Besides signalling through the tyrosine kinase receptors TRK A, B, and C, the mature neurotrophins NGF, BDNF, and NT3/4 signal through their common receptor p75NTR. NGF binding to p75NTR activates a number of downstream signalling events controlling survival, death, proliferation, and axonogenesis, according to the cellular context. p75NTR is devoid of enzymatic activity, and signals by recruiting other proteins to its own intracellular domain. p75 interacting proteins include NRIF, TRAF2, 4, and 6, NRAGE, necdin, SC1, NADE, RhoA, Rac, ARMS, RIP2, FAP and PLAIDD. Here we annotate only the proteins for which a clear involvement in p75NTR signalling was demonstrated. A peculiarity of p75NTR is the ability to bind the pro-neurotrophins proNGF and proBDNF. Proneurotrophins do not associate with TRK receptors, whereas they efficiently signal cell death by apoptosis through p75NTR. The biological action of neurotrophins is thus regulated by proteolytic cleavage, with proforms preferentially activating p75NTR, mediating apoptosis, and mature forms activating TRK receptors, to promote survival. Moreover, the two receptors are utilised to differentially modulate neuronal plasticity. For instance, proBDNF-p75NTR signalling facilitates LTD, long term depression, in the hippocampus (Woo NH, et al, 2005), while BDNF-TRKB signalling promotes LTP (long term potentiation). Many biological observations indicate a functional interaction between p75NTR and TRKA signaling pathways.
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Mukai J, Hachiya T, Shoji-Hoshino S, Kimura MT, Nadano D, Suvanto P, Hanaoka T, Li Y, Irie S, Greene LA, Sato TA.; ''NADE, a p75NTR-associated cell death executor, is involved in signal transduction mediated by the common neurotrophin receptor p75NTR.''; PubMedEurope PMCScholia
Cao Z, Henzel WJ, Gao X.; ''IRAK: a kinase associated with the interleukin-1 receptor.''; PubMedEurope PMCScholia
Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, Levesque M, Allaire N, Perrin S, Sands B, Crowell T, Cate RL, McCoy JM, Pepinsky RB.; ''LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex.''; PubMedEurope PMCScholia
Kinsella BT, Erdman RA, Maltese WA.; ''Carboxyl-terminal isoprenylation of ras-related GTP-binding proteins encoded by rac1, rac2, and ralA.''; PubMedEurope PMCScholia
Geetha T, Kenchappa RS, Wooten MW, Carter BD.; ''TRAF6-mediated ubiquitination regulates nuclear translocation of NRIF, the p75 receptor interactor.''; PubMedEurope PMCScholia
Kanning KC, Hudson M, Amieux PS, Wiley JC, Bothwell M, Schecterson LC.; ''Proteolytic processing of the p75 neurotrophin receptor and two homologs generates C-terminal fragments with signaling capability.''; PubMedEurope PMCScholia
Zampieri N, Xu CF, Neubert TA, Chao MV.; ''Cleavage of p75 neurotrophin receptor by alpha-secretase and gamma-secretase requires specific receptor domains.''; PubMedEurope PMCScholia
Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG.; ''Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.''; PubMedEurope PMCScholia
DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M.; ''A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB.''; PubMedEurope PMCScholia
Huang EJ, Reichardt LF.; ''Trk receptors: roles in neuronal signal transduction.''; PubMedEurope PMCScholia
Bhakar AL, Howell JL, Paul CE, Salehi AH, Becker EB, Said F, Bonni A, Barker PA.; ''Apoptosis induced by p75NTR overexpression requires Jun kinase-dependent phosphorylation of Bad.''; PubMedEurope PMCScholia
Gentry JJ, Rutkoski NJ, Burke TL, Carter BD.; ''A functional interaction between the p75 neurotrophin receptor interacting factors, TRAF6 and NRIF.''; PubMedEurope PMCScholia
Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV.; ''TRAF6 is a signal transducer for interleukin-1.''; PubMedEurope PMCScholia
Troy CM, Friedman JE, Friedman WJ.; ''Mechanisms of p75-mediated death of hippocampal neurons. Role of caspases.''; PubMedEurope PMCScholia
Andersson ER, Lendahl U.; ''Therapeutic modulation of Notch signalling--are we there yet?''; PubMedEurope PMCScholia
Shi Y.; ''Mechanisms of caspase activation and inhibition during apoptosis.''; PubMedEurope PMCScholia
Keep NH, Barnes M, Barsukov I, Badii R, Lian LY, Segal AW, Moody PC, Roberts GC.; ''A modulator of rho family G proteins, rhoGDI, binds these G proteins via an immunoglobulin-like domain and a flexible N-terminal arm.''; PubMedEurope PMCScholia
Friedman WJ, Greene LA.; ''Neurotrophin signaling via Trks and p75.''; PubMedEurope PMCScholia
Kaplan DR, Miller FD.; ''Neurotrophin signal transduction in the nervous system.''; PubMedEurope PMCScholia
Kimura MT, Irie S, Shoji-Hoshino S, Mukai J, Nadano D, Oshimura M, Sato TA.; ''14-3-3 is involved in p75 neurotrophin receptor-mediated signal transduction.''; PubMedEurope PMCScholia
Lessmann V, Gottmann K, Malcangio M.; ''Neurotrophin secretion: current facts and future prospects.''; PubMedEurope PMCScholia
He XL, Garcia KC.; ''Structure of nerve growth factor complexed with the shared neurotrophin receptor p75.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Wong ST, Henley JR, Kanning KC, Huang KH, Bothwell M, Poo MM.; ''A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein.''; PubMedEurope PMCScholia
Fournier AE, GrandPre T, Strittmatter SM.; ''Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Burns K, Martinon F, Esslinger C, Pahl H, Schneider P, Bodmer JL, Di Marco F, French L, Tschopp J.; ''MyD88, an adapter protein involved in interleukin-1 signaling.''; PubMedEurope PMCScholia
Yang K, Zhu J, Sun S, Tang Y, Zhang B, Diao L, Wang C.; ''The coiled-coil domain of TRAF6 is essential for its auto-ubiquitination.''; PubMedEurope PMCScholia
Becker EB, Howell J, Kodama Y, Barker PA, Bonni A.; ''Characterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis.''; PubMedEurope PMCScholia
Khursigara G, Bertin J, Yano H, Moffett H, DiStefano PS, Chao MV.; ''A prosurvival function for the p75 receptor death domain mediated via the caspase recruitment domain receptor-interacting protein 2.''; PubMedEurope PMCScholia
Salama-Cohen P, Arévalo MA, Meier J, Grantyn R, Rodríguez-Tébar A.; ''NGF controls dendrite development in hippocampal neurons by binding to p75NTR and modulating the cellular targets of Notch.''; PubMedEurope PMCScholia
Lallena MJ, Diaz-Meco MT, Bren G, Payá CV, Moscat J.; ''Activation of IkappaB kinase beta by protein kinase C isoforms.''; PubMedEurope PMCScholia
Kenchappa RS, Zampieri N, Chao MV, Barker PA, Teng HK, Hempstead BL, Carter BD.; ''Ligand-dependent cleavage of the P75 neurotrophin receptor is necessary for NRIF nuclear translocation and apoptosis in sympathetic neurons.''; PubMedEurope PMCScholia
Wehrman T, He X, Raab B, Dukipatti A, Blau H, Garcia KC.; ''Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors.''; PubMedEurope PMCScholia
Harrington AW, Kim JY, Yoon SO.; ''Activation of Rac GTPase by p75 is necessary for c-jun N-terminal kinase-mediated apoptosis.''; PubMedEurope PMCScholia
Navarro-Lérida I, Sánchez-Perales S, Calvo M, Rentero C, Zheng Y, Enrich C, Del Pozo MA.; ''A palmitoylation switch mechanism regulates Rac1 function and membrane organization.''; PubMedEurope PMCScholia
Lee R, Kermani P, Teng KK, Hempstead BL.; ''Regulation of cell survival by secreted proneurotrophins.''; PubMedEurope PMCScholia
Mukai J, Shoji S, Kimura MT, Okubo S, Sano H, Suvanto P, Li Y, Irie S, Sato TA.; ''Structure-function analysis of NADE: identification of regions that mediate nerve growth factor-induced apoptosis.''; PubMedEurope PMCScholia
