Biological Activity of Nerve Growth Factor Precursor Is Dependent upon Relative Levels of Its Receptors

Masoudi, Raheleh; Ioannou, Maria S.; Coughlin, Michael D.; Pagadala, Promila; Neet, Kenneth E.; Clewes, Oliver; Allen, Shelley J; Dawbarn, David; Fahnestock, Margaret

doi:10.1074/jbc.m109.007104

Cited by 115 publications

(117 citation statements)

References 52 publications

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“…In melanoma cells, it has previously been shown that the addition of proNGF can lead to a stimulation of cell invasion through activation of p75 NTR and sortilin (28); in this model, TrkA was not found to be necessary. However, the activation of TrkA by proNGF has also been reported in other models (8), with the biological activity of proNGF dependent upon relative levels of TrkA versus p75 NTR (29). Therefore, although p75 NTR appears to be mediating proNGF invasive effects in melanoma, in breast cancer, the present study indicates that TrkA is involved without the participation of p75 NTR .…”

Section: Discussionmentioning

confidence: 42%

Pro-nerve Growth Factor Induces Autocrine Stimulation of Breast Cancer Cell Invasion through Tropomyosin-related Kinase A (TrkA) and Sortilin Protein

Demont

Corbet

Page

et al. 2012

Journal of Biological Chemistry

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The precursor of nerve growth factor (proNGF) has been described as a biologically active polypeptide able to induce apoptosis in neuronal cells, via the neurotrophin receptor p75 NTR and the sortilin receptor. Herein, it is shown that proNGF is produced and secreted by breast cancer cells, stimulating their invasion. Using Western blotting and mass spectrometry, proNGF was detected in a panel of breast cancer cells as well as in their conditioned media. Immunohistochemical analysis indicated an overproduction of proNGF in breast tumors, when compared with benign and normal breast biopsies, and a relationship to lymph node invasion in ductal carcinomas. Interestingly, siRNA against proNGF induced a decrease of breast cancer cell invasion that was restored by the addition of noncleavable proNGF. The activation of TrkA, Akt, and Src, but not the MAP kinases, was observed. In addition, the proNGF invasive effect was inhibited by the Trk pharmacological inhibitor K252a, a kinase-dead TrkA, and siRNA against TrkA sortilin, neurotensin, whereas siRNA against p75 NTR and the MAP kinase inhibitor PD98059 had no impact. These data reveal the existence of an autocrine loop stimulated by proNGF and mediated by TrkA and sortilin, with the activation of Akt and Src, for the stimulation of breast cancer cell invasion. Nerve growth factor (NGF),5 the prototypical member of the neurotrophin family of polypeptides, is essential for the survival and differentiation of central and peripheral neurons, and its role in the development and regeneration of the sympathetic and sensory nervous systems has been extensively described (1). NGF binds to the tropomyosin-related kinase A (TrkA) receptor, a tyrosine kinase receptor, and to the p75 neurotrophin receptor (p75 NTR ), a member of the tumor necrosis factor receptor family, to induce its neurotrophic effects. NGF is synthesized as a 25-kDa precursor protein, named proNGF, that yields the mature NGF polypeptide of 13.5 kDa and an inactive prosegment of 11.5 kDa, released from the N terminus intracellularly by furin, or extracellularly by plasmin as well as by several matrix metalloproteases (2). Importantly, proNGF can be secreted without being processed to mature NGF and can have its own biological effects (3). As more than just a source for NGF, proNGF was shown to induce neuronal death by apoptosis where mature NGF induced survival and differentiation (4, 5). For inducing its proapoptotic effect on neurons, proNGF forms a trimeric complex with two plasma membrane receptors: p75 NTR and sortilin (4). Sortilin, a 95-kDa type I receptor,

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Section: Discussionmentioning

confidence: 42%

Pro-nerve Growth Factor Induces Autocrine Stimulation of Breast Cancer Cell Invasion through Tropomyosin-related Kinase A (TrkA) and Sortilin Protein

Demont

Corbet

Page

et al. 2012

Journal of Biological Chemistry

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“…High proNGF concentrations can stimulate PC12 cell survival when the p75NTR/TrkA ratio is low (Fahnestock et al 2004). It was established that the receptors balance, i.e., the relative level of Trk and p75NTR, is a crucial determinant of cell fate during development and that it is required for further modulation of neurite outgrowth/synaptic plasticity in the adult brain (Masoudi et al 2009). ProNGF has indeed been demonstrated to induce neuronal apoptosis in vivo after injury or seizures when p75NTR expression is induced, shifting the balance of signaling towards apoptosis (Volosin et al 2008).…”

