Inhibition Of Phosphorylation Of Trkb And Trkc And Their Signal Transduction By Alpha(2)-macroglobulin

Inhibition Of Phosphorylation Of Trkb And Trkc And Their Signal Transduction By Alpha(2)-macroglobulin

Hu Y Q; Koo P H

Journal of Neurochemistry

1998

1998-07

Monoamine-activated alpha(2)-macroglobulin (alpha(2)M) 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 alpha(2)M on signal transduction by trkB and trkC was investigated. The results show that monoamine-activated alpha(2)M 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 alpha(2)M also blocks tyrosine phosphorylation of phospholipase C-gamma 1 and extracellular signal-regulated protein kinase(ERK)-1,which are key intracellular proteins involved in trkB signal transduction. Similarly, monoamine-activated alpha(2)M 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 alpha(2)M, normal alpha(2)M 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-gamma 1, ERK-1, and/or ERK-2 in SH-SY5Y cells was unaffected by monoamine-activated alpha(2)M; this suggests that the inhibitory effect of activated alpha(2)M on the neurotrophin-stimulated phosphorylation of intracellular signalling proteins may be specific. Taken together, the data indicate that activated alpha(2)M 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.

alpha(2)-macroglobulin; alpha(2)-macroglobulin; alpha(2)-macroglobulin; Alzheimer's disease; Biochemistry & Molecular Biology; cerebrospinal-fluid; dopaminergic-neurons; mitogen-activated protein kinases; nerve growth-factor; neurite outgrowth; Neurodegenerative diseases; Neurosciences & Neurology; neurotrophic factor; neurotrophins; phospholipase C-gamma 1; rat caudate-putamen; signal-transduction; tyrosine protein-kinase

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Journal Article or Conference Abstract Publication

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