Neurotrophins use the Erk5 pathway to mediate a retrograde survival response.
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.
Watson
F L
FL
Department of Neurobiology, Harvard Medical School, Dana 620, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Heerssen
H M
HM
Bhattacharyya
A
A
Klesse
L
L
Lin
M Z
MZ
Segal
R A
RA
D000818:Animals; D001369:Axons / Q000502:physiology; D002458:Cell Fractionation; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D017930:Genes, Reporter / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008856:Microscopy, Fluorescence; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism*; D009475:Neurons, Afferent / Q000502:physiology*; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009414:Nerve Growth Factors; D017475:Receptors, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one