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J. Cell Biol. 168 (7): 1077-1086

Copyright © 2005 by the Rockefeller University Press.

Article

TGF-ß1 activates two distinct type I receptors in neurons

implications for neuronal NF-{kappa}B signaling

Hans-Georg König1, Donat Kögel1, Abdelhaq Rami2, , and Jochen H.M. Prehn1,3

1 Experimental Neurosurgery, Center for Neurology and Neurosurgery
2 Department of Anatomy III, Johann Wolfgang Goethe-University Clinics, D-60590 Frankfurt, Germany
3 Department of Physiology, Neuroscience Research Centre, Royal College of Surgeons in Ireland, Dublin 2, Ireland

Correspondence to Jochen H.M. Prehn: prehn{at}rcsi.ie

Abstract: Transforming growth factor-ßs (TGF-ßs) are pleiotropic cytokines involved in development and maintenance of the nervous system. In several neural lesion paradigms, TGF-ß1 exerts potent neuroprotective effects. Neurons treated with TGF-ß1 activated the canonical TGF-ß 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-ß1 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-ß receptor in endothelial cells. Interestingly, we detected significant basal expression of ALK1 and its injury-induced up-regulation in neurons. Treatment with TGF-ß1 also induced a pronounced increase in downstream Smad1 phosphorylation. Overexpression of a constitutively active ALK1 mimicked the effect of TGF-ß1 on NF-{kappa}B activation and neuroprotection. Our data suggest that TGF-ß1 simultaneously activates two distinct receptor pathways in neurons and that the ALK1 pathway mediates TGF-ß1–induced NF-{kappa}B survival signaling.

Abbreviations used in this paper: ALK5, activin-like kinase 5; BMP, bone morphogenetic protein; DIV, days in vitro; GFAP, glial acidic fibrillary protein; MCAO, middle cerebral artery occlusion; NF-{kappa}B, nuclear factor-{kappa}B; NMDA, N-methyl-D-aspartate; NO, nitric oxide; PI, propidium iodide; SNOC, S-nitroso-cysteine; TßRI, TGF-ß receptor type I; TGF-ß, transforming growth factor-ß.

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