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Neurotrophin Signaling (Trk Signaling Pathway) Neurotrophins • The neurotrophins are a family of proteins that are essential for the development of the vertebrate nervous system. NGF – Nerve growth factor BDNF – Brain-derived neurotrophic factor NT3 – Neurotrophin 3 NT4 – Neurotrophin 4 Function • A class of growth factors, secreted proteins that are capable of signaling particular cells to survive, differentiate, or grow. • Growth factors such as neurotrophins that promote the survival of neurons are known as neurotrophic factors. • Secreted by target tissue and act by preventing the associated neuron from initiating programmed cell death(PCD) - thus allowing the neurons to survive. • Neurotrophins also induce differentiation of progenitor cells, to form neurons. PDB 1SG1 Chao MV. 2004 Biogenesis • The neurotrophins are initially synthesized as precursors or pro-neurotrophins, which are cleaved to produce the mature proteins. (ProNGF -> NGF) • Pro-neurotrophins are cleaved intracellularly by FURIN or pro-convertases at a highly conserved dibasic amino-acid cleavage site to release carboxy-terminal mature proteins. • The mature proteins: – about 12 kDa in size, form stable, non-covalent dimers, – normally expressed at very low levels during development. – The amino-terminal half (or pro-domain) of the proneurotrophin is believed to be important for the proper folding and intracellular sorting of neurotrophins. Neurotrophin Receptors • Each neurotrophin can signal through two different types of cell surface receptor – Trk receptor tyrosine kinases – p75 neurotrophin receptor (p75NTR). • Transmembrane receptor, also known as TNFRSF16. • a member of the tumour necrosis factor receptor (TNFR) deathreceptor family. Models of Trk and p75 receptor Chao MV. 2004 • Different neurotrophins show binding specificity for particular receptors. • These interactions have generally been considered to be of high affinity. • However, in reality, the binding of NGF to TrkA, and of BDNF to TrkB is of low affinity, but it can be regulated by receptor dimerization, structural modifications or association with the p75 receptor. • The p75 receptor can bind to each neurotrophin, and also acts as a co-receptor for Trk receptors. • Expression of p75 can increase the affinity of TrkA for NGF and can enhance its specificity for cognate neurotrophins. • As a result, increased ligand selectivity can be conferred on the Trk receptors by the p75 receptor. Chao MV. 2004 Crystal Structure of the Receptor Complex between TrkA and p75 Secondary structure Symmetry Models of Trk and p75 receptor • • Trk receptors contain extracellular immunoglobulin G (IgG) domains for ligand binding and a catalytic tyrosine kinase sequence in the intracellular domain. The extracellular portion of p75 contains four cysteine-rich repeats, and the intracellular part contains a death domain. Neurotrophin binding to the p75 receptor mediates survival, cell migration and myelination through several signalling pathways. Chao MV. 2004 • The ratio of receptors is important in dictating the numbers of surviving cells. • Interactions between p75 and Trk receptors provide greater discrimination between different neurotrophins. • 1 Nykjaer et al. 2004 & 2008 • The interaction of p75NTR with TrkA enhances the responsiveness of TrkA to nerve growth factor (NGF) to promote survival and growth. • b, In contrast, when bound to unprocessed NGF (proNGF), a complex of p75NTR and sortilin induces cell death. Nykjaer et al. 2004 & 2008 • How could NGF promote survival through TrkA and death through p75NTR — sometimes in the same cell type? Nykjaer et al. 2004 & 2008 • • The function of p75NTR depends on the cellular context; activation of p75NTR promotes death in numerous cells, including injured neurons, but promotes migration, growth and survival in other cells. In the next development (2008), NGF was found to exist in both unprocessed ('pro') and mature forms. On some cells the mature NGF preferentially activates TrkA, whereas proNGF only activates p75NTR. Importantly, proNGF is much more efficient than NGF at inducing the death of responsive cells, leading to speculation that the nature of the NGF itself is a key determinant of the ultimate outcome of p75NTR activation. • Sometimes CREB phosphorylation requires activation and endocytosis of TrKA located at the axon terminals. • distal axons are sometimes more than one meter away from the cell soma; • To transmit the signal over a long distance, neurotrophins and activated Trks are transported together in endocytic vesicles to the cell soma. TRAF6 (TNF receptor associated factor) Ub (Ubiquitin) – Proteasome pathway of protein degradation Thangiah Geetha, Jianxiong Jiang, Marie W. Wooten. 2005 • Internalization and signaling is regulated by polyubiquitination of Lys485 of TrkA. Ubiquitin properties (human) Lys-11 or Lys-48: marking the substrate for ubiquitin–proteasomemediated degradation. Lys-63: Marking substrates for endocytosis or a role in intracellular signaling such as NF-κB activation. Lys-6, Lys-27, Lys-29 and Lys-33: have not been elucidated.