Downregulation of LAR tyrosine phosphatase prevents apoptosis and augments NGF-induced neurite outgrowth.
The identity of the protein tyrosine phosphatases (PTPs) regulating cell death and responses to neurotrophins during neural development remain unknown. To determine if the leukocyte common antigen-related (LAR) PTP regulates these processes, PC12 cells were made LAR-deficient via stable transfection with an LAR antisense transgene. LAR-deficient cells demonstrated a stable novel phenotype, including a two-fold increase in nerve growth factor- but not fibroblast growth factor-induced neurite outgrowth. Upon serum-deprivation, LAR-deficient cells exhibited a two- to three-fold decrease in cell death. The findings that an endogenous PTP promotes cell death and counter-regulates neurotrophin actions introduce a major new receptor gene family to neurotrophic processes and suggest novel strategies for preventing cell death and augmenting neurotrophin function.
Tisi
M A
MA
Neurology Service, Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California 94121, USA.
Xie
Y
Y
Yeo
T T
TT
Longo
F M
FM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation / Q000235:genetics*; D005456:Fluorescent Dyes; D005786:Gene Expression Regulation / Q000187:drug effects; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D020320:Oligoribonucleotides, Antisense / Q000096:biosynthesis / Q000494:pharmacology; D016716:PC12 Cells; D017027:Protein Tyrosine Phosphatases; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D019076:Transgenes / Q000235:genetics
D005456:Fluorescent Dyes; D009419:Nerve Tissue Proteins; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D020932:Nerve Growth Factor; D017027:Protein Tyrosine Phosphatases; C516774:Ptprf protein, rat; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2