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Neu1 sialidase and matrix metalloproteinase-9 cross-talk is essential for neurotrophin activation of Trk receptors and cellular signaling |
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| Authors: | Preethi Jayanth Schammim Ray Amith Katrina Gee Myron R. Szewczuk |
| Affiliation: | 1. Queen''s University, Microbiology & Immunology, 18 Stuart St., Bollerell Hall Rm 828, Kingston, Ontario, Canada K7L 3N6;2. Department of Microbiology & Immunology, Queen''s University, Kingston, Ontario, Canada K7L3N6;3. Departments of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland 21201;4. Departments of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201;5. Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201;6. Department of Otolaryngology, University of Arizona College of Medicine, Tucson, Arizona 85724;1. Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA;1. Division of Epidemiology and Public Health, University of Nottingham, Nottingham NG5 1PB, UK;2. National Heart and Lung Institute, Imperial College, London, UK;3. Department of Infection, Immunity and Inflammation, University of Leicester, Leicester;2. Saitama Medical University, Moroyama, Saitama, Japan;3. Kagoshima University, Kagoshima, Japan |
| Abstract: | Neurotrophin-induced Trk tyrosine kinase receptor activation and neuronal cell survival responses have been reported to be under the control of a membrane associated sialidase. Here, we identify an unprecedented membrane sialidase mechanism initiated by nerve growth factor (NGF) binding to TrkA to potentiate GPCR-signaling via membrane Gαi subunit proteins and matrix metalloproteinase-9 (MMP-9) activation to induce Neu1 sialidase activation in live primary neurons and TrkA- and TrkB-expressing cell lines. Central to this process is that Neu1/MMP-9 complex is bound to TrkA on the cell surface of naïve primary neurons and TrkA-expressing cells. Tamiflu completely blocks this sialidase activity in live TrkA-PC12 cells treated with NGF with an IC50 of 3.876 μM with subsequent inhibition of Trk activation in primary neurons and neurite outgrowth in TrkA-PC12 cells. Our findings uncover a Neu1 and MMP-9 cross-talk on the cell surface that is critically essential for neurotrophin-induced Trk tyrosine kinase receptor activation and cellular signaling. |
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