Apoptosis and survival - NGF activation of NF-kB

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NGF activation of NF-kB

Nerve growth factor (NGF) mediates both neuron survival and differentiation via selective binding to the receptor tyrosinekinase TrkA [1] and the tumor necrosis factor receptor NGFR, which enhances its binding to the TrkA [2].Unlike the TrkA receptor, the cytoplasmic domain of NGFR lacks intrinsic tyrosine kinase activity [3].

It is usually considered that TrkA inhibits apoptosis, whereas NGFR promotes apoptosis in certain neuronal cell populations [2], [4], [5].

In contrast to this view, NGFR was found to have a dual function for NGF signaling properties. NGFR activation by NGF was demonstrated to provide both survival and differentiation of some cell lines via nuclear factor NF-kB activation [6], [7], [8]. The antiapoptotic effects of NF-kB make this transcription factor a potentially important neuroprotective agent in vivo.

NF-kB stimulation was shown to occur via both NGFR and TrkA activation [6], [8]. Although different membrane proximal-signaling intermediates are involved, these distinct pathways converge and commonly activate the IKK (I kappaB kinase) complex.

Stimulation of NGFR by NGF leads to the formation of the complexof myeloid differentiation factor 88 MyD88 (which is activated by Toll-like receptors [9])with IRAK (interleukin-1 receptor-associated kinase 1) and its recruitment to the NGFR receptor. After recruiting IRAK, MyD88 leaves the receptor complex. At the time of recruitment to the NGFR receptor, IRAK is rapidly phosphorylated and activated by an unknown mechanism. Activation of IRAK leads to recruitment of TRAF6 (TNF receptor-associated factor 6) followed by binding of ubiquitin-binding protein p62 (p62). Then p62 binds the atypical protein kinase C isoforms (PKC-zeta and PKC-lambda/iota) and recruits the IKK complex. PKC-zeta and PKC-lambda/iota can phosphorylate thebeta-subunit of the IKK complex, thereby serving as an IKK kinase [8], [10].

IKK proteins phosphorylate I-kB (NF-kB inhibitor), by which NF-kB is sequestered in the cytoplasm [11]. Phosphorylation of I-kB leads to its ubiquitination and degradation within the 26S proteasome. Degradation of I-kB liberates NF-kB, allowing its rapid translocation into the nucleus, where it triggers transcription of various target antiapoptotic genes [12], such as Bcl-x and Bcl-2 [13], [14], [15], [16], [17].

There are differences in the requirement of TrkA, depending upon the state of differentiation, the cell type, and the NGFR co-expression. Because p62 can bind TrkA [18], it is possible that TrkA competes for the p62 scaffold required by the NGFR receptor for NF-kB activation, thus explaining its ability to diminish cell response. Alternatively, the region of p62 where TrkA binds, may play a regulatory role in NF-kB activation [8].

Another signaling cascade leading to the activation of NF-kB is likely to be PI3K/AKT pathway. Some investigators suggest TrkA to be involved in this process [6], [8], whereas other authors consider NGFR to be the mainreceptor mediating PI3K/AKT/NF-kB signaling [2], [7].

Both receptors (TrkA andNGFR) activated by NGF canrecruit the complex of adapter molecules Shc/Grb2 [19], [20], which may activate phosphoinositide-3-kinase PI3K through the Grb2-associated protein Gab1 or SOS (guanine nucleotide exchange factor)/H-RAS (p21 protein). Activation of PI3K mediates AKT kinase activation, which can play a role in promoting of NF-kB signaling [12].

Complex NGF signaling via the functionally distinct TrkA and NGFR determines the biological outcome; however, the NF-kB signal generated by both receptors exerts neuroprotective effects.



References

  1. Sah DW, Ossipo MH, Porreca F
    Neurotrophic factors as novel therapeutics for neuropathic pain. Nature reviews. Drug discovery 2003 Jun;2(6):460-72
  2. 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
  3. Dechant G, Barde YA
    Signalling through the neurotrophin receptor p75NTR. Current opinion in neurobiology 1997 Jun;7(3):413-8
  4. 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
  5. 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
  6. Foehr ED, Lin X, O'Mahony A, Geleziunas R, Bradshaw RA, Greene WC
    NF-kappa B signaling promotes both cell survival and neurite process formation in nerve growth factor-stimulated PC12 cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 2000 Oct 15;20(20):7556-63
  7. Roux PP, Bhakar AL, Kennedy TE, Barker PA
    The p75 neurotrophin receptor activates Akt (protein kinase B) through a phosphatidylinositol 3-kinase-dependent pathway. The Journal of biological chemistry 2001 Jun 22;276(25):23097-104
  8. Mamidipudi V, Li X, Wooten MW
    Identification of interleukin 1 receptor-associated kinase as a conserved component in the p75-neurotrophin receptor activation of nuclear factor-kappa B. The Journal of biological chemistry 2002 Aug 2;277(31):28010-8
  9. Takeuchi O, Akira S
    MyD88 as a bottle neck in Toll/IL-1 signaling. Current topics in microbiology and immunology 2002;270:155-67
  10. Zhou H, Lapointe BM, Clark SR, Zbytnuik L, Kubes P
    A requirement for microglial TLR4 in leukocyte recruitment into brain in response to lipopolysaccharide. Journal of immunology (Baltimore, Md. : 1950) 2006 Dec 1;177(11):8103-10
  11. Foo SY, Nolan GP
    NF-kappaB to the rescue: RELs, apoptosis and cellular transformation. Trends in genetics : TIG 1999 Jun;15(6):229-35
  12. Datta SR, Brunet A, Greenberg ME
    Cellular survival: a play in three Akts. Genes & development 1999 Nov 15;13(22):2905-27
  13. Qiu J, Grafe MR, Schmura SM, Glasgow JN, Kent TA, Rassin DK, Perez-Polo JR
    Differential NF-kappa B regulation of bcl-x gene expression in hippocampus and basal forebrain in response to hypoxia. Journal of neuroscience research 2001 May 1;64(3):223-34
  14. Glasgow JN, Qiu J, Rassin D, Grafe M, Wood T, Perez-Pol JR
    Transcriptional regulation of the BCL-X gene by NF-kappaB is an element of hypoxic responses in the rat brain. Neurochemical research 2001 Jun;26(6):647-59
  15. Bui NT, König HG, Culmsee C, Bauerbach E, Poppe M, Krieglstein J, Prehn JH
    p75 neurotrophin receptor is required for constitutive and NGF-induced survival signalling in PC12 cells and rat hippocampal neurones. Journal of neurochemistry 2002 May;81(3):594-605
  16. Culmsee C, Gerling N, Lehmann M, Nikolova-Karakashian M, Prehn JH, Mattson MP, Krieglstein J
    Nerve growth factor survival signaling in cultured hippocampal neurons is mediated through TrkA and requires the common neurotrophin receptor P75. Neuroscience 2002;115(4):1089-108
  17. Azoitei N, Wirth T, Baumann B
    Activation of the IkappaB kinase complex is sufficient for neuronal differentiation of PC12 cells. Journal of neurochemistry 2005 Jun;93(6):1487-501
  18. Wooten MW, Seibenhener ML, Mamidipudi V, Diaz-Meco MT, Barker PA, Moscat J
    The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor. The Journal of biological chemistry 2001 Mar 16;276(11):7709-12
  19. 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
  20. 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

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