerative disease. Traffic. 2017 Mar 7. doi: 10.1111/tra.12477. Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer's disease amyloid plaques. Gowrishankar S, Yuan P, Wu Y, Schrag M, Paradise S, Grutzendler J, De Camilli P, Ferguson SM. Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer's disease amyloid plaques. Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):E3699-708. doi: 10.1073/pnas.1510329112. Amick J, Ferguson SM: C9orf72: At the intersection of lysosome cell biology and neurodegenerative disease. Traffic. 2017 May; 2017 Mar 23. PMID: 28266105 Gayle S, Landrette S, Beeharry N, Conrad C, Hernandez M, Beckett P, Ferguson SM, Mandelkern T, Zheng M, Xu T, Rothberg J, Lichenstein H: Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood. 2017 Mar 30; 2017 Jan 19. PMID: 28104689 Gayle S, Landrette S, Beeharry N, Conrad C, Hernandez M, Beckett P, Ferguson SM, Xu T, Rothberg J, Lichenstein H: B-cell non-Hodgkin lymphoma: Selective vulnerability to PIKFYVE inhibition. Autophagy. 2017 Mar 28; 2017 Mar 28. PMID: 28350209 Amick J, Roczniak-Ferguson A, Ferguson SM: C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling. Mol Biol Cell. 2016 Oct 15; 2016 Aug 24. PMID: 27559131 Gray MA, Choy CH, Dayam RM, Ospina-Escobar E, Somerville A, Xiao X, Ferguson SM, Botelho RJ: Phagocytosis Enhances Lysosomal and Bactericidal Properties by Activating the Transcription Factor TFEB. Curr Biol. 2016 Aug 8; 2016 Jul 7. PMID: 27397893 Nicholson AM, Finch NA, Almeida M, Perkerson RB, van Blitterswijk M, Wojtas A, Cenik B, Rotondo S, Inskeep V, Almasy L, Dyer T, Peralta J, Jun G, Wood AR, Frayling TM, Fuchsberger C, Fowler S, Teslovich TM, Manning AK, Kumar S, Curran J, Lehman D, Abecasis G, Duggirala R, Pottier C, Zahir HA, Crook JE, Karydas A, Mitic L, Sun Y, Dickson DW, Bu G, Herz J, Yu G, Miller BL, Ferguson S, Petersen RC, Graff-Radford N, Blangero J, Rademakers R: Prosaposin is a regulator of progranulin levels and oligomerization. Nat Commun. 2016 Jun 30; 2016 Jun 30. PMID: 27356620 Gowrishankar S, Ferguson SM: Lysosomes relax in the cellular suburbs. J Cell Biol. 2016 Mar 14. PMID: 26975848 Ferguson SM: MEDICINE. Membrane traffic en route to cancer. Science. 2015 Oct 9. PMID: 26450197 Ferguson SM: Beyond indigestion: emerging roles for lysosome-based signaling in human disease. Curr Opin Cell Biol. 2015 Aug; 2015 May 15. PMID: 25950843 Gowrishankar S, Yuan P, Wu Y, Schrag M, Paradise S, Grutzendler J, De Camilli P, Ferguson SM: Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer's disease amyloid plaques. Proc Natl Acad Sci U S A. 2015 Jul 14; 2015 Jun 29. PMID: 26124111 Willinger T, Staron M, Ferguson SM, De Camilli P, Flavell RA: Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes. Proc Natl Acad Sci U S A. 2015 Apr 7; 2015 Mar 23. PMID: 25831514 Shin NY, Choi H, Neff L, Wu Y, Saito H, Ferguson SM, De Camilli P, Baron R: Dynamin and endocytosis are required for the fusion of osteoclasts and myoblasts. J Cell Biol. 2014 Oct 13; 2014 Oct 6. PMID: 25287300