“Regulation of CNS Inflammation” Francisco Quintana, PhD Associate Professor of Neurology Center for Neurological Diseases Harvard...
Barbara E. Slack, PhD
Academic Title – Associate Professor of Pathology and Laboratory Medicine
72 East Concord Street, Rm. L808
Telephone – 617-638-5487
Email – email@example.com
- BSc, Life Sciences, Queen’s University, Kingston, Ontario, Canada
- PhD, Pharmacology, Queen’s University, Kingston, Ontario, Canada
- Postdoctoral Fellow, Department of Applied Biological Sciences, MIT
- Research Fellow, Department of Physiology and Biophysics, Harvard Medical School
- Research Scientist, Department of Brain and Cognitive Sciences, MIT
Our laboratory studies signal transduction pathways coupled to G protein-coupled receptors. In recent work, we have examined aspects of the regulation of mitogen-activated protein kinases (MAPK), mammalian target of rapamycin (mTOR), and integrin-dependent signaling by muscarinic receptor subtypes.
We are also interested in the signaling pathways that regulate limited proteolysis catalyzed by the ADAM (a disintegrin and metalloprotease) family of proteases. ADAMs cleave a number of transmembrane proteins within their extracellular domains, resulting in the release (shedding) of their ectodomains. In some cases, these shed fragments are biologically active. Ectodomain shedding is often followed by, and is a prerequisite for, cleavage of the remaining C-terminal stub by gamma-secretase. This liberates the cytoplasmic domain, which, in the case of a number of proteins, has been shown to be signaling-competent.
The amyloid precursor protein (APP) is an ADAM substrate that plays a central role in the pathology of Alzheimer’s disease (AD). APP proteolysis by beta- and gamma-secretases generates amyloidogenic, neurotoxic Abeta peptides, which form insoluble deposits in the brain in AD. Signaling pathways that activate ADAM10 or ADAM17 inhibit amyloidogenesis by cleaving APP within the Abeta domain. Moreover, the liberated N-terminal fragment (sAPPalpha) exhibits neurotrophic and neuroprotective properties. Upregulation of APP-directed ADAM activity might therefore ameliorate amyloid formation, and promote neuronal survival.
Work from my laboratory and others has established roles for G protein-coupled (including muscarinic) receptors, growth factor receptors, protein kinases and calcium influx as activators of APP ectodomain shedding. We are currently investigating the regulation by dynamin-dependent endocytosis of ADAM10 trafficking, maturation, and activity as an APP sheddase. Other ADAM substrates being studied in this laboratory include the discoidin domain receptor (DDR)1, which undergoes ectodomain shedding in response to collagen binding, and ADAM10 itself, which is constitutively cleaved by ADAM9 and ADAM15 to generate a soluble ectodomain, and a C-terminal fragment that is a substrate for gamma-secretase.
Many different proteins are cleaved by ADAM proteases, and although ADAMs are believed to exert a mitigating influence in Alzheimer’s disease, they may exacerbate the pathologies of cancer, inflammation, and vascular disease. It is therefore important to fully understanding the roles played by ADAMs in the entire spectrum of normal and pathologic situations before their potential as therapeutic targets can be effectively exploited.
See Selected Recent Publications below or Search Additional Publications in MyBibliography
- Carey, R.M., Blusztajn, J.K., and Slack, B.E. (2011) Surface expression and limited proteolysis of ADAM10 are increased by a dominant negative inhibitor of dynamin. BMC Cell Biol. (in press)
- Kishi, S., Slack, B.E., Uchiyama, J., and Zhdanova, I.V. (2009) Zebrafish as a genetic model in biological and behavioral gerontology: where development meets aging in vertebrates – a mini-review. Gerontology 55: 430-441.
- Slack, B.E. and Blusztajn, J.K. (2008) Differential regulation of mTOR-dependent S6 phosphorylation by muscarinic acetylcholine receptor subtypes. J. Cell. Biochem. 104: 1818-1831, 2008.
- Alfa Cissé, M., Louis, K., Braun, U., Mari, B., Leitges, M., Slack, B.E., Fisher, A., Auberger, P., Checler, F., and Vincent, B. (2008) Isoform specific contribution of protein kinase C to prion processing. Mol. Cell. Neurosci. 39: 400-410.
- Slack, B.E. and Wurtman, R.J. (2007) Regulation of Synthesis and Metabolism of the Amyloid Precursor Protein by Extracellular Signals. In: Research Progress in Alzheimer’s Disease and Dementia, M.-K. Sun, ed., Vol. 2, pp. 1-25, Nova Science Publishers, Inc.
- Alfa Cissé, M., Sunyach,C., Slack, B.E., Fisher, A., Vincent, B., and Checler, F. (2007) M1 and M3 muscarinic receptors control physiological processing of cellular prion by modulating ADAM17 phosphorylation and activity. J. Neurosci. 27: 4083-4092.
- Slack, B.E., Siniaia, M.S., and Blusztajn, J.K. (2006) Collagen type I selectively activates ectodomain shedding of the discoidin domain receptor I: Involvement of Src tyrosine kinase. J. Cell. Biochem. 98: 672-684.
- Slack, B.E. and Siniaia, M.S. (2005) Adhesion-dependent redistribution of MAP kinase and MEK promotes muscarinic receptor-mediated signaling to the nucleus. J. Cell. Biochem. 95: 366-378.
- Carey, R.M., Balcz, B.A., Lopez-Coviella, I., Slack, B.E. (2005) Inhibition of dynamin-dependent endocytosis increases shedding of the amyloid precursor protein ectodomain and reduces generation of amyloid betaprotein. BMC Cell Biol. 6:30.
- Lopez-Coviella, I., Follettie, M., Mellott, T.J., Kovacheva, V.P., Slack, B.E.., Diesl, V., Berse, B., Thies, R.S., and Blusztajn, J.K. (2005) Bone morphogenetic protein 9 induces the transcriptome of basal forebrain cholinergic neurons. Proc. Natl. Acad. Sci. USA 102: 6984-6989.
- Slack, B.E., Ma, L. K., and Seah, C.C. (2001) Constitutive shedding of the amyloid precursor ectodomain is up-regulated by tumor necrosis factor-alpha converting enzyme (TACE). Biochem. J. 357, 787-794.
- Slack, B.E. (2000) The m3 muscarinic acetylcholine receptor is coupled to mitogen-activated protein kinase via protein kinase C and epidermal growth factor receptor kinase. Biochem. J. 348, 381-387.
- Slack, B.E. (1998) Tyrosine phosphorylation of paxillin and focal adhesion kinase by activation of muscarinic m3 receptors is dependent on integrin engagement by the extracellular matrix. Proc. Natl. Acad. Sci. USA 95, 7281-7286.