Signaling Through the Right Pathway

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Science's STKE  12 Apr 2005:
Vol. 2005, Issue 279, pp. tw134
DOI: 10.1126/stke.2792005tw134

Transforming growth factor-β (TGF-β), whose expression is upregulated during brain injury, has neuroprotective effects that are mediated through a pathway involving the transcription factor nuclear factor κB (NF-κB) and its targets Bcl-2 and Bcl-XL. These actions are in contrast to the actions of TGF-β in other cell types, such as B cells and hepatocytes, in which TGF-β inhibits NF-κB 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-β type I receptor, activin-like kinase receptor 5 (ALK5), primary cultures of rat hippocampal neurons expressed an alternative TGF-β type I receptor, ALK1. Moreover, exposure to N-methyl-D-aspartate, to elicit excitotoxic neuronal injury, enhanced ALK1 mRNA and protein expression. TGF-β1 elicited transient Smad2 phosphorylation in hippocampal neurons, consistent with activation of the ALK5 signaling pathway, and transcriptionally activated a Smad3 target gene reporter. TGF-β1 also elicited sustained Smad1 phosphorylation, consistent with activation of ALK1 signaling, and promoted ALK1-ALK5 coimmunoprecipitation. TGF-β1 stimulated expression of a NF-κB-dependent gene reporter, increased Bcl-XL protein abundance, and promoted binding of the p65 NF-κB subunit to DNA. Transfection of hippocampal neurons with constitutively active ALK1 stimulated expression of the NF-κB-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-β1 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-β1 activates two distinct type I receptors in neurons: Implications for neuronal NF-κB signaling. J. Cell Biol. 168, 1077-1086 (2005). [Abstract] [Full Text]

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