A TrkA-selective, fast internalizing nerve growth factor-antibody complex induces trophic but not neuritogenic signals.
Nerve growth factor (NGF) is a neurotrophin that induces neuritogenic and trophic signals by binding to TrkA and/or p75 receptors. We report a comparative study of the binding, internalization, and biological activity of NGF versus that of NGF in association with an anti-NGF monoclonal antibody (mAb NGF30), directed against the C termini of NGF. NGF.mAb complexes do not bind p75 effectively but bind TrkA with high affinity. After binding, NGF. mAb complexes stimulate internalization faster and to a larger degree than NGF. NGF.mAb-induced activation of TrkA, Shc, and MAPK is transient compared with NGF-induced activation; yet NGF and NGF. mAb afford identical trophic responses. In contrast, NGF induces Suc-1-associated neurotrophic activating protein phosphorylation and neuritogenic differentiation, but NGF.mAb does not. Thus, an absolute separation of trophic and neuritogenic function is seen for NGF.mAb, suggesting that biological response modifiers of neurotrophins can afford ligands with selected activities.
Saragovi
H U
HU
Department of Pharmacology and Therapeutics, McGill University, Montréal, Quebec H3G 1Y6, Canada. Uri@pharma.mcgill.ca
Zheng
W
W
Maliartchouk
S
S
DiGugliemo
G M
GM
Mawal
Y R
YR
Kamen
A
A
Woo
S B
SB
Cuello
A C
AC
Debeir
T
T
Neet
K E
KE
D000911:Antibodies, Monoclonal / Q000378:metabolism; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D002795:Choline O-Acetyltransferase / Q000032:analysis; D004705:Endocytosis; D004789:Enzyme Activation; D008024:Ligands; D009414:Nerve Growth Factors / Q000276:immunology / Q000378:metabolism*; D016501:Neurites; D009474:Neurons / Q000166:cytology; D011485:Protein Binding; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D008024:Ligands; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D017871:Calcium-Calmodulin-Dependent Protein Kinases