Khursigara G, Orlinick JR, Chao MV.; ''Association of the p75 neurotrophin receptor with TRAF6.''; PubMedEurope PMCScholia
Bazenet CE, Mota MA, Rubin LL.; ''The small GTP-binding protein Cdc42 is required for nerve growth factor withdrawal-induced neuronal death.''; PubMedEurope PMCScholia
Jung KM, Tan S, Landman N, Petrova K, Murray S, Lewis R, Kim PK, Kim DS, Ryu SH, Chao MV, Kim TW.; ''Regulated intramembrane proteolysis of the p75 neurotrophin receptor modulates its association with the TrkA receptor.''; PubMedEurope PMCScholia
Chao MV.; ''Neurotrophins and their receptors: a convergence point for many signalling pathways.''; PubMedEurope PMCScholia
All neurotrophins (NTs) are generated as pre-pro-neurotrophin precursors. The signal peptide is cleaved off as NT is associated with the endoplasmic reticulum (ER). The resulting pro-NT can form a homodimer spontaneously which then transits to the Golgi apparatus and then onto the trans-Golgi network (TGN). Resident protein convertases (PCs) can cleave off the pro-sequence and mature NT is is targeted to constitutively released vesicles. The pro-NT form can also be released to the extracellular region.
Trk receptors signal from the plasma membrane and from intracellular membranes, particularly from early endosomes. Signalling from the plasma membrane is fast but transient; signalling from endosomes is slower but long lasting. Signalling from the plasma membrane is annotated here. TRK signalling leads to proliferation in some cell types and neuronal differentiation in others. Proliferation is the likely outcome of short term signalling, as observed following stimulation of EGFR (EGF receptor). Long term signalling via TRK receptors, instead, was clearly shown to be required for neuronal differentiation in response to neurotrophins.
The p75NTR extracellular domain interacts with NOGO receptor (NgR), a glycosyl phosphatidylinositol (GPI)-anchored protein present as a homomultimer at the cell surface. As NgR lacks an intracellular domain, it utilizes p75NTR as a co-receptor for intracellular signalling.
NGF stimulation results in recruitment of IKK-beta (Inhibitor of nuclear factor kappa-B kinase subunit beta) to the p75NTR receptor complex. IKK-beta recruitment involves p62 (Wooten et al. 2001, Cao et al. 1996a, et al. 1996b ).
Sortilin is a membrane protein that acts as co-receptor for p75NTR. Superior cervical ganglion (SCG) neurons, vascular smooth muscle (SM-11) cells, oligodendrocytes and CNS neurons (including basal forebrain neurons) (Volosin et al, 2006) express significant levels of sortilin and p75NTR. Schwann cells, instead, do not express sortilin. It is expressed during embryogenesis in areas where NGF and proNGF have well-characterized effects. It is important for proNGF signalling, but has little or no role on mature NGF initiated signalling. ProNGF preferentially binds to a p75NTR:sortilin complex, whereas mature NGF preferentially binds p75NTR alone. ProNGF binds to p75NTR with a dissociation constant (Kd) ~15-20 nM, and to sortilin with a Kd ~5 nM. In the presence of sortilin, proNGF binds to p75NTR with a Kd 0.2 nM. In contrast, mature NGF binds to p75NTR with a Kd of 1-2 nM, whereas it binds sortilin very weakly (Kd ~ 90 nM). Therefore, in the presence of sortilin, p75NTR binds more strongly to proNGF than to NGF, and proNGF signalling predominates. In the absence of sortilin, NGF binding is stronger than proNGF, and it is the mature NGF signalling that prevails. proNGF interacts with sortilin via its pro-domain, whereas the interaction with p75NTR is mediated by the mature domain.
