Rat alpha(2)-macroglobulin inhibits NGF-promoted neurite outgrowth, TrK phosphorylation, and gene expression of pheochromocytoma PC12 cells.
Rat alpha-1-macroglobulin (alpha(1)M) and alpha-2-macroglobulin (alpha(2)M) are murine homologs of human alpha(2)M, and rat alpha(2)M is generally known as an acute-phase protein. Monoamine-activated forms of human alpha(2)M have been shown to inhibit various neuronal functions, but the effect of rat alpha(1)M and acute-phase alpha(2)M on neurons is largely unknown. In this report, rat serotonin-activated alpha(2)M (5HT-alpha(2)M) has been demonstrated to inhibit nerve growth factor (NGF)-promoted neurite extension in pheochromocytoma PC12 cells, and we investigated its possible mechanism of action including its effect on NGF-promoted signal transduction and gene expression in these cells. Especially in the absence of NGF, 5HT-alpha(2)M was found to bind to TrkA (the high-affinity receptor for NGF) much better than normal alpha(2)M (N-alpha(2)M). 5HT-alpha(2)M dose-dependently inhibited NGF-promoted autophosphorylation of TrkA, and decreased the expression of two immediate-early genes (NGFI-A and c-jun) and two delayed-response genes (SCG10 and transin) which are associated with neurite outgrowth in PC12 cells. The unmodified N-alpha(2)M, on the other hand, exhibited very little or no inhibitory effects on neurite extension, Trk phosphorylation, or expression of these genes. The results of this study taken together suggest that monoamine-activated acute-phase rat alpha(2)M appears to inhibit neurite outgrowth in PC12 cells possibly via its direct binding to TrkA and subsequent blocking of TrkA-mediated signal transduction and gene expression.
Lee
P G
PG
Department of Microbiology and Immunology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio 44272-0095, USA.
Koo
P H
PH
D000310:Adrenal Gland Neoplasms / Q000378:metabolism; D000818:Animals; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors*; D016501:Neurites / Q000187:drug effects*; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000378:metabolism; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000378:metabolism*; D000511:alpha-Macroglobulins / Q000494:pharmacology*
D009414:Nerve Growth Factors; D016755:Proto-Oncogene Proteins c-jun; D000511:alpha-Macroglobulins; D020917:Receptor, trkA