p75 Co-receptors Regulate Ligand-dependent and Ligand-independent Trk Receptor Activation, in Part by Altering Trk Docking Subdomains

Zaccaro, Maria Clara; Ivanisevic, Ljubica; Pérez, Pilar; Meakin, Susan O.; Saragovi, H. Uri

doi:10.1074/jbc.m104630200

Cited by 91 publications

(133 citation statements)

References 38 publications

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“…We have confirmed (data not shown) the differential effect of NT-3 and NGF with various receptor constructs (18). In wild type TrkA-expressing cells, 2 nM NGF affords optimal survival.…”

Section: Chimeras Exhibit Trophic Signals In Response Tosupporting

confidence: 68%

“…Quantitative Western blot analysis (20) with a polyclonal antibody directed to the Trk intracellular domain (203 antisera, a gift of David Kaplan, University of Toronto) indicated that the stable HEK293 4.1 TrkA/B cells express 40,000 -150,000 chimeric receptors/cell (data not shown) (18). All cells were grown in RPMI 1640 supplemented with 5% fetal calf serum, antibiotics, and glutamine.…”

Section: Methodsmentioning

confidence: 99%

“…Neurotrophins-Full-length TrkB receptors expressing the D5 (Ig-C2) subdomain of rat TrkA were generated, and the resulting chimera was termed 4.1 (18). The 4.1 TrkA/B chimeric receptor cDNA and TrkA wild type receptor cDNA were stably transfected in HEK293 and NIH cells.…”

Section: Chimeras Exhibit Trophic Signals In Response Tomentioning

confidence: 99%

“…Moreover, it has also been shown that the D4 subdomain has a role in regulating receptor dimerization (17) and in constitutive activation of the receptors (18). The D1 subdomain of TrkA can be utilized by NGF to activate the receptor, through a potentially allosteric or conformational mechanism regulated by co-expression of p75 on the cell surface (18).…”

mentioning

confidence: 99%

“…Biacore Binding Studies-The rat TrkA-rat TrkB 4.1 ECD chimera was generated by PCR using the full-length rat TrkArat TrkB receptor chimeric cDNAs (18) and cloned into pBlueBac4.5/V5-His vector (Invitrogen). The integrity and frame of the constructs were verified by sequencing (data not shown).…”

mentioning

confidence: 99%

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TrkA Receptor “Hot Spots” for Binding of NT-3 as a Heterologous Ligand

Ivanisevic

Zheng

Woo

et al. 2007

Journal of Biological Chemistry

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Neurotrophins signal via Trk tyrosine kinase receptors. Nerve growth factor (NGF) is the cognate ligand for TrkA, the brainderived neurotrophic factor for TrkB, and NT-3 for TrkC. NT-3 also binds TrkA as a lower affinity heterologous ligand. Because neurotrophin-3 (NT-3) interactions with TrkA are biologically relevant, we aimed to define the TrkA "hot spot" functional docking sites of NT-3. The Trk extracellular domain consists of two cysteine-rich subdomains (D1 and D3), flanking a leucinerich subdomain (D2), and two immunoglobulin-like subdomains IgC1(D4) and IgC2(D5). Previously, the D5 subdomain was defined as the primary ligand-binding site of neurotrophins for their cognate receptors (e.g. NGF binds and activates through TRKA-D5 hot spots). Here binding studies with truncated and chimeric extracellular subdomains show that TRKA-D5 also includes an NT-3 docking and activation hot spot (site 1), and competition studies show that the NGF and NT-3 hot spots on TRKA-D5 are distinct but partially overlapping. In addition, ligand binding studies provide evidence for an NT-3-binding/allosteric site on TRKA-D4 (site 2). NT-3 docking on sites 1 and/or 2 partially blocks NGF binding. Functional survival studies showed that sites 1 and 2 regulate TrkA activation. NT-3 docking on both sites 1 and 2 affords full agonism, which can be additive with NGF activation of Trk. However, NT-3 docking solely on site 1 is partially agonistic but noncompetitively antagonizes NGF binding and activation of Trk. This study demonstrates that Trk signaling is more complex than previously thought because it involves several receptor subdomains and hot spots.

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“…We have confirmed (data not shown) the differential effect of NT-3 and NGF with various receptor constructs (18). In wild type TrkA-expressing cells, 2 nM NGF affords optimal survival.…”

Section: Chimeras Exhibit Trophic Signals In Response Tosupporting

confidence: 68%

Section: Methodsmentioning

confidence: 99%

Section: Chimeras Exhibit Trophic Signals In Response Tomentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

TrkA Receptor “Hot Spots” for Binding of NT-3 as a Heterologous Ligand

Ivanisevic

Zheng

Woo

et al. 2007

Journal of Biological Chemistry

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The dual nature of neurotrophins

Schweigreiter

2006

BioEssays

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Neurotrophins are a small family of dimeric secretory proteins in vertebrate neurons with a broad spectrum of functions. They are generated as pro-proteins with a functionality that is distinct from the proteolytically processed form. The cellular responses of neurotrophins are mediated by three different types of receptor proteins, the receptor tyrosine kinases of the Trk family, the neurotrophin receptor p75(NTR), which is a member of the tumor necrosis factor receptor (TNFR) superfamily, and sortilin, previously characterized as neurotensin receptor. Recent studies have revealed an intriguing pattern: neurotrophins can elicit opposing signals utilising their variable configuration and different receptor types.

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Neurotrophic rationale in glaucoma: A TrkA agonist, but not NGF or a p75 antagonist, protects retinal ganglion cells in vivo

Shi

Birman

Saragovi

2007

Developmental Neurobiology

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Glaucoma is a major cause of vision impairment, which arises from the sustained and progressive apoptosis of retinal ganglion cells (RGC), with ocular hypertension being a major risk or co-morbidity factor. Because RGC death often continues after normalization of ocular hypertension, growth factor-mediated protection of compromised neurons may be useful. However, the therapeutic use of nerve growth factor (NGF) has not proven effective at delaying RGC death in glaucoma. We postulated that one cause for the failure of NGF may be related to its binding to two receptors, TrkA and p75. These receptors have distinct cellular distribution in the retina and in neurons they induce complex and sometimes opposing activities. Here, we show in an in vivo therapeutic model of glaucoma that a selective agonist of the pro-survival TrkA receptor was effective at preventing RGC death. RGC loss was fully prevented by combining the selective agonist of TrkA with intraocular pressure-lowering drugs. In contrast, neither NGF nor an antagonist of the pro-apoptotic p75 receptor protected RGCs. These results further a neurotrophic rationale for glaucoma.

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p75 Co-receptors Regulate Ligand-dependent and Ligand-independent Trk Receptor Activation, in Part by Altering Trk Docking Subdomains

Cited by 91 publications

References 38 publications

TrkA Receptor “Hot Spots” for Binding of NT-3 as a Heterologous Ligand

TrkA Receptor “Hot Spots” for Binding of NT-3 as a Heterologous Ligand

The dual nature of neurotrophins

Neurotrophic rationale in glaucoma: A TrkA agonist, but not NGF or a p75 antagonist, protects retinal ganglion cells in vivo

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