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
-
Sah DW, Ossipo MH, Porreca F
Neurotrophic
factors as novel therapeutics for neuropathic pain. Nature
reviews. Drug discovery 2003 Jun;2(6):460-72
-
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
-
Dechant G, Barde YA
Signalling
through the neurotrophin receptor p75NTR. Current opinion in
neurobiology 1997 Jun;7(3):413-8
-
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
-
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
-
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
-
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
-
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
-
Takeuchi O, Akira S
MyD88
as a bottle neck in Toll/IL-1 signaling. Current topics in
microbiology and immunology 2002;270:155-67
-
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
-
Foo SY, Nolan GP
NF-kappaB
to the rescue: RELs, apoptosis and cellular transformation. Trends
in genetics : TIG 1999 Jun;15(6):229-35
-
Datta SR, Brunet A, Greenberg ME
Cellular
survival: a play in three Akts. Genes & development 1999 Nov
15;13(22):2905-27
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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