PRDM4, usually named SC1, for Schwann Cell factor 1, is a zinc finger protein that functions as a repressor of transcription. It is present in many tissues, and abundant in brain. It interacts with the NGF:p75NTR complex to signal cell cycle arrest. It is unclear whether it already forms a complex with p75NTR before NGF binding to p75.
Neurotrophin (NGF or BDNF) binding to p75NTR increases RHO-GDI activity, possibly by loosening the grip of p75NTR on RHO-GDI, which prevents the dissociation of GDP thus allowing axonal growth to occur (Gehler et al. 2004).
Upon recruitment to p75NTR, Interleukin-1 receptor-associated kinase (IRAK) is rapidly phosphorylated and activated by an unknown mechanism and protein.
The NADE protein interacts with p75NTR to mediate cell death. The interaction is mediated by NADE NES (nuclear export signal), also responsible for self-association of NADE (Mukai J et al, 2002).
p75NTR exists in a multimeric form both in presence or absence of NGF. In the NGF:p75NTR complex, a single p75 molecule is asymmetrically bound to a NGF homodimer, along the homodimeric interface of NGF. This causes an allosteric conformational change, which disables the NGF symmetry-related second p75 binding site. Therefore, it is possible that NGF has to perturb or alter the preformed p75 dimer orientation in order to initiate intracellular signalling. NGF:p75NTR complexes are not so long living as the NGF:TRKA complexes. This is due, at least in part, to the fact that TRKA homodimers are internalized, and continue signalling in endosomes. Contrary to what is commonly believed, NGF bind to p75NTR and TRKA, individually, with a similar equilibrium binding constant (Kd ~ 1-2 nM). As a matter of fact, the association constant for NGF binding to p75NTR (k+1 = 8x10 to power of 6 M-1 s-1) is faster than for TRKA (k+1 = 8x10 to power of 5 M-1 s-1). On the other hand, the off rate of the NGF:TRKA complex ( k-1 = 7.2x10 to power of -5 s-1) is much slower than the NGF:p75NTR complex (k-1 = 1x10 to power of -3 s-1) . p75NTR and TRK receptors functionally interact, but the precise means by which this occurs has remained unresolved. This could result from a direct physical interaction or be explained by convergent signalling of these two receptors. Co-expression of both p75NTR and TRKA at the cell surface appears to result in the formation of a “high-affinity� binding site that has an accelerated rate of NGF association and a 30- to 100-fold higher affinity for NGF (Kd ~ 1-3 x 10 to power of -11 M) than either receptor alone. The high-affinity binding sites appear to constitute 10%–15% of the total NGF binding sites. The nature of such high affinity binding sites is still unclear. They could be due to a multimeric complex of p75:TRKA proteins. Alternatively, NGF might first rapidly bind to p75NTR and then be presented to TRKA in a conformation that lowers its TRKA association rate. Some authors even question the existence of these high affinity sites. Structural data on NGF complexes with p75NTR and TRKA extracellular domains suggest that formation of a ternary complex TRKA:NGF:p75NTR in a 1:2:1 ration is theoretically possible, although unlikely. However, biochemical data so far failed to show that this complex forms.
A group of myelin components named MDGIs (myelin-derived growth-inhibitors), bind to NgR and inhibit neurite outgrowth. Examples of such components are NOGO, OMGP (oligodendrocyte myelin glycoprotein) and MAG (myelin-associated glycoprotein). The amino-terminal region of NgR, covering eight leucine-rich repeats (LRR) and the LRR carboxy-terminal domain (LRRCT) is sufficient to interact with MAG, OMGP and NOGO. Their binding to NgR enhances the NgR-p75 interaction.These inhibitors bind to a receptor complex made up of the NOGO receptor, NgR, and p75NTR. Such complexes then activate RHOA, thereby inhibiting axonal growth.
