Molecular investigations on the high-affinity nerve growth factor receptor

Meakin, Susan O.; Shooter, Eric M.

doi:10.1016/0896-6273(91)90130-r

Cited by 150 publications

(67 citation statements)

References 63 publications

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“…Antibodies to the fNGFR, however, immunoprecipitate '25I-NGF cross-linked fNGFR but not the sNGFR complex (15). Furthermore, the sNGFR, but not the fNGFR, can be immunoprecipitated with antibodies to phosphotyrosine (15). These results suggested a molecular independence of the NGFR complexes and suggested that the sNGFR was possibly a tyrosine kinase receptor.…”

mentioning

confidence: 53%

“…cDNAs encoding the fNGFR have been cloned from several species (12,13) and evidence has been presented suggesting that the sNGFR contains the fNGFR and an additional protein (8,14). Antibodies to the fNGFR, however, immunoprecipitate '25I-NGF cross-linked fNGFR but not the sNGFR complex (15). Furthermore, the sNGFR, but not the fNGFR, can be immunoprecipitated with antibodies to phosphotyrosine (15).…”

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confidence: 94%

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The rat trk protooncogene product exhibits properties characteristic of the slow nerve growth factor receptor.

Meakin

Suter

Drinkwater

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

177

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Two distinct nerve growth factor receptor (NGFR) complexes are present on NGF-responsive cell types; these correspond to 100 kDa and 158 kDa for the fast (fNGFR) and the slow (sNGFR) NGFRs, respectively. Previous studies indicate that each complex is derived from a separate gene product and that the sNGFR contains tyrosine kinase activity.The cDNA encoding the fNGFR has previously been cloned. In this report, a rat trk protooncogene cDNA has been isolated from PC12 cells and Trk has been shown to bind NGF, generating a complex of 158 kDa. Characterization of NGFTrk interactions indicates that Trk and NGF dissociate more slowly than do NGF and the fNGFR. Moreover, NGF-bound Trk is not destroyed by trypsin digestion whereas the NGFfNGFR complex is sensitive to trypsin digestion. These observations suggest that the trk protooncogene product, expressed in the absence of the fNGFR, binds NGF with properties characteristic of the sNGFR, which was identified as the high-affinity NGFR on primary neurons and PC12 cells.Previous work has established that two types of nerve growth factor receptors (NGFRs; type I and type II) can be distinguished on neurons of the peripheral nervous system (1, 2) and on NGF-responsive cell lines such as the rat pheochromocytoma cell line PC12 (3). More recent evidence indicates that both NGFR populations are also present in the central nervous system (4). Type I NGFRs are thought to mediate the biological responses of neuronal survival and neurite outgrowth (5, 6), whereas the role(s) of type II NGFRs is less clear.The most distinguishing feature of the NGFR subtypes is the difference in their rates of NGF dissociation. Kinetic measurements indicate that the rate of NGF dissociation from type I NGFRs is considerably slower than from type II NGFRs (1-3).

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mentioning

confidence: 53%

mentioning

confidence: 94%

The rat trk protooncogene product exhibits properties characteristic of the slow nerve growth factor receptor.

Meakin

Suter

Drinkwater

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

177

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“…Association with gpl40trk subunits has been highly controversial despite evidence of participation by NTR in high-affinity complexes (Berg et al, 1991;Hempstead et al, 1991;Battleman et al, 1993;Benedetti et al, 1993;Barker & Shooter, 1994;Hantzopoulos et al, 1994;Mahadeo et al, 1994;Wolf et al, 1995). Failure of chemical crosslinking to reveal a physical complex between NTR and gpl40trk (Meakin & Shooter, 1991) and a report that gpl40trk homodimers account for NGF signaling (Jing et al, 1992) have suggested that NTR does not form a heterodimer with gpl4Otrk.…”

Section: Applications Of the Modelmentioning

confidence: 99%

“…Our model predicts that the extracellular NTR-gpl40trk contact zone will include NTR subdomain 11. In proposing subdomain I1 as part of the high-affinity binding site, we account for experiments showing that NGF is more readily crosslinked to NTR in its low-affinity than in its high-affinity state (Hosang & Shooter, 1985;Meakin & Shooter, 1991) and that monoclonal antibody MC192 has opposite effects on lowand high-affinity NGF binding (Chandler et al, 1984).…”

Section: Versatility Of Modular Architecture and Interactions Betweenmentioning

confidence: 99%

Modeled structure of the 75-kDa neurotrophin receptor

Chapman

Kuntz

1995

Protein Sci.

