Transcript Chen_Zheng_-_TrkA_signaling

Neurotrophin Signaling
(Trk Signaling Pathway)
Neurotrophins
• The neurotrophins are a family of proteins
that are essential for the development of
the vertebrate nervous system.
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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
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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.
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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
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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.