High Resolution Mapping of the Binding Site of TrkA for Nerve Growth Factor and TrkC for Neurotrophin-3 on the Second Immunoglobulin-like Domain of the Trk Receptors

Urfer, Roman; Tsoulfas, Pantelis; O'Connell, Lori; Hongo, Jo Anne; Zhao, Wei; Presta, Leonard G.

doi:10.1074/jbc.273.10.5829

Cited by 68 publications

(63 citation statements)

References 61 publications

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“…The activation caused by deletion of the first Ig-like domain was weak in all the assays compared to that caused by deleting the second domain. The second Ig-like domain appears to be more critical in preventing spontaneous receptor dimerization, and this correlates with the more important role played by this domain in NGF binding (24,33,34,36). In platelet-derived growth factor receptors, Ig-like domains 1 to 3 participate in ligand binding; however, only deletion of the Ig-like domain 3 caused oncogenic activation (32).…”

Section: Discussionmentioning

confidence: 99%

TrkA Immunoglobulin-Like Ligand Binding Domains Inhibit Spontaneous Activation of the Receptor

Arévalo

Conde

Hempstead

et al. 2000

Molecular and Cellular Biology

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The extracellular region of the nerve growth factor (NGF) receptor, TrkA, contains two immunoglobulin (Ig)-like domains that are required for specific ligand binding. We have investigated the possible role of these two Ig-like domains in receptor dimerization and activation by using different mutants of the TrkA extracellular region. Deletions of each Ig-like domain, of both, and of the entire extracellular region were made. To probe the structural constraints on ligand-independent receptor dimerization, chimeric receptors were generated by swapping the Ig-like domains of the TrkA receptor for the third or fourth Ig-like domain of c-Kit. We also introduced single-amino-acid changes in conserved residues within the Ig-like domains of TrkA. Most of these TrkA variants did not bind NGF, and their expression in PC12nnr5 cells, which lack endogenous TrkA, promoted ligand-independent neurite outgrowth. Some TrkA mutant receptors induced malignant transformation of Rat-1 cells, as assessed by measuring proliferation in the absence of serum, anchorage-independent growth, and tumorigenesis in nude mice. These mutants exhibited constitutive phosphorylation and spontaneous dimerization consistent with their biological activities. Our data suggest that spontaneous dimerization of TrkA occurs when the structure of the Ig-like domains is altered, implying that the intact domains inhibit receptor dimerization in the absence of NGF.

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Section: Discussionmentioning

confidence: 99%

TrkA Immunoglobulin-Like Ligand Binding Domains Inhibit Spontaneous Activation of the Receptor

Arévalo

Conde

Hempstead

et al. 2000

Molecular and Cellular Biology

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“…Although the sequences of the three Trk receptors are highly similar in their intracellular domains, substantial differences in their extracellular domains (including leucine-rich regions and Ig-like regions) have been shown to contribute to NT binding specificity (Urfer et al, 1995;Windisch et al, 1995a,b;Holden et al, 1997;Ninkina et al, 1997). One recent study identified regions in and around the second Ig-like domain that were particularly important to TrkA and TrkC specificity (Urfer et al, 1998). NGF is proposed to have interactions with TrkA that are unfavorable with NT-3, based on differences in binding affinity observed with TrkA and TrkC mutants.…”

Section: Discussionmentioning

confidence: 99%

The Staurosporine-Like Compound L-753,000 (NB-506) Potentiates the Neurotrophic Effects of Neurotrophin-3 by Acting Selectively at the TrkA Receptor

Pollack

Young²,

Bilsland³

et al. 1999

Mol Pharmacol

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K-252b, a member of the staurosporine family of protein kinase inhibitors, selectively potentiates the activation of the nerve growth factor receptor, TrkA, by a nonpreferred ligand, neurotrophin-3 (NT-3), in a variety of cell types. At higher (micromolar) concentrations of K-252b, an inhibitory effect occurs because of the inhibitory action of K-252b on the Trk kinase. By examining analogs of K-252b, we identified the compound L-753,000 (NB-506), which potentiates the action of NT-3 on TrkA but is devoid of the inhibitory action of K-252b. L-753,000 was effective at nanomolar concentrations in a Chinese hamster ovary cell line that expressed TrkA but was devoid of p75, the low-affinity neurotrophin receptor. L-753,000 also potentiated the activation of mitogen-activating protein kinase signaling (downstream from Trk activation) by NT-3 in this cell line.Although L-753,000, like K-252b, had a negligible effect in the absence of NT-3, the compound was found to potentiate NT-3-induced survival in both rat and chick primary cultures of dissociated dorsal root ganglia (DRG) and on neurite outgrowth of chick DRG explants. Unlike K-252b, which at micromolar concentrations inhibits the survival response of NT-3 in dissociated rat DRG, L-753,000 continued to potentiate the actions of NT-3 up to a concentration of 10 M. Furthermore, the compound, unlike K-252b, did not inhibit an unrelated protein kinase, protein kinase C, at concentrations up to 10 M. Because L-753,000 selectively potentiates the NT-3-induced stimulation of TrkA without inhibiting Trks and other protein kinases, it represents a novel class of selective modifiers of neurotrophin actions.

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“…They are tyrosine kinases with an extracellular ligand-binding domain containing multiple repeats of leucine-rich motifs (LRR1-3), two cysteine clusters (C1, C2), two immunoglobulin-like domains (Ig1, Ig2), and a single transmembrane domain (Schneider and Schweiger 1991). Binding specificity of the Trk receptors is mostly determined by the second Ig-like domain, whereby each Trk receptor binds the corresponding ligand through a distinct specific sequence (Urfer et al 1995(Urfer et al , 1998. NGF has been crystallized in complex with the Ig2 domain of the TrkA receptor, revealing a ligand-receptor interface of two patches, where one seems to be a conserved binding motif for all family members, the other specific for the interaction between NGF and TrkA (Wiesmann et al 1999).…”

Section: Neurotrophin Signaling Uses a Two-receptor Systemmentioning

confidence: 99%

Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system

Bibel

Barde²

2000

Genes Dev.

965

702

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High Resolution Mapping of the Binding Site of TrkA for Nerve Growth Factor and TrkC for Neurotrophin-3 on the Second Immunoglobulin-like Domain of the Trk Receptors

Abstract: The neurotrophins form a highly homologous family of growth factors responsible for differentiation, survival, and function of neurons sensitive to their presence (reviewed in Ref.

Cited by 68 publications

References 61 publications

TrkA Immunoglobulin-Like Ligand Binding Domains Inhibit Spontaneous Activation of the Receptor

TrkA Immunoglobulin-Like Ligand Binding Domains Inhibit Spontaneous Activation of the Receptor

The Staurosporine-Like Compound L-753,000 (NB-506) Potentiates the Neurotrophic Effects of Neurotrophin-3 by Acting Selectively at the TrkA Receptor

Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system

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