The secreted brain-derived neurotrophic factor precursor pro-BDNF binds to TrkB and p75NTR but not to TrkA or TrkC

Fayard, Bérengère; Loeffler, Sébastien; Weis, Joachim; Vögelin, Esther; Krüttgen, Alex

doi:10.1002/jnr.20432

Cited by 85 publications

(64 citation statements)

References 39 publications

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“…For this purpose, pro-BDNF protein produced using conditioned media from COS-7 cells transfected with furinresistant pro-BDNF (Fayard et al, 2005) was quantified with the BDNF Emax Immunosystem and used as standard. After coating a 96-well plate with mouse anti-BDNF (provided in BDNF Emax Immunosystem), nerve lysates and 25, 50, 100, 200, and 250 pg/ml pro-BDNF standard were added.…”

Section: Methodsmentioning

confidence: 99%

Mice Lacking Protease Nexin-1 Show Delayed Structural and Functional Recovery after Sciatic Nerve Crush

Lino¹,

Atanasoski²,

Kvajo³

et al. 2007

J. Neurosci.

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Multiple molecular mechanisms influence nerve regeneration. Because serine proteases were shown to affect peripheral nerve regeneration, we performed nerve crush experiments to study synapse reinnervation in adult mice lacking the serpin protease nexin-1 (PN-1). PN-1 is a potent endogenous inhibitor of thrombin, trypsin, tissue plasminogen activators (tPAs), and urokinase plasminogen activators. Compared with the wild type, a significant delay in synapse reinnervation was detected in PN-1 knock-out (KO) animals, which was associated with both reduced proliferation and increased apoptosis of Schwann cells. Various factors known to affect Schwann cells were also altered. Fibrin deposits, tPA activity, mature BDNF, and the low-affinity p75 neurotrophin receptor were increased in injured sciatic nerves of mutant mice. To test whether the absence of PN-1 in Schwann cells or in the axon caused delay in reinnervation, PN-1 was overexpressed exclusively in the nerves of PN-1 KO mice. Neuronal PN-1 expression did not rescue the delayed reinnervation. The results suggest that Schwann cell-derived PN-1 is crucial for proper reinnervation through its contribution to the autocrine control of proliferation and survival. Thus, the precise balance between distinct proteases and serpins such as PN-1 can modulate the overall impact on the kinetics of recovery.

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Section: Methodsmentioning

confidence: 99%

Mice Lacking Protease Nexin-1 Show Delayed Structural and Functional Recovery after Sciatic Nerve Crush

Lino¹,

Atanasoski²,

Kvajo³

et al. 2007

J. Neurosci.

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confidence: 99%

“…Unlike p75NTR and TrkA, sortilin shows considerably higher affinity for proNGF than for NGF (5 nM versus 90 nM, respectively), and proNGF promotes formation of heterotrimeric complexes containing sortilin and p75NTR (15). However, some studies have indicated that proneurotrophins are not selective p75NTR ligands and that they are capable of binding and activating Trk receptors to exert a neurotrophic, rather than a pro-apoptotic effect (16,17).In this study, we have compared proneurotrophin binding to p75NTR and TrkA and determined the signaling events acti-* This work was supported, in whole or in part, by National Institutes of Health Grant NS24380.This work was also supported by Grant MOP37850 from the Canadian Institute of Health Research (CIHR) and a grant from the United States Public Health Service. The costs of publication of this article were defrayed in part by the payment of page charges.…”

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confidence: 99%

Proneurotrophins Require Endocytosis and Intracellular Proteolysis to Induce TrkA Activation

