Pathway maps

Development_Neurotrophin family signaling
Development_Neurotrophin family signaling

Object List (links open in MetaCore):

Bax, NT-3, RAP-1A, C3G, GRB2, NRAGE, SHP-2, GAB2, ERK1/2, MEK2, c-Jun, Elk-1, NT-4/5, JNK1-3, MEK1, c-Raf-1, SH2B, TrkB, XIAP, Rac1, H-Ras, PtdIns(3,4,5)P3, TrkC, CrkL, Sortilin, MEKK1, p53, SOS, GAB1, NGF, NGFR, PtdIns(4,5)P2, 2.7.1.137, B-Raf, BDNF, TrkA, PI3K cat class IA, PI3K reg class IA, AKT, Shc

Description

Neurotrophin family signaling

Factors of the neurotrophin family ( NGF, BDNF and neurotrophins NT-3 and NT-4/5 ), promote neuronal survival or death. The best characterized receptors for these trophic factors are the tropomyosin-related tyrosine kinase receptors TrkA, TrkB, and TrkC, and a member of the tumor necrosis factor receptor family NGFR [1].

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

NGFR receptor binds NGF, BDNF, NT-3, and NT-4/5 [3], [2], [1]. High-affinity ligand-binding site is formed 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 increase their ligand affinity and selectivity. Whether the association of NGFR with TrkC influences neurotrophin affinity is not known [5], [6].

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

Neurotrophin binding to TrkA, TrkB and TrkC induces receptor dimerization and autophosphorylation, which leads to the recruitment of the complex signaling molecules, including Shc [9], [10] and SH2-B [11]. These signaling molecules then initiate activation of multiple signaling pathways.

Tyrosyl phosphorylation of Shc by Trk-receptors enables Shc to recruit Grb2-SOS complexes to the plasma membrane. [9] This results in the activation 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/ERK pathway in developing neurons [11].

In addition to H-RAS, RAP-1A is likely to play an important role in the sustained activation of Raf/MEK/ERK kinases. Formation of a long-lived complex containing C3G/CrkL/Shp2/Gab2 induces RAP-1A activation and continuing MEK1/2 and ERK1/2 activation with simultaneous inhibition of H-RAS [13].

Another Grb2 -associated protein Gab1 undergoes tyrosine phosphorylation in response to NGF stimulation. Phosphoinositide-3-kinase regulatory subunit ( PI3K reg (p85) ) binds Gab1, allowing it to serve as a substrate for receptor 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 vitro is mediated by ligand activation of NGFR [15], [16], [17]. Sortilin is a type I transmembrane protein expressed in a wide variety of tissues, but is most abundant in the central nervous system during development and in adults. NGFR and Sortilin form a receptor complex that binds NGF at the 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 in vitro and in vivo. NRAGE associates with the plasma membrane when NGF is bound to NGFR. NRAGE blocks the physical association of NGFR with TrkA, which facilitates cell cycle arrest and induces neuron apoptosis [19]. Intracellular signaling events associated with cell death are less well understood than the survival-promoting cascades initiated by Trk receptor activation. Upon activation, NGFR assembles a signaling complex that may include NRAGE and other proteins and adaptors. Rac1 [18] and H-Ras [1] are likely to be activated, which leads to MEKK1/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 neuronal survival and act independently, as each receptor can engage survival-promoting or death-promoting signaling pathways. There is evidence of crosstalk between signaling pathways engaged by NGFR and Trk receptors, although correct mechanisms are not well understood [1].