The RIP2 (receptor-interacting protein-2) kinase is a mediator of NGF-dependent NF-kB activity. It contains a serine/threonine kinase domain and a caspase recruitment domain (CARD) at the C terminus. It binds to the death domain of p75NTR via its CARD domain in an NGF-dependent manner. RIP2 may also bind TRAF proteins, suggesting the existence of complexes of TRAF and RIP2 proteins with the p75 receptor. RIP2 is also able to interact with p62. It is highly expressed in Schwann cells.
PRDM4 is found in the cytoplasm. Following binding of NGF to p75NTR, after 1 hour of NGF treatment, PRDM4 is redistributed from the cytoplasm to the nucleus. The relocalisation of PRDM4 appears to be specific for NGF, as it is not affected by BDNF or NT3.
After recruiting IRAK, MYD88 leaves the receptor complex. The amount of MYD88 that associates with p75 peaks at 1 min of NGF treatment and declines thereafter.
The different molecules listed (NRAGE, NRIF, NADE, TRAF6) mediate, through unclear mechanisms, JNK activation by threonine and tyrosine phosphorylation. While active JNK does move to the nucleus and phosphorylates and activate transcription factors such as c-JUN and ATF2, these have not been implicated in p75-mediated cell death, but rather the direct activation of the cell death machinery by JNK has been implicated. p75 activates the intrinsic caspase pathway (involving mitochondrial release of cytochrome c, Apaf-1, and caspases-9) rather than the extrinsic (caspase-8) pathway activated by most other death receptors.
p75NTR directly complexes with RHO-GDI (RHO-GDP Dissociation Inhibitor). RHO-GDI inhibits the dissociation of GDP and the subsequent binding of GTP to RHOA, thus preventing formation of active RHOA. Once bound to p75NTR, RHOA-GDI is less active. p75NTR acts on RHOB in a similar mechanism.
Upon neurotrophin stimulation, p75NTR interacts with the ubiquitin 3 ligase TRAF6 (TNF receptor-associated factor 6). It is unclear whether TRAF6 binds to p75NTR directly, or whether it needs to be recruited through an adaptor protein such as MyD88.Recruitment of NRIF and TRAF6 to p75NTR is followed by an interaction between the two cytoplasmic proteins, It is possible that the NRIF:TRAF6 interaction promotes formation of a multimeric signalling complex. TRAF6 appears to promote NRIF release from p75NTR
NGF binding to p75NTR activates N-SMase (Neutral sphingomyelinase), and possibly A-SMase (acid sphingomyelinase), an enzyme that converts sphingomyelin to ceramide. The mode and mechanism of interaction between p75 and N-SMase have not been determined but is thought to involve the recruitment of Mg2+ to the active site of the enzyme.
NRIF is a ubiquitously expressed zinc finger protein of the Kruppel family that may transduce cell death signals during development and functions in association with TRAF6 to induce activation of JNK. NRIF-induced cell death through p75NTR requires p53 and NRIF nuclear translocation, which is modulated by TRAF6-mediated polyubiquitination of NRIF at lysine 63.
alpha-secretase (ADAM17) is a metalloprotese that has the ability to cleave the p75NTR extracellular domain, in proximity of the transmembrane region. The cleaved extracellular domain is shed from the cell membrane, whereas the rest of the protein, the C-terminal fragment, stays anchored to the membrane. The released extracellular domain represents a binding protein for many potential ligands, including neurotrophins, pro-neurotrophin precursors, beta-amyloid. Shedding of the p75NTR extracellular region can be both constituve and stimulated. The constitutive shedding is dependent on signalling via the p38 MAP kinase. Shedding can be stimulated by the phorbol ester PMA, acting through protein kinase C and ERK activation, and by a tyrosine phosphatase inhibitor. Activation of TRKA by NGF (or TRKB by BDNF) also induces release of the p75NTR extracellular domain. The alpha-secretase cleavage is required for the subsequent cleavage by gamma-secretase.
