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

Ivanisevic, Ljubica; Zheng, Wenhua; Woo, Sang B.; Neet, Kenneth E.; Saragovi, H. Uri

doi:10.1074/jbc.m701996200

Cited by 35 publications

(40 citation statements)

References 33 publications

(53 reference statements)

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“…3a) or from cisplatin toxicity (data not shown), although this neurotrophin be a TrkA agonist [14, 36]. These data indicate that TrkA agonism by NT-3 and NGF also differ with respect to protection of cytotoxicity; consistent with reports that these ligands differ in terms of their TrkA binding affinity and activation of signaling pathways [13, 14]. …”

Section: Resultssupporting

confidence: 84%

Differential roles of Trk and p75 neurotrophin receptors in tumorigenesis and chemoresistance ex vivo and in vivo

Bassili

Birman

Schor

et al. 2009

Cancer Chemother Pharmacol

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The neurotrophin receptors TrkA (NGF receptor) and TrkC (NT-3 receptor) have been shown to be important in staging disease and predicting progression and drug response for various neoplasias such as neuroblastoma, medulloblastoma and prostate cancer. Less is known about the role of the p75 neurotrophin receptor in cancer, but it influences metastatic potential in glioblastoma. To determine the effect of each neurotrophin receptor or coreceptor expression in tumorigenesis, we examined PC12 pheochromocytomas. PC12 wild type (TrkA+, p75++) were compared to three PC12-derived cell lines expressing varying levels of TrkA or TrkC and/or p75. Growth rates, tumorigenic potential ex vivo and in vivo, and chemotherapeutic drug response profiles differed depending on the neurotrophin receptor phenotype. The ability of neurotrophins to rescue cells from doxorubicin or cisplatin induced cell death also varied depending on phenotype. Thus, unique neurotrophin receptor tumor profiles may determine tumor aggressiveness and chemoresistance. This work may help to develop tailored therapies for specific tumor phenotypes by combining traditional chemotherapy with neurotrophin receptor modulators.

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Section: Resultssupporting

confidence: 84%

Differential roles of Trk and p75 neurotrophin receptors in tumorigenesis and chemoresistance ex vivo and in vivo

Bassili

Birman

Schor

et al. 2009

Cancer Chemother Pharmacol

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“…We found that there is a third agonistic receptor hot spot on TrkA that is cryptic and silent; but becomes functional when p75 is co-expressed [36]. We also found that the receptor hot spots that TrkA has for binding and function of the heterologous ligand NT-3 are different than those used for NGF binding and function [37].…”

Section: Receptor-binding Agents (Receptor Hot Spots)mentioning

confidence: 92%

A Neurotrophic Rationale for the Therapy of Neurodegenerative Disorders

Saragovi¹,

Hamel²,

Polo

2009

CAR

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The concept and rationale for neuroprotection are presented. Several examples of small molecule neurotrophic agents with favourable drug-like and pharmacological properties are shown. Compound efficacy in acute neurodegenerative models (optic nerve axotomy) and chronic neurodegenerative models (glaucoma, age-associated cognitive impairment, Alzheimer's Disease) are evaluated and discussed. Targeting neurotrophin receptors with ligands that activate survival pathways or inhibit death pathways is an alternative worth pursuing.

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“…(53,54) Briefly, PC12 cells or nnr5-TrkC cells were plated at low density in complete media and allowed to adhere to the dish. Then the indicated treatment (NGF, NT-3 or peptidomimetics) was added for 48-72 h. The morphology of the cells was scored from pictures taken randomly and in a blinded fashion (4 pictures/well, 4 independent wells per condition).…”

Section: Methodsmentioning

confidence: 99%

Bivalent Peptidomimetic Ligands of TrkC Are Biased Agonists and Selectively Induce Neuritogenesis or Potentiate Neurotrophin-3 Trophic Signals

et al. 2009

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This study was initiated to find small molecule ligands that would induce a functional response when docked with neurotrophin Trk receptors. "Minimalist" mimics of β-turns were designed for this purpose. These mimics are: (i) rigid, yet easily folded into turn-like conformations, and (ii) readily accessible from amino acids bearing most of the natural side chains. Gram quantities of sixteen of these turn mimics were prepared, then assembled into 152 fluorescein-labeled bivalent peptidomimetics via a solution-phase combinatorial method. Fluorescence-based screening of these molecules using cells transfected with the Trk receptors identified 10 potential ligands of TrkC, the receptor for neurotrophin-3 (NT-3). Analogs of these bivalent peptidomimetics with biotin replacing the fluorescein label were then prepared and tested to confirm that binding was not due to the fluorescein. Several assays were conducted to find the mode of action of these biotinylated compounds. Thus, direct binding, survival and neuritogenic, and biochemical signal transduction assays showed 8 of the original 10 hits were agonistic ligands binding to the ectodomain of TrkC. Remarkably, some peptidomimetics afford discrete signals leading to either cell survival or neuritogenic differentiation. The significance of this work is three fold. First, we succeeded in finding small, selective, proteolytically stable ligands for the TrkC receptor; there are very few of these in the literature. Second, we show that it is possible to activate distinct and biased signaling pathways with ligands binding at the ectodomain of wild type receptors. Third, the discovery that some peptidomimetics initiate different modes of cell signaling increases their potential as pharmacological probes and therapeutic leads.The neurotrophins are dimeric protein growth factors that help regulate the peripheral and central nervous systems and other tissues that express the Trk and p75 neurotrophin receptors.(1,2) Trk receptors are relatively selective for, and bind with high affinity (∼K d 10 -11 M) to the neurotrophin. Nerve growth factor (NGF) docks with TrkA, Brain Derived Neurotrophic Factor (BDNF) interacts with TrkB(3), and Neurotrophin-3 (NT-3) interacts preferentially with TrkC but can also bind TrkA and TrkB ( Figure 1a). Ligand binding induces phosphorylation (pTyr) of Trk receptors and associated signaling partners and activation of the neurotrophic biological signals: cell growth, cell survival under stress (trophic activity), and/or cellular differentiation (neuritogenic or neurogenic activity).(4-6) * Correspondence regarding design and synthesis of the peptidomimetics to burgess@mail.tamu.edu, and on the biology and pharmacology to uri.saragovi@mcgill.ca. There is also a second receptor for the neurotrophins, p75, a member of the tumor necrosis factor (TNF) receptor superfamily. All the neurotrophins also bind the p75 receptor, but with lesser affinities (10 -9 to 10 -11 M) than for the Trk receptors. (7-9) The p75 receptor can transduce signals which ...

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

Cited by 35 publications

References 33 publications

Differential roles of Trk and p75 neurotrophin receptors in tumorigenesis and chemoresistance ex vivo and in vivo

Differential roles of Trk and p75 neurotrophin receptors in tumorigenesis and chemoresistance ex vivo and in vivo

A Neurotrophic Rationale for the Therapy of Neurodegenerative Disorders

Bivalent Peptidomimetic Ligands of TrkC Are Biased Agonists and Selectively Induce Neuritogenesis or Potentiate Neurotrophin-3 Trophic Signals

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