Inhibition of phosphorylation of TrkB and TrkC and their signal transduction by alpha2-macroglobulin.
Monoamine-activated alpha2-macroglobulin (alpha2M) was shown to reduce the dopamine concentration in corpus striatum of adult rat brains and inhibit other neuronal functions in vivo and in vitro. As brain-derived neurotrophic factor, neurotrophin-4, and neurotrophin-3 are important neurotrophic factors for dopaminergic neurons, the effect of monoamine-activated alpha2M on signal transduction by trkB and trkC was investigated. The results show that monoamine-activated alpha2M binds to trkB and inhibits brain-derived neurotrophic factor/neurotrophin-4-promoted autophosphorylation of trkB in a dose-dependent manner in both trkB-expressing NIH3T3 (NIH3T3-trkB) and human neuroblastoma SH-SY5Y cells. Monoamine-activated alpha2M also blocks tyrosine phosphorylation of phospholipase C-gamma1 and extracellular signal-regulated protein kinase (ERK)-1, which are key intracellular proteins involved in trkB signal transduction. Similarly, monoamine-activated alpha2M inhibits tyrosine phosphorylation of neurotrophin-3-induced trkC and its signal transduction in a dose-dependent manner in NIH3T3 cells expressing trkC (NIH3T3-trkC). In contrast to monoamine-activated alpha2M, normal alpha2M has little or no significant inhibitory effect on the phosphorylation of trkB and trkC. In addition, the retinoic acid-promoted tyrosine phosphorylation of phospholipase C-gamma1, ERK-1, and/or ERK-2 in SH-SY5Y cells was unaffected by monoamine-activated alpha2M; this suggests that the inhibitory effect of activated alpha2M on the neurotrophin-stimulated phosphorylation of intracellular signalling proteins may be specific. Taken together, the data indicate that activated alpha2M is a pan-trk inhibitor, which by virtue of its binding to trk receptors may block trk-mediated signal transduction in dopaminergic neurons and lead to reduction of dopamine concentration in corpus striatum.
Hu
Y Q
YQ
Department of Microbiology and Immunology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio 44272, USA.
Koo
P H
PH
D016475:3T3 Cells / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009414:Nerve Growth Factors / Q000494:pharmacology; D009447:Neuroblastoma; D018696:Neuroprotective Agents / Q000378:metabolism*; D020933:Neurotrophin 3; D051966:Phospholipase C gamma; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020801:Receptor, Ciliary Neurotrophic Factor; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D010738:Type C Phospholipases / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000494:pharmacology*
D000970:Antineoplastic Agents; D019208:Brain-Derived Neurotrophic Factor; D007527:Isoenzymes; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D000511:alpha-Macroglobulins; C065661:alpha2-macroglobulin-methylamine; D012701:Serotonin; D014212:Tretinoin; D020794:Receptor Protein-Tyrosine Kinases; D020812:Receptor, trkC; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; C073922:neurotrophin 4