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

Transforming growth factor-βs (TGF-βs) are pleiotropic cytokines involved in development and maintenance of the nervous system. In several neural lesion paradigms, TGF-β1 exerts potent neuroprotective effects. Neurons treated with TGF-β1 activated the canonical TGF-β receptor I/activin-like kinase receptor 5 (ALK5) pathway. The transcription factor nuclear factor-κB (NF-κB) plays a fundamental role in neuroprotection. Treatment with TGF-β1 enhanced NF-κB 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-β receptor in endothelial cells. Interestingly, we detected significant basal expression of ALK1 and its injury-induced up-regulation in neurons. Treatment with TGF-β1 also induced a pronounced increase in downstream Smad1 phosphorylation. Overexpression of a constitutively active ALK1 mimicked the effect of TGF-β1 on NF-κB activation and neuroprotection. Our data suggest that TGF-β1 simultaneously activates two distinct receptor pathways in neurons and that the ALK1 pathway mediates TGF-β1–induced NF-κB survival signaling.