Rat Alpha(1)-macroglobulin Enhances Nerve Growth Factor-promoted Neurite Outgrowth, Trka Phosphorylation, And Gene Expression Of Pheochromocytoma Pc12 Cells
alpha-2-macroglobulin receptor; alpha-macroglobulins; alpha(2)-macroglobulin; Biochemistry & Molecular Biology; caudate putamen; cerebral cortical-neurons; choline-acetyltransferase; delayed-response genes; immediate-early genes; myelin-associated glycoprotein; nerve growth factor receptor; neurite-promoting factor; Neurosciences & Neurology; ngf receptor; protein; signal; signal-transduction; transduction
Monoamine-activated human alpha(2)-macroglobulin (alpha(2)M) has been previously demonstrated to inhibit TrkA-, TrkB-, and TrkC-mediated signal transduction. Rat alpha(1),-macroglobulin (alpha(1)M) and alpha(2)M are structural homologues of human alpha(2)M, but rat alpha(1)M is distinctly different from rat alpha(2)M in many ways and its role in the mammalian nervous system is unknown. In this report, monoamine-activated rat alpha(1)M was demonstrated to enhance in a dose-dependent manner nerve growth factor (NGF)-promoted neurite outgrowth in pheochromocytoma PC12 cells. Monoamine-activated alpha(1)M by itself, however, was neither neurotrophic nor mitogenic to PC12 cells. To investigate further its possible mode of action, the ability of monoamine-activated alpha(1)M and normal alpha(1)M to bind and to activate the NGF receptor (TrkA) was investigated. Monoamine-activated alpha(1)M formed a more stable complex with TrkA than normal alpha(1)M, but the binding of mono-amina-activated alpha(1)M to TrkA was adversely affected by prior stimulation of TrkA with NGF. In addition, monoamine-activated alpha(1)M enhanced the NGF-promoted TrkA phosphorylation and up-regulated the expression of NGF-inducible immediate-early genes (c-jun and NGFI-A) and delayed-response genes (SCG10 and transin) in PC12 cells; normal alpha(1)M, in contrast, produced little or no effect, This study demonstrates that alpha(1)M, the constitutive form of ar-macroglobulin in the rat, possesses the ability to promote NGF-mediated differentiation in PC12 cells, possibly via its direct action on TrkA receptors and TrkA-mediated signal transduction and gene expression.
Lee P G; Koo P H
Journal of Neurochemistry
2000
2000-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1046/j.1471-4159.2000.0740081.x" target="_blank" rel="noreferrer noopener">10.1046/j.1471-4159.2000.0740081.x</a>
Monoamine-activated Alpha(2)-macroglobulin Inhibits Neurite Outgrowth, Survival, Choline-acetyltransferase, And Dopamine Concentration Of Neurons By Blocking Neurotrophin-receptor (trk) Phosphorylation And Signal-transduction
alpha(2)-macroglobulin; alpha-macroglobulin; nerve growth-factor
Koo P H; Liebl D J; Qiu W S; Hu Y Q; Dluzen D E
Biology of Alpha2-Macroglobulin, Its Receptor, and Related Proteins
1994
1994
Book Chapter
<a href="http://doi.org/10.1111/j.1749-6632.1994.tb44340.x" target="_blank" rel="noreferrer noopener">10.1111/j.1749-6632.1994.tb44340.x</a>
Inhibition Of Phosphorylation Of Trkb And Trkc And Their Signal Transduction By Alpha(2)-macroglobulin
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
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.
Hu Y Q; Koo P H
Journal of Neurochemistry
1998
1998-07
Journal Article or Conference Abstract Publication
n/a