This work was submitted by Shivanand P. Lad in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Finch University of Health Sciences/The Chicago Medical School, 2002.
Activation of the mitogen-activated protein kinase pathway through p75NTR: A common mechanism for the neurotrophin family
Article first published online: 14 JUL 2003
Copyright © 2003 Wiley-Liss, Inc.
Journal of Neuroscience Research
Volume 73, Issue 5, pages 614–626, 1 September 2003
How to Cite
Lad, S. P. and Neet, K. E. (2003), Activation of the mitogen-activated protein kinase pathway through p75NTR: A common mechanism for the neurotrophin family. J. Neurosci. Res., 73: 614–626. doi: 10.1002/jnr.10695
- Issue published online: 14 AUG 2003
- Article first published online: 14 JUL 2003
- Manuscript Accepted: 5 MAY 2003
- Manuscript Revised: 2 MAY 2003
- Manuscript Received: 16 JAN 2003
- U.S. PHS
- NIH. Grant Numbers: NS24380, NS36700
- signal transduction;
Neurotrophins interact with two distinct classes of cell-surface receptors, the Trk receptor tyrosine kinase family and the common neurotrophin receptor p75NTR. For many years, the biological role of p75NTR remained obscure, being relegated to modulating Trk binding of neurotrophins. Recently, the importance of p75NTR as a signaling receptor in itself has become increasingly clear. The signals initiated by p75NTR are likely to be as complex as those for the Trk family and probably depend on the cell system in which such signaling is being studied. In this study, all members of the neurotrophin family were demonstrated to be capable of stimulating p75NTR-mediated activation of the mitogen-activated protein kinase (MAPK) family (ERK1,2). This activation is rapid and transient, peaking at 5–15 min, depending on the cell system. The classical MAPK cascade consists of the reaction series Ras-Raf-MEK-MAPK. The p75NTR-induced MAPK activation is MEK dependent but Raf independent. This result implies that neurotrophin activation of p75NTR results in some cascade (as yet unknown) that bypasses Raf and converges on MEK to result in activation of MAPK. This activated MAPK is then able to translocate to the nucleus. The effect of this MAPK activation on cell survival is dependent on cell type. These results support the concept that signaling from the p75NTR receptor is more diverse and extensive than previously believed. © 2003 Wiley-Liss, Inc.