References:

  1. Kalb R
    The protean actions of neurotrophins and their receptors on the life and death of neurons. Trends in neurosciences 2005 Jan;28(1):5-11
  2. Sah DW, Ossipo MH, Porreca F
    Neurotrophic factors as novel therapeutics for neuropathic pain. Nature reviews. Drug discovery. 2003 Jun;2(6):460-72
  3. Kaplan DR, Miller FD
    Signal transduction by the neurotrophin receptors. Current opinion in cell biology 1997 Apr;9(2):213-21
  4. Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C, Kliemannel M, Schwarz E, Willnow TE, Hempstead BL, Petersen CM
    Sortilin is essential for proNGF-induced neuronal cell death. Nature 2004 Feb 26;427(6977):843-8
  5. Bibel M, Hoppe E, Barde YA
    Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR. The EMBO journal 1999 Feb 1;18(3):616-22
  6. Brennan C, Rivas-Plata K, Landis SC
    The p75 neurotrophin receptor influences NT-3 responsiveness of sympathetic neurons in vivo. Nature neuroscience 1999 Aug;2(8):699-705
  7. Yoon SO, Casaccia-Bonnefil P, Carter B, Chao MV
    Competitive signaling between TrkA and p75 nerve growth factor receptors determines cell survival. The Journal of neuroscience : the official journal of the Society for Neuroscience 1998 May 1;18(9):3273-81
  8. Majdan M, Miller FD
    Neuronal life and death decisions functional antagonism between the Trk and p75 neurotrophin receptors. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 1999 Jun;17(3):153-61
  9. Stephens RM, Loeb DM, Copeland TD, Pawson T, Greene LA, Kaplan DR
    Trk receptors use redundant signal transduction pathways involving SHC and PLC-gamma 1 to mediate NGF responses. Neuron 1994 Mar;12(3):691-705
  10. Postigo A, Calella AM, Fritzsch B, Knipper M, Katz D, Eilers A, Schimmang T, Lewin GR, Klein R, Minichiello L
    Distinct requirements for TrkB and TrkC signaling in target innervation by sensory neurons. Genes & development 2002 Mar 1;16(5):633-45
  11. Qian X, Riccio A, Zhang Y, Ginty DD
    Identification and characterization of novel substrates of Trk receptors in developing neurons. Neuron 1998 Nov;21(5):1017-29
  12. Marshall CJ
    Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 1995 Jan 27;80(2):179-85
  13. Wu C, Lai CF, Mobley WC
    Nerve growth factor activates persistent Rap1 signaling in endosomes. The Journal of neuroscience : the official journal of the Society for Neuroscience 2001 Aug 1;21(15):5406-16
  14. Onishi-Haraikawa Y, Funaki M, Gotoh N, Shibuya M, Inukai K, Katagiri H, Fukushima Y, Anai M, Ogihara T, Sakoda H, Ono H, Kikuchi M, Oka Y, Asano T
    Unique phosphorylation mechanism of Gab1 using PI 3-kinase as an adaptor protein. Biochemical and biophysical research communications 2001 Oct 26;288(2):476-82
  15. Casaccia-Bonnefil P, Carter BD, Dobrowsky RT, Chao MV
    Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 1996 Oct 24;383(6602):716-9
  16. Soilu-Hanninen M, Ekert P, Bucci T, Syroid D, Bartlett PF, Kilpatrick TJ
    Nerve growth factor signaling through p75 induces apoptosis in Schwann cells via a Bcl-2-independent pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 1999 Jun 15;19(12):4828-38
  17. Bamji SX, Majdan M, Pozniak CD, Belliveau DJ, Aloyz R, Kohn J, Causing CG, Miller FD
    The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death. The Journal of cell biology 1998 Feb 23;140(4):911-23
  18. Barker PA
    p75NTR is positively promiscuous: novel partners and new insights. Neuron 2004 May 27;42(4):529-33
  19. Salehi AH, Roux PP, Kubu CJ, Zeindler C, Bhakar A, Tannis LL, Verdi JM, Barker PA
    NRAGE, a novel MAGE protein, interacts with the p75 neurotrophin receptor and facilitates nerve growth factor-dependent apoptosis. Neuron 2000 Aug;27(2):279-88
  20. Aloyz RS, Bamji SX, Pozniak CD, Toma JG, Atwal J, Kaplan DR, Miller FD
    p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors. The Journal of cell biology 1998 Dec 14;143(6):1691-703