Activation of STAT5-dependent transcription by the neurotrophin receptor Trk.
Neurotrophins exert many of their biological effects via the Trk receptor tyrosine kinases and require the regulated activation of distinct transcriptional and post-translational cellular events. Here we provide evidence for a novel signaling cascade from activated Trks to the transcription factor STAT5. Utilizing the STAT5 responsive element derived from the p21(WAF1/Cip1) promoter to modulate luciferase expression, neurotrophin-dependent activation of Trk A, B, and C was found to induce STAT5-mediated transcriptional response. Structure-function analysis using Trk A mutants in heterologous cells further revealed that the kinase activity and an intact phospholipase C-gamma binding site are required for STAT5 activation. In most cytokine responsive cell systems, STAT5 function is modulated by JAK2-dependent tyrosine phosphorylation. However, reconstitution studies using a JAK2 deficient cell line indicate that neurotrophin-induced STAT5 activation does not require the cognate upstream kinase JAK2. In contrast, the Src kinase inhibitor PP1 significantly abolishes STAT5-dependent transcription in Trk A expressing 293T cells and in BDNF-treated primary cortical neurons. Together these results suggest that neurotrophins may regulate neuronal gene expression via STAT5 in a JAK2 independent manner.
Klein
Mathias
M
Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Hempstead
Barbara L
BL
Teng
Kenneth K
KK
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004268:DNA-Binding Proteins / Q000502:physiology*; D004347:Drug Interactions; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D053614:Janus Kinase 2; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008894:Milk Proteins; D009154:Mutation; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000145:classification / Q000502:physiology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D014162:Transfection / Q000379:methods
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D019208:Brain-Derived Neurotrophic Factor; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D020932:Nerve Growth Factor; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2