Neu1 sialidase and matrix metalloproteinase-9 cross-talk is essential for neurotrophin activation of Trk receptors and cellular signaling

• Published in: Cellular signalling 2010-08, Vol.22 (8), p.1193-1205
• Main Authors: Jayanth, Preethi, Amith, Schammim Ray, Gee, Katrina, Szewczuk, Myron R.
• Format: Article
• Language: English
• Subjects: Activation; Animals; Cell Membrane - enzymology; Cells, Cultured; Cellular; Enzyme Inhibitors - pharmacology; GPCR; Kinases; Matrix Metalloproteinase 9 - metabolism; Membranes; Mice; MMP-9; Nerve Growth Factor - pharmacology; Neu1 sialidase; Neuraminidase - analysis; Neuraminidase - metabolism; Neurons; Neurons - enzymology; Neurons - metabolism; Neurotrophin factors; PC12 Cells; Primary neurons; Rats; Receptor, trkA - metabolism; Receptors; Signal Transduction; Surface chemistry; Trk receptors; Trk-expressing cells; Tyrosine
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2010.03.011

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 IC 50 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.