TGF-{beta}1 activates two distinct type I receptors in neurons: implications for neuronal NF-{kappa}B signaling.
Transforming growth factor-betas (TGF-betas) are pleiotropic cytokines involved in development and maintenance of the nervous system. In several neural lesion paradigms, TGF-beta1 exerts potent neuroprotective effects. Neurons treated with TGF-beta1 activated the canonical TGF-beta receptor I/activin-like kinase receptor 5 (ALK5) pathway. The transcription factor nuclear factor-kappaB (NF-kappaB) plays a fundamental role in neuroprotection. Treatment with TGF-beta1 enhanced NF-kappaB activity in gelshift and reporter gene analyses. However, ectopic expression of a constitutively active ALK5 failed to mimic these effects. ALK1 has been described as an alternative TGF-beta receptor in endothelial cells. Interestingly, we detected significant basal expression of ALK1 and its injury-induced up-regulation in neurons. Treatment with TGF-beta1 also induced a pronounced increase in downstream Smad1 phosphorylation. Overexpression of a constitutively active ALK1 mimicked the effect of TGF-beta1 on NF-kappaB activation and neuroprotection. Our data suggest that TGF-beta1 simultaneously activates two distinct receptor pathways in neurons and that the ALK1 pathway mediates TGF-beta1-induced NF-kappaB survival signaling.
König
Hans-Georg
HG
Experimental Neurosurgery, Center for Neurology and Neurosurgery, Johann Wolfgang Goethe-University Clinics, D-60590 Frankfurt, Germany.
Kögel
Donat
D
Rami
Abdelhaq
A
Prehn
Jochen H M
JH
D030201:Activin Receptors, Type I / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D016716:PC12 Cells; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D017208:Rats, Wistar; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051785:Smad Proteins; D051898:Smad1 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D018696:Neuroprotective Agents; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D051898:Smad1 Protein; C497400:Smad1 protein, rat; C508962:Tgfb1 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat