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.


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