NEUROPROTECTION Signaling Through the Right Pathway

Transforming growth factor-ß (TGF-ß), whose expression is upregulated during brain injury, has neuroprotective effects that are mediated through a pathway involving the transcription factor nuclear factor B (NF-B) and its targets Bcl-2 and Bcl-X_L. These actions are in contrast to the actions of TGF-ß in other cell types, such as B cells and hepatocytes, in which TGF-ß inhibits NF-B activation and promotes cell death. König et al. used a combination of reverse transcription polymerase chain reaction, Western blot analysis, and immunofluorescence analysis to show that, in addition to the canonical TGF-ß type I receptor, activin-like kinase receptor 5 (ALK5), primary cultures of rat hippocampal neurons expressed an alternative TGF-ß type I receptor, ALK1. Moreover, exposure to N-methyl-D-aspartate, to elicit excitotoxic neuronal injury, enhanced ALK1 mRNA and protein expression. TGF-ß1 elicited transient Smad2 phosphorylation in hippocampal neurons, consistent with activation of the ALK5 signaling pathway, and transcriptionally activated a Smad3 target gene reporter. TGF-ß1 also elicited sustained Smad1 phosphorylation, consistent with activation of ALK1 signaling, and promoted ALK1-ALK5 coimmunoprecipitation. TGF-ß1 stimulated expression of a NF-B-dependent gene reporter, increased Bcl-X_L protein abundance, and promoted binding of the p65 NF-B subunit to DNA. Transfection of hippocampal neurons with constitutively active ALK1 stimulated expression of the NF-B-dependent gene reporter, promoted translocation into the nucleus of a p65-EGFP fusion protein, and protected cells from oxidative stress, whereas constitutively active ALK5 had none of these effects. Thus, the authors conclude that, although TGF-ß1 activates neuronal signaling pathways through both ALK1 and ALK5, only activation of the ALK1 pathway has neuroprotective effects.

H.-G. König, D. Kögel, A. Rami, J. H. M. Prehn, TGF-ß1 activates two distinct type I receptors in neurons: Implications for neuronal NF-B signaling. J. Cell Biol. 168, 1077-1086 (2005). [Abstract] [Full Text]