An agonistic mAb directed to the TrkC receptor juxtamembrane region defines a trophic hot spot and interactions with p75 coreceptors.
The D5 domain of TrkC receptors is a docking site for Neurotrophin-3 (NT-3), but other domains may be relevant for function or harmonizing signals with p75(NTR) coreceptors. We report a monoclonal antibody (mAb) 2B7 targeting the juxtamembrane domain of TrkC. mAb 2B7 binds to murine and human TrkC receptors and is a functional agonist that affords activation of TrkC, AKT, and MAPK. These signals result in cell survival but not in cellular differentiation. Monomeric 2B7 Fabs also affords cell survival. Binding of 2B7 mAb and 2B7 Fabs to TrkC are blocked by NT-3 in a dose-dependent manner but not by pro-NT-3. Expression of p75(NTR) coreceptors on the cell surface block the binding and function of mAb 2B7, whereas NT-3 binding and function are enhanced. mAb 2B7 defines a previously unknown neurotrophin receptor functional hot spot; that exclusively generates survival signals; that can be activated by non-dimeric ligands; and potentially unmasks a site for p75-TrkC interactions.
Guillemard
Veronique
V
Department of Pharmacology and Therapeutics, Lady Davis Research Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Ivanisevic
Ljubica
L
Garcia
Alba Galan
AG
Scholten
Vicki
V
Lazo
Oscar M
OM
Bronfman
Francisca C
FC
Saragovi
H Uri
HU
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020812:Receptor, trkC / Q000819:agonists / Q000378:metabolism*; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C518911:neurotropin 3, mouse; C068313:Ngfr protein, rat; D020812:Receptor, trkC; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases