TY - JOUR
T1 - Neurotrophins use the Erk5 pathway to mediate a retrograde survival response
AU - Watson, Fiona L.
AU - Heerssen, Heather M.
AU - Bhattacharyya, Anita
AU - Klesse, Laura
AU - Lin, Michael Z.
AU - Segal, Rosalind A.
N1 - Funding Information:
We thank S. Gutkind (NIH) for Erk5 and Mek5 plasmids. We thank A. Welcher (Amgen, California) for donating the BDNF, T. Roberts for Raf1 antibodies and P. Silver for GFP antibodies (Dana-Farber, Massachusetts), M. Greenberg (Children’s Hospital, Massachusetts) for P-CREB antibodies and E. Schaefer (QCB Biosource, Massachusetts) for P-Erk5 antibodies. We thank D. Moheban, M. Pazyra and D. Micomonaco for technical assistance. We thank M. Greenberg, J. Kornhauser, L. Parada and C. Stiles for comments. This work was supported by grants from NIH(NS35148) and the Klingenstein Foundation.
PY - 2001
Y1 - 2001
N2 - Growth factors synthesized and released by target tissues promote survival and differentiation of innervating neurons. This retrograde signal begins when growth factors bind receptors at nerve terminals. Activated receptors are then endocytosed and transported through the axon to the cell body. Here we show that the mitogen-activated protein kinase (MAPK) signaling pathways used by neurotrophins during retrograde signaling differ from those used following direct stimulation of the cell soma. During retrograde signaling, endocytosed neurotrophin receptors (Trks) activate the extracellular signal-related protein kinase 5 (Erk5) pathway, leading to nuclear translocation of Erk5, phosphorylation of CREB, and enhanced neuronal survival. In contrast, Erk1/2, which mediates nuclear responses following direct cell body stimulation, does not transmit a retrograde signal. Thus, the Erk5 pathway has a unique function in retrograde signaling. Differential activation of distinct MAPK pathways may enable an individual growth factor to relay information that specifies the location and the nature of stimulation.
AB - Growth factors synthesized and released by target tissues promote survival and differentiation of innervating neurons. This retrograde signal begins when growth factors bind receptors at nerve terminals. Activated receptors are then endocytosed and transported through the axon to the cell body. Here we show that the mitogen-activated protein kinase (MAPK) signaling pathways used by neurotrophins during retrograde signaling differ from those used following direct stimulation of the cell soma. During retrograde signaling, endocytosed neurotrophin receptors (Trks) activate the extracellular signal-related protein kinase 5 (Erk5) pathway, leading to nuclear translocation of Erk5, phosphorylation of CREB, and enhanced neuronal survival. In contrast, Erk1/2, which mediates nuclear responses following direct cell body stimulation, does not transmit a retrograde signal. Thus, the Erk5 pathway has a unique function in retrograde signaling. Differential activation of distinct MAPK pathways may enable an individual growth factor to relay information that specifies the location and the nature of stimulation.
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U2 - 10.1038/nn720
DO - 10.1038/nn720
M3 - Article
C2 - 11544482
AN - SCOPUS:0034804675
SN - 1097-6256
VL - 4
SP - 981
EP - 988
JO - Nature neuroscience
JF - Nature neuroscience
IS - 10
ER -