Preferred Label : Neuronal Survival Pathway;
NCIt related terms : Role of Erk5 in Neuronal Survival;
Alternative definition : BIOCARTA: Axons extend significant distances to innervate target tissues. At the site
of innervation, target tissues release neurotrophins including NGF, BDNF and neurotrophin-3
that stimulate the survival of the associated neuron. Local signaling by activated
Trk receptors at the synaptic terminus mediates some presynaptic neuronal responses
to neurotrophins. Map kinase pathways activated by Trk receptor activate Erk1 and
Erk2 at the terminus stimulating axonal growth, and PI3K activates AKT in the terminus
as well. Activation of these kinases does not propagate a signal to the cell body
though and does not induce a transcriptional response. This local signaling at the
terminus or local signaling at the cell body appears distinct from the signaling pathway
that transduces the survival signal from the target tissue. Retrograde axonal transport
plays an essential role in neuronal survival induced by neurotrophins released at
the target tissue. Failure of retrograde neurotrophin signaling may play a role in
neurodegenerative conditions. The neuronal survival signal is initiated by binding
of neurotrophins to Trk receptors in the presynaptic membrane, and then travels back
along the axon to the neuronal cell body. To transmit the signal back along the axon,
activated Trk receptors are internalized through receptor-mediated endocytosis and
receptor containing vesicles then rapidly travel back to the cell body along axonal
microtubules. Several reports indicate that neurotrophins remain receptor-bound during
the retrograde axonal transport to the cell body, but recently it was reported that
retrograde transport of NGF was not required to induce neuronal survival. Once in
the cell body, Trk receptors activate multiple pathways. A key pathway activated by
Trk after retrograde transport involves Erk5, also called BMK1. Trk activates Mek5,
which activates Erk5, inducing phosphorylation of the CREB and Mef2 transcription
factors. Erk5 does not directly phosphorylate CREB, but translocates into the nucleus
and phosphorylates the kinase Rsk, which phosphorylates CREB in turn. Both CREB and
Mef2 induce a transcriptional program that contributes to neuronal survival. Local
activation of Erk5 on the cell body does not appear to induce the same signaling system
or neuronal survival, indicating that the retrograde transport is an essential part
of the survival signaling system. Also, activation of Erk1 and Erk2 in the cell body
can induce CREB activation and neuronal survival, but these kinases are not activated
by neurotrophins applied to the axonal terminus. Another pathway activated by retrograde
neurotrophin signaling though Erk5 is PI3 Kinase. (This definition may be outdated
- see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_erk5Pathway;
Origin ID : C39071;
UMLS CUI : C1518295;
Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element