Within early endosomes, p75NTR C-Terminal Fragment undergoes processing by gamma-secretase, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such a minimal complex is sufficient for secretase activity, although other components may exist. The p75NTR cleavage by gamma-secretase gives rise to a 20-kD ICD (IntraCellular Domain) fragment, and to a small peptide, the significance of which is unknown but that is analogous to the A-beta peptides generated from amyloid precursor protein. p75NTR ICD may have cytoplasmic and nuclear signalling functions and it is unstable.
The atypical protein kinase C-iota isoform (aPKC-i) is recruited to the p75NTR receptor complex by p62 and becomes active. p62 recruits aPKC both via TRAF6 and RIP2.
The serine/threonine kinase IRAK (interleukin-1 receptor-associated kinase) is necessary for NF-kB activation. Under basal conditions, IRAK is not bound to the p75 receptor, and stays inactive in the cytoplasm. It associates with p75NTR following neurotrophin binding. MYD88 functions as an adapter, by recruiting IRAK to the p75 receptor. Upon stimulation with NGF, a MYD88: IRAK1 complex quickly forms that is recruited to p75NTR.
Once dissociated from IkB, NF-kB moves to the nucleus. Once in the nucleus, NF-kB binds DNA at promoters of target genes. This entails transcription of several genes including the two HLH transcriptional regulators HES1 and HES5. HES1 and HES5 transcription can also be activated via NOTCH signalling. Increased production of HES1 and HES5 reduces the number of primary dendrites and promotes dendrite elongation.
NGF binding to p75NTR induces recruitment of the atypical PKC interacting protein, p62, necessary for coupling IKKbeta with p75NTR. The kinase activity of IRAK1 is necessary for p62 (sequestosome-1) recruitment. IRAK1 interaction with TRAF6 precedes (1 min) its interaction with p62 (5 min). p62 has two protein interaction domains, named UBA and PB1. The UBA domain binds non-covalently to polyubiquitin chains. The PB1 domain has structural homology with the UbL (ubiquitin like) domain, and is able to interact with the 26S proteasome subunit Rpt1. Other protein interaction domains also exist within p62, suggesting that it may have a role in the formation of multimeric signalling complexes.p62 forms a complex with TRAF6, which involves the two domains PB1 at the p62 C-terminal end, and UBA, at the N-terminus.
Neurotrophin binding to p75NTR leads to recruitment of TRAF6. This protein is an E3 ubiquitin ligase, which, together with an E2 Ubiquitin conjugating enzyme, mediates the assembly of lysine 63-linked polyubiquitin chains and their attachment to a lysine of a substrate protein. Activation of IRAK1 promotes recruitment of TRAF6. TRAF6 is able to bind to p75NTR (juxtamembrane region, residues 113-128), IRAK1 (N-terminal residues 1-198 and C-terminal residues 523-618), and MYD88. It might be recruited through the MYD88:IRAK1 complex.
In the presence of a myelin component (GMDI), such as MAG, NOGO or OMG, bound to a complex of the NOGO receptor (RTN4R, also known as NgR) and NGFR (p75NTR), binding of NGFR to ARHGDIA, a RHO-GDI, associated with RHOA:GDP, is strengthened (Yamashita and Tohyama 2003). The presence of LINGO1 in the complex of NGFR, RTN4R and MAG, NOGO or OMG is needed for NGFR-dependent activation of RHOA (Mi et al. 2004).
The p75NTR ICD has the potential to bind many intracellular proteins, including TRAF6, SC1, NADE, NRAGE, and RHOA. It may bring these proteins to function in different cellular compartments. p75NTR ICD was shown to activate NF-kB via TRAF6.