Boutilier

Ceni

Pagdala

et al. 2008

Journal of Biological Chemistry

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The uncleaved, pro-form of nerve growth factor (proNGF) functions as a pro-apoptotic ligand for the p75 neurotrophin receptor (p75NTR). However, some reports have indicated that proneurotrophins bind and activate Trk receptors. In this study, we have examined proneurotrophin receptor binding and activation properties in an attempt to reconcile these findings. We show that proNGF readily binds p75NTR expressed in HEK293T cells but does not interact with TrkA expressed under similar circumstances. Importantly, proNGF activates TrkA tyrosine phosphorylation, induces Erk and Akt activation, and causes PC12 cell differentiation. We show that inhibiting endocytosis or furin activity reduced TrkA activation induced by proNGF but not that induced by mature NGF and that proNGF123, a mutant form of NGF lacking dibasic cleavage sites in the prodomain, does not induce TrkA phosphorylation in PC12 cells. Therefore, endocytosis and cleavage appear to be prerequisites for proNGF-induced TrkA activity. We also found that proBDNF induces activation of TrkB in cerebellar granule neurons and that proBDNF cleavage by furin and metalloproteases facilitates this effect. Taken together, these data indicate that under physiological conditions, proneurotrophins do not directly bind or activate Trk receptors. However, endocytosis and cleavage of proneurotrophins produce processed forms of neurotrophins that are capable of inducing Trk activation.The four mammalian neurotrophins comprise a family of related secreted factors required for differentiation, survival, development, and death of specific populations of neurons and non-neuronal cells. The effects of the neurotrophins are mediated by binding to TrkA, TrkB and TrkC receptor tyrosine kinases and to the p75 neurotrophin receptor (p75NTR) 4 . The Trk receptors play critical roles in mediating neuronal survival and growth and are important modulators of synaptic function (1). p75NTR is a component of distinct cell surface signaling platforms that function to induce apoptosis and mediate neuronal growth inhibition. However, p75NTR also acts as a Trk co-receptor that increases the binding specificity and affinity of Trk receptors for neurotrophins (2, 3).Neurotrophins are produced as proforms of ϳ240 amino acids that are cleaved by furins and proconvertases to yield mature neurotrophins of about 120 amino acids (4). The main functions ascribed to the neurotrophin prodomain include facilitating neurotrophin folding and directing neurotrophins to the regulated secretory pathway (5-7). Several recent studies have indicated that nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are secreted from cells as prodomain-containing forms (proNGF and proBDNF, respectively) (8 -10). In some types of primary neurons and in endothelial cells, proneurotrophin binding to the p75NTR-sortilin receptor complex is a potent apoptotic stimulus (8, 9, 11). Additional work demonstrating the predominance of proNGF and proBDNF in vivo (12-14) and its up-regulation following injury (8, 11) adds...

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“…A previous study failed to observe pericellular processing of furin-resistant pro-BDNF [19], however, Arg 125 within the furin consensus motif had been mutated to Ala, inadvertently destroying the plasmin-cleavage site identified here. From the observed activity of plasmin-processed BDNF against TrkB and the known apoptotic effects of pro-BDNF [9], this pericellular processing would be expected to shift a pro-apoptotic response towards a pro-survival effect.…”

Section: Discussionmentioning

confidence: 47%

Activation of pro‐BDNF by the pericellular serine protease plasmin

Gray

Ellis

2008

FEBS Letters

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Brain-derived neurotrophic factor (BDNF) is secreted as either a mature furin-processed form or an unprocessed proform. Here, we characterise the extracellular processing of pro-BDNF by the serine protease plasmin. Using recombinant BDNF, maintained in the pro-form by site-directed mutagenesis or inhibition of furin, we demonstrate that plasmin (but not related proteases) is a specific and efficient activator of pro-BDNF. The proteolytic cleavage site is identified as Arg 125 -Val, within the consensus furin-cleavage motif (RVRR), generating an active form that stimulated neurite outgrowth on TrkB-transfected PC12 cells. Furthermore, we demonstrate that this processing can also occur in the pericellular environment by the action of cell-associated plasminogen activators.

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The secreted brain-derived neurotrophic factor precursor pro-BDNF binds to TrkB and p75NTR but not to TrkA or TrkC

Cited by 85 publications

References 39 publications

Mice Lacking Protease Nexin-1 Show Delayed Structural and Functional Recovery after Sciatic Nerve Crush

Mice Lacking Protease Nexin-1 Show Delayed Structural and Functional Recovery after Sciatic Nerve Crush

Proneurotrophins Require Endocytosis and Intracellular Proteolysis to Induce TrkA Activation

Activation of pro‐BDNF by the pericellular serine protease plasmin

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