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Motifs in ligand-binding domains of the neurotrophin (NTR) and lymphotoxin (TNFR-I) receptors define a family of receptors that mediates programmed cell death. We have explored relationships of architecture and function in this family through a molecular model of NTR, also called p75NGFR or LANR. Modeling by homology took advantage of four modular subdomains in the crystal structure of TNFR-I that also occur in NTR. Hypothetical complexes between the model and a ligand structure (for nerve growth factor, NGF) were then examined using docking software. NTR appears to bind in the dimer interface of NGF, making two sets of contacts. NTR subdomains 111 and IV provide the ligand-contact surfaces, in contrast to TNFR, in which subdomains 11 and III contact TNF-6. NTR subdomain I1 appears to have been evolutionarily modified, potentially contributing to an interface between receptor subunits. These and other specific predictions of the model will require experimental confirmation.

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“…Neurotrophins exert their effects through specific binding to cell surface receptors that exist in both low (Kd ~ 10 −9 )-and high (Kd ~ 10 −11 )-affinity forms (Meakin and Shooter, 1991). The low-affinity NGF receptor (p75 NGFR ) comprises a 75 kD protein (Chao et al, 1986) and binds all known members in the neurotrophin family.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Brain‐derived neurotrophic factor‐transduced fibroblasts: Production of BDNF and effects of grafting to the adult rat brain

Lucidi-Phillipi

Gage

Shults

et al. 1995

J of Comparative Neurology

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Local delivery of brain-derived neurotrophic factor (BDNF) by genetically modified cells provides the unique opportunity to examine the effects of BDNF on adult dopaminergic and cholinergic neurons in vivo. Primary rat fibroblasts were genetically engineered to produce BDNF. Conditioned media from BDNF-transduced fibroblasts supported embryonic chick dorsal root ganglion neurons as well as rat fetal mesencephalic neurons. BDNF-transduced fibroblasts grafted to the rat brain survived and showed continued mRNA production for at least 2 weeks. The effects of BDNFtransduced fibroblast grafts on the dopaminergic and cholinergic systems were then assessed. BDNFtransduced fibroblasts grafted into the normal intact substantia nigra induced sprouting of tyrosine hydroxylase-and neurofilament-immunoreactive fibers into the graft. Fibroblast grafts implanted into the normal intact striatum and midbrain as well as the 6-hydroxydopamine-lesioned brain did not induce sprouting of dopaminergic fibers; neither did they affect drug-induced rotational behavior. BDNF-transduced fibroblasts did, however, significantly increase the homovanillic acid/dopamine ratio when grafted into the normal midbrain. Following transection of the fimbria-fornix, BDNFtransduced fibroblasts grafted into the septum were unable to rescue the septal cholinergic population, as did nerve growth factor-producing fibroblast grafts. Genetically modified fibroblast grafts may provide an effective, localized method of BDNF delivery in vivo to test biological effects of this factor on the central nervous system. Indexing termscholinergic; dopaminergic; neurotrophic factor; NGF; transplantation Neurotrophic factors are present in the central nervous system (CNS) and play important roles in neural development, differentiation, and survival (for reviews, see Barde, 1989; Thoenen, 1991). A family of related neurotrophic molecules, called neurotrophins, whose members affect overlapping as well as distinct populations of neurons, has been recently isolated. Members of the neurotrophin family include nerve growth factor (NGF), brain-derived NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript neurotrophic factor (BDNF), neurotrophic factor-3 (NT-3), and neurotrophic factors-4/-5 (NT-4/5). Extensive conservation between species and sequence similarity between members (over 50% homology in amino acid identity) suggest important roles for neurotrophins in the CNS (Leibrock et al., 1989;Maisonpierre et al., 1990;Berkemeier et al., 1991).Neurotrophins exert their effects through specific binding to cell surface receptors that exist in both low (Kd ~ 10 −9 )-and high (Kd ~ 10 −11 )-affinity forms (Meakin and Shooter, 1991). The low-affinity NGF receptor (p75 NGFR ) comprises a 75 kD protein (Chao et al., 1986) and binds all known members in the neurotrophin family. Specificity in binding is afforded by high-affinity binding sites on trk protooncogenes: trkA., trkB, and trkC. Neurotrophic factors appear to mediate their effects by inducing phos...

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Molecular investigations on the high-affinity nerve growth factor receptor

Cited by 150 publications

References 63 publications

The rat trk protooncogene product exhibits properties characteristic of the slow nerve growth factor receptor.

The rat trk protooncogene product exhibits properties characteristic of the slow nerve growth factor receptor.

Modeled structure of the 75-kDa neurotrophin receptor

Brain‐derived neurotrophic factor‐transduced fibroblasts: Production of BDNF and effects of grafting to the adult rat brain

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