FK506 requires stimulation of the extracellular signal-regulated kinase 1/2 and the steroid receptor chaperone protein p23 for neurite elongation.
The immunosuppressant drug FK506 (tacrolimus) accelerates nerve regeneration in vivo and increases neurite elongation in vitro. We have proposed that the mechanism involves binding to the FK506-binding protein 52, a chaperone component of mature steroid receptor complexes, and a subsequent 'gain-of-function' involving p23 dissociation from Hsp-90 in the complex and extracellular signal-regulated kinase (ERK) activation. Here, we tested the involvement of the ERK and p23 in neurite elongation by FK506 in human SH-SY5Y cells. FK506 (10 nM) increased ERK1/2 phosphorylation at 12 and 24 h, eliciting a 3.5-fold increase at 24 h, which was inhibited in a concentration-dependent manner by an antibody (JJ3) to recombinant human p23. Neurite elongation by FK506 (10 nM), determined by measuring neurite lengths at 96 and 168 h, was completely blocked by the mitogen-activated protein kinase inhibitor PD 098059 (10 microM) and prevented, in a concentration-dependent fashion, by the p23 antibody. Taken together, the results demonstrate the functional role for ERK and p23 in the neurite elongation activity of FK506 and reveal a novel signal transduction pathway involving p23 activation of ERK. We suggest that compounds that stimulate or mimic p23 may be useful for accelerating nerve regeneration.
Gold
Bruce G
BG
Center for Research on Occupational and Environmental Toxicology, and Department of Cell and Devlopmental Biology, Oregon Health and Science University, Portland, 97201-3098, USA. gold@ohsu.edu
Zhong
Yong-Ping
YP
D015153:Blotting, Western / Q000379:methods; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004347:Drug Interactions; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D009447:Neuroblastoma; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction; D016559:Tacrolimus / Q000494:pharmacology*; D013997:Time Factors
D004268:DNA-Binding Proteins; D005419:Flavonoids; D007166:Immunosuppressive Agents; C073446:protein p23; D020932:Nerve Growth Factor; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D016559:Tacrolimus