Atypical PKC isoforms phosphorylate the beta subunit of the IKK complex (on Serines 177 and 181) thereby serving as an IKK kinase. TRAF6 and p62 as well appear to have a role in IKK activation. TRAF6 mediates the assembly of K63-linked poly-Ub chains required for IKK activation. The ubiquitin binding property of p62 may also be relevant in regulating IKK activation.
IkB is an inhibitory protein that sequesters NF-kB in the cytoplasm, by masking a nuclear localization signal, located just at the C-terminal end in each of the NF-kB subunits. A key event in NF-kB activation involves phosphorylation of IkB by an IkB kinase (IKK). NGF stimulates the activity of the IkB kinase IKK-beta, and, possibly, IKK-alpha as well. Once IkB is phosphorylated, the IkB:NF-kB complex dissociates.
Sphingomyielinase promotes the conversion of sphingomyelin to ceramide. Ceramide can activate JNK and other targets. The molecular details of the p75NTR-activated ceramide signalling cascade are only partially understood.
RHOA is activated by guanine nucleotide exchange factors (RhoGEFs), exchanging GDP for GTP. RHOA, activated following binding of MDGIs (RTN4, MAG or OMG) to the complex of NOGO receptor (RTN4R, also known as NgR) and NGFR (p75NTR), rigidifies the actin cytoskeleton, thereby inhibiting axonal elongation and causing growth cone collapse. MCF2 (Dbl) RHO GEF was used to demonstrate activation of RHOA downstream of NGFR and RTN4R-mediated sequestration of ARHGDIA, a RHO-GDI, but other RHO GEFs may also be involved in RHOA activation (Yamashita and Tohyama 2003).
NRIF polyubiquitination is necessary for nuclear translocation. The carboxyl terminus of NRIF mediates nuclear localization, whereas the amino terminus prevents it. Once in the nucleus, NRIF regulates gene expression, acting as a transcriptional repressor.
NRIF and TRAF6 appear to cooperate in JNK activation. TRAF6 is involved both in JNK activation and in NF-kB activation. Although the NRIF:TRAF6 interaction enhances by threefold the TRAF6-mediated activation of JNK, it only modestly affects TRAF6-mediated activation of NF-kB.
CHE1, also named AATF, is an Apoptosis Antagonizing Transcription Factor in cortical neurons. NRAGE binds to CHE1, inhibiting its nuclear localization by sequestering it in the cytoplasm, and, consequently, antagonizes its anti-apoptotic function.
NADE forms a complex with the 14-3-3epsilon isoform. The last one interacts with caspase 3 through its C terminal region. The NADE:4-3-3epsilon complex negatively regulates p75NTR-mediated apoptosis, probably by down regulating caspase activity.
Within the nucleus, PRDM4 is found in a complex with HDACs (histone deacetylases) 1, 2, and 3. It interacts with the regulatory regions of the cyclin E gene, strongly inhibiting transcription. It was also shown to weakly affect cyclib B transcription. PRDM4 is believed to interact with regulatory regions of other genes, which are unknown.
Once activated, JNK phosphorylates targets in cytoplasm, including BIM and BAD that promote the release of cytochrome c and activation of caspases 9, 6 and 3.
Neurotrophin or proneurotrophin signalling promotes p75NTR cleavage by gamma-secretase, allowing the release of p75 ICD and NRIF. This mechanism was shown in sympathetic neurons. Gamma-secretase can be activated in a number of ways, including signalling via p75NTR. The phorbol esther PMA induces p75 cleavage, followed by NRIF nuclear translocation, after 30 min. Neurotrophin binding to p75, instead, triggers the same events only after 12 h.
NRAGE (neurotrophin receptor-interacting MAGE homolog), a member of the MAGE family of proteins, is a cytoplasmic protein that mediates neurotrophin-induced cell death. NRAGE binding is stimulated following NGF (or proNGF) binding to p75NTR. Some studies indicate that NRAGE expression is limited to proliferative neural populations, whereas others indicate its presence in differentiated neurons in hippocampus. Another MAGE protein, Necdin, was reported to interact with p75NTR and affect cell death.