Section: Discussionmentioning

confidence: 99%

BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat

Perović

Tešić

Djordjevic

et al. 2012

AGE

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Neurotrophins are established molecular mediators of neuronal plasticity in the adult brain. We analyzed the impact of aging on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) protein isoforms, their receptors, and on the expression patterns of multiple 5′ exon-specific BDNF transcripts in the rat cortex and hippocampus throughout the life span of the rat (6, 12, 18, and 24 months of age). ProNGF was increased during aging in both structures. Mature NGF gradually decreased in the cortex, and, in 24-month-old animals, it was 30 % lower than that in adult 6-month-old rats. The BDNF expression did not change during aging, while proBDNF accumulated in the hippocampus of aged rats. Hippocampal total BDNF mRNA was lower in 12-month-old animals, mostly as a result of a decrease of BDNF transcripts 1 and 2. In contrast to the regionspecific regulation of specific exon-containing BDNF mRNAs in adult animals, the same BDNF RNA isoforms (containing exons III, IV, or VI) were present in both brain structures of aged animals. Deficits in neurotrophin signaling were supported by the observed decrease in Trk receptor expression which was accompanied by lower levels of the two main downstream effector kinases, pAkt and protein kinase C. The proteolytic processing of p75NTR observed in 12-monthold rats points to an additional regulatory mechanism in early aging. The changes described herein could contribute to reduced brain plasticity underlying the age-dependent decline in cognitive function.

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“…Activation of the two receptor types can elicit opposing effects -survival and differentiation via Trks, or apoptosis via p75NTR 9,10 . Adding to the complexity, TrkA and TrkC can act as dependence receptors that elicit apoptosis when unstimulated 11 , and the biological effect of secreted proneurotrophins might depend on the expression ratio of Trk receptors and p75NTR 12,13 and on expression of p75NTR co-receptors 14,15 .…”

Section: Schwann Cells and Their Interactionsmentioning

confidence: 99%

Schwann cell interactions with axons and microvessels in diabetic neuropathy

et al. 2017

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The incidence of diabetes mellitus has increased dramatically over the past two to three decades. According to the International Diabetes Federation Diabetes Atlas, 415 million people worldwide had diabetes in 2015, and this number is expected to grow by 5% annually, predominantly as a result of increasing prevalence of type 2 diabetes. Furthermore, an estimated 100 million Europeans and 80 million Americans have impaired glucose tolerance or prediabetes. Few people die from acute diabetes in countries with comprehensive health care systems, but the disease is inflicting a huge medical, social and economic burden on society owing to the need for lifelong treatment of its systemic consequences and the insidious development of multi-organ damage.Peripheral neuropathy (BOXES 1,2) is a common but often neglected complication of long-term diabetes, and the lack of treatment options reflects an incomplete understanding of the pathogenic mechanisms. Hyperglycaemia is generally accepted as the primary pathogenic insult in type 1 and type 2 diabetic neuropathy, although roles are emerging for other factors, such as impaired insulin signalling, hypertension and dyslipidaemia (particularly for type 2 diabetes), which might precede overt hyperglycaemia 1 . Many preclinical studies, and occasional clinical studies, have indicated that diabetic neuropathy -like diabetic nephropathy and retinopathy -results from microvascular disease, with a focus on axonal degeneration as a consequence of ischaemia and/or hypoxia. This mechanism, however, is likely to be only one aspect of a more complex pathogenesis.The earliest descriptions of pathology in diabetic neuropathy indicated that Schwannopathy accompanied axonal degeneration. The majority of clinical and basic research in diabetic neuropathy since then has focused on the effects on neurons. However, accumulating data from research into the development and regeneration of the PNS has identified Schwann cells as equally indispensable components that maintain neuronal structure and function, nourish axons, and promote survival and growth upon injury. The early reports from 1979 that demonstrated morphological changes in Schwann cells in human diabetic neuropathy 2 are now supported by an increased awareness of molecular alterations in Schwann cells during diabetes 3 . Schwann cells express a wide range of receptors and, when they sense insults or danger signals, they upregulate synthesis and secretion of factors that stimulate neuroprotection, regrowth and remyelination, or factors that aggravate disease phenotypes 4 . The most recent studies have demonstrated that Schwann cells regulate many aspects of axonal function, so that disruption of their metabolism by diabetes results in the accumulation of neurotoxic intermediates and compromises production of neuronal support factors, contributing to axonal degeneration, endothelial dysfunction and diabetic neuropathy. Abstract | The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annu...

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Biological Activity of Nerve Growth Factor Precursor Is Dependent upon Relative Levels of Its Receptors

Cited by 115 publications

References 52 publications

Pro-nerve Growth Factor Induces Autocrine Stimulation of Breast Cancer Cell Invasion through Tropomyosin-related Kinase A (TrkA) and Sortilin Protein

Pro-nerve Growth Factor Induces Autocrine Stimulation of Breast Cancer Cell Invasion through Tropomyosin-related Kinase A (TrkA) and Sortilin Protein

BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat

Schwann cell interactions with axons and microvessels in diabetic neuropathy

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