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Development Neurotrophin family signaling

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Development Neurotrophin family signaling

Neurotrophin family signaling

Factors of the neurotrophin family ( NGF, BDNF and neurotrophinsNT-3 and NT-4/5 ), promote neuronal survival or death. The bestcharacterized receptors for these trophic factors are the tropomyosin-related tyrosinekinase receptors TrkA, TrkB, and TrkC, and a member of the tumornecrosis factor receptor family NGFR [1].

TrkA is a high-affinity receptor for NGF; TrkB is ahigh-affinity receptor for BDNF and NT-4/5; TrkC is a high-affinityreceptor for NT-3 [2], [1].

NGFR receptor binds NGF, BDNF, NT-3, and NT-4/5[3], [2], [1]. High-affinity ligand-binding site isformed by a complex of NGFR and Sortilin, a co-receptor  for NGF [4].

The NGFR receptor physically binds to the Trk receptors , and complexes of NGFR with TrkA or TrkB increasetheir ligand affinity and selectivity. Whether the association of NGFR withTrkC influences neurotrophin affinity is not known [5], [6].

Many investigations indicate that the survival-promoting signals of neurotrophins aregenerated by activation of Trk receptors and that their death-promoting signalsare generated by activation of NGFR [7], [8].

Neurotrophin binding to TrkA, TrkB and TrkC induces receptordimerization and autophosphorylation, which leads to the recruitment of the complexsignaling molecules, including Shc [9], [10] andSH2-B [11]. These signaling molecules then initiate activation ofmultiple signaling pathways.

Tyrosyl phosphorylation of Shc by Trk-receptors enables Shc to recruitGrb2-SOS complexes to the plasma membrane. [9] This results in theactivation of RAS/RAF/MEK/ERK pathway and promotes cell proliferation [12], [1].

SH2-B also can bind Grb2 and mediate the same RAS/RAF/MEK/ERKpathway in developing neurons [11].

In addition to H-RAS, RAP-1A is likely to play an important role in thesustained activation of Raf/MEK/ERK kinases. Formation of a long-lived complexcontaining C3G/CrkL/Shp2/Gab2 induces RAP-1A activation and continuingMEK1/2 and ERK1/2 activation with simultaneous inhibition of H-RAS[13].

Another Grb2 -associated protein Gab1 undergoes tyrosine phosphorylationin response to NGF stimulation. Phosphoinositide-3-kinase regulatory subunit (PI3K reg (p85) ) binds Gab1, allowing it to serve as a substrate forreceptor tyrosine kinases [14].

Moreover, activation of PI3K mediates the RAC-alpha serine/threonine-protein kinase (AKT ) signaling, which plays the leading role in promoting neuron survival [1].

NGFR receptor, in contrast, has been repeatedly implicated in neuronal death.Apoptosis of neuronal cell lines, glia and a variety of primary neurons in vitrois mediated by ligand activation of NGFR [15], [16], [17]. Sortilin is a type I transmembrane protein expressed in a wide varietyof tissues, but is most abundant in the central nervous system during development and inadults. NGFR and Sortilin form a receptor complex that binds NGF atthe cell surface. Both receptors appear to be required to transduce apoptotic effects[18].

Some NGFR -associated proteins may play an important role in apoptosis induction.Neurotrophin receptor-interacting MAGE homolog ( NRAGE) binds NGFR invitro and in vivo. NRAGE associates with the plasma membrane whenNGF is bound to NGFR. NRAGE blocks the physical association ofNGFR with TrkA, which facilitates cell cycle arrest and induces neuronapoptosis [19]. Intracellular signaling events associated with cell deathare less well understood than the survival-promoting cascades initiated by Trk receptoractivation. Upon activation, NGFR assembles a signaling complex that may includeNRAGE and other proteins and adaptors. Rac1 [18] andH-Ras [1] are likely to be activated, which leads toMEKK1/JNK/P53/BAX signaling. This pathway appears to be crucial for NGF -NGFR induced apoptosis [20].

It seems unlikely, that neurotrophin receptors have such opposite effects on neuronalsurvival and act independently, as each receptor can engage survival-promoting ordeath-promoting signaling pathways. There is evidence of crosstalk between signalingpathways engaged by NGFR and Trk receptors, although correct mechanisms arenot well understood [1].