Once bound to the NGF:p75NTR complex, NADE contributes to cell death signalling by promoting activation of caspases 2 and 3. It is unclear whether JNK activation is involved. The apoptotic function of NADE was observed in oligodendrocytes (Mukai et al. 2002).
TRAF6 attaches a lysine 63-linked polyubiquitin chain to lysine 19 of NRIF. Mutation of NRIF lysine 19 prevents p75-mediated apoptosis. p75NTR cleavage by gamma-secretase is required for NRIF ubiquitination.
RAC activation was described as essential for p75NTR to induce JNK and apoptosis in cortical oligodendrocytes. The simultaneous activation of TRKA counteracts the apoptotic action of p75, by modulating the kinetics of p75-mediated RAC activation.
The activity of TRAF6 is regulated by autoubiquitination. This process, in turn, is regulated by p62. Cells devoid of p62 exhibit low basal TRAF6 polyubiquitination. When p62 is expressed, auto-ubiquitination of TRAF6 is enhanced. The details curated in this event represent the ubiquitination of TRAF6, even as ubiquitin is shown as 1 stoichiometrically.
The NgR1:p75NTR complex also interacts with LINGO1, a nervous system-specific transmembrane protein. LINGO1 is a potent axonal inhibitor of oligodendrocyte differentiation and myelination, and is regulated by NGF and its receptor TRKA .
In the presence of a myelin component (GMDI), such as MAG, NOGO or OMG, bound to a complex of the NOGO receptor (RTN4R, also known as NgR) and NGFR (p75NTR), binding of NGFR to ARHGDIA, a RHO-GDI, associated with RHOA:GDP, is strengthened (Yamashita and Tohyama 2003). The presence of LINGO1 in the complex of NGFR, RTN4R and MAG, NOGO or OMG is needed for NGFR-dependent activation of RHOA (Mi et al. 2004).
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metalloprotease (Zn
cofactor)Annotated Interactions
metalloprotease (Zn
cofactor)Contrary to what is commonly believed, NGF bind to p75NTR and TRKA, individually, with a similar equilibrium binding constant (Kd ~ 1-2 nM). As a matter of fact, the association constant for NGF binding to p75NTR (k+1 = 8x10 to power of 6 M-1 s-1) is faster than for TRKA (k+1 = 8x10 to power of 5 M-1 s-1). On the other hand, the off rate of the NGF:TRKA complex ( k-1 = 7.2x10 to power of -5 s-1) is much slower than the NGF:p75NTR complex (k-1 = 1x10 to power of -3 s-1) . p75NTR and TRK receptors functionally interact, but the precise means by which this occurs has remained unresolved. This could result from a direct physical interaction or be explained by convergent signalling of these two receptors. Co-expression of both p75NTR and TRKA at the cell surface appears to result in the formation of a “high-affinity� binding site that has an accelerated rate of NGF association and a 30- to 100-fold higher affinity for NGF (Kd ~ 1-3 x 10 to power of -11 M) than either receptor alone.
The high-affinity binding sites appear to constitute 10%–15% of the total NGF binding sites. The nature of such high affinity binding sites is still unclear. They could be due to a multimeric complex of p75:TRKA proteins. Alternatively, NGF might first rapidly bind to p75NTR and then be presented to TRKA in a conformation that lowers its TRKA association rate. Some authors even question the existence of these high affinity sites. Structural data on NGF complexes with p75NTR and TRKA extracellular domains suggest that formation of a ternary complex TRKA:NGF:p75NTR in a 1:2:1 ration is theoretically possible, although unlikely. However, biochemical data so far failed to show that this complex forms.
Gamma-secretase can be activated in a number of ways, including signalling via p75NTR. The phorbol esther PMA induces p75 cleavage, followed by NRIF nuclear translocation, after 30 min. Neurotrophin binding to p75, instead, triggers the same events only after 12 h.