TGF-β1 activates two distinct type 1 receptors in neurons:: implications for neuronal NF-κB signaling

Transforming growth factor-beta s ( TGF-beta s) are pleiotropic cytokines involved in development and maintenance of the nervous system. In several neural lesion paradigms, TGF-beta 1 exerts potent neuroprotective effects. Neurons treated with TGF-beta 1 activated the canonical TGF-beta receptor I/activin-like kinase receptor 5 ( ALK5) pathway. The transcription factor nuclear factor-kappa B ( NF-kappa B) plays a fundamental role in neuroprotection. Treatment with TGF-beta 1 enhanced NF-kappa B 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-beta 1 also induced a pronounced increase in downstream Smad1 phosphorylation. Overexpression of a constitutively active ALK1 mimicked the effect of TGF-beta 1 on NF-kappa B activation and neuroprotection. Our data suggest that TGF-beta 1 simultaneously activates two distinct receptor pathways in neurons and that the ALK1 pathway mediates TGF-beta 1-induced NF-kappa B survival signaling.