Neurotrophin pathway / signaling

Neurotrophin signaling / pathway mediated by Trk receptors

Neurotrophin pathway / signaling activated by neurotrophins through binding to Trk family leads to a series of neuronal functions. Such as axonal growth, cell survival, differentiation, dendritic arborization, synapse formation, plasticity and axonal guidance. When neurotrophins bind to Trk receptor, Trk receptor experiences dimerization , phosphorylation, recruitment of different adaptors and enzymes, and activation of several signaling pathways. Other receptor tyrosine kinases take part in these Neurotrophin pathways / signaling. In Trk receptors, Y490 and Y785 in the human TrkA receptor and their corresponding tyrosines in TrkB and TrkC, are phosphorylated in response to neurotrophins and serve as the major docking sites for binding of adaptor proteins and enzymes. Downstream protein Shc is recruited by Y490 while phospholipase C-γ (PLC-γ) is recruited by Y785. The phosphorylated tyrosines located at the kinase domain, Y670, Y674, and Y675, can also engage adaptor proteins, including SH2B, APS, and Grb2. There are so many Neurotrophin pathway / signaling activated by Trk receptors in response to neurotrophins. Among them, the Shc-Ras-MAPK, Rap-MAPK, PI3K-Akt, and PLCγ-protein kinase C (PKC) pathways are the most studied (Fig. 1).

Neurotrophin signaling / pathway mediated by the p75NTR receptor

Neurotrophin pathway / signaling that activated by p75NTR results in diverse, complex and even contradictory functions. p75NTR has been implicated in both promoting survival and inducing apoptosis, enhancing neurite outgrowth and facilitating growth-cone collapse, and mediating differentiation and enhancing proliferation. Moreover, p75NTR may also play a role in myelination. Before generating mature neurotrophins, precursor neurotrophin proteins are synthesized. Recently, a research of pro-NGF as a ligand for p75NTR provides several answers to many long-standing questions. Compared to mature NGF, pro-NGF binds with higher affinity to p75NTR in A875 cells and triggers cell death at much lower concentrations. pro- NGF causes oligodendrocyte cell death through p75NTR in a spinal injury model and apoptosis of adult corticospinal neurons in a brain injury model. Additionally, the pro-region of the NGF precursor protein contains two novel bioactive peptides that may induce the rapid phosphorylation of the Trk receptor protein. Another important advance in the field of p75NTR signaling has been the discovery that sortilin, a member of the Vps10p-domain receptor family, binds to pro-NGF and works as a co-receptor with p75NTR to mediate apoptosis. The apoptotic effect mediated by p75NTR and sortilin is not exclusive to pro-NGF, as pro-BDNF has similar consequences in cells expressing both receptors. Thus, the presence or absence of sortilin at the cell surface will affect the way p75NTR-expressing cells will ultimately respond to pro-neurotrophin molecules. The Neurotrophin pathway / signaling that activated by p75NTR can be seen in figure 2.

Neurotrophin cross-talk with other signaling pathways

Receptor tyrosine kinases are usually activated upon binding of their cognate ligands, but they can also be transactivated in response to G protein-coupled receptor (GPCR) signaling. This type of activation has been previously described for the receptors for epidermal growth factor, platelet-derived growth factor, and insulin-like growth factor 1. Transactivation of TrkA receptors in PC12 cells and TrkB in hippocampal neurons has been observed after treatment with adenosine or PACAP neuromodulators, both of which act through GPCRs. Interestingly, in contrast to other receptor transactivation events, Trk receptor transactivation by adenosine or PACAP requires a longer time course. The increase in Trk activity can be inhibited by the use of K252a, a Trk receptor inhibitor, and PP1, a Src family-specific inhibitor. Transactivated Trk receptors lead to activation of the PI3K-Akt pathway, which results in increased cell survival after NGF or BDNF withdrawal in PC12 cells and hippocampal neurons, respectively. Surprisingly, most of the transactivated Trk receptors are found in intracellular locations, particularly associated with Golgi membranes. The effects of adenosine- and PACAP-dependent activation of Trk receptors raise the possibility that small molecules may be used to elicit neurotrophic effects for the treatment of neurodegenerative diseases.

Trk receptor mediated signaling pathway

Figure 1: Trk receptor mediated Neurotrophin signaling / pathway (photocredit: J. C. Arévalo* and S. H. Wu, 2006)

p75 receptor mediated signaling pathway

Figure 2: p75 receptor mediated Neurotrophin signaling / pathway (photocredit: J. C. Arévalo* and S. H. Wu, 2006)

23000+ Products
Proteins
Antibodies
ELISA Kits
cDNA Clones
Recombinant Cytokines
Neurotrophin & Receptor
NGF Related Information +
- NGF molecular weight
- NGF structure
- NGF function
- NGF signaling / pathway
- NGF receptor
-- NGF TrkA
-- NGFR / p75
BDNF Related Information +
- BDNF Gene
- BDNF function
- BDNF signaling / pathway
- BDNF receptor
-- BDNF TrkB
-- NGFR / p75
• Other Neurotrophin & Receptor+
- Neurotrophin-3 / NT-3
- TrkA / NTRK1
- TrkB / NTRK2
- TrkC / NTRK3
- NGFR (p75 / p75 NTR)
GDNF Family
GDNF (Glial cell line-derived neurotrophin)
GFRA1
GFRA2
GFRA3
NCAM / CD56
Other Neurotrophic Factors & Receptors
MANF / ARMET
Gp130 / IL6ST
LIFR / CD118
CNTF / Ciliary Neurotrophic Factor
CDNF / ARMETL1
NRG1 / Neuregulin 1
NRG4 / Neuregulin 4
Pleiotrophin / PTN
CNTFR
Growth Factor Family
Angiopoietin/Tie
Ephrin & Eph Receptor
EGF & Receptor
FGF & Receptor
Insulin-like Growth Factor System
Neurotrophin & Receptor
PDGF & Receptor
Receptor Tyrosine Kinase
R-Spondin Protein
VEGF & Receptor
Wnt Ligands & Receptors