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

Nerve growth factor (NGF) is produced as a precursor called pro-nerve growth factor (proNGF), which is secreted by many tissues and is the predominant form of NGF in the central nervous system. In Alzheimer disease brain, cholinergic neurons degenerate and can no longer transport NGF as efficiently, leading to an increase in untransported NGF in the target tissue. The protein that accumulates in the target tissue is proNGF, not the mature form. The role of this precursor is controversial, and both neurotrophic and apoptotic activities have been reported for recombinant proNGFs. Differences in the protein structures, protein expression systems, methods used for protein purification, and methods used for bioassay may affect the activity of these proteins. Here, we show that proNGF is neurotrophic regardless of mutations or tags, and no matter how it is purified or in which system it is expressed. However, although proNGF is neurotrophic under our assay conditions for primary sympathetic neurons and for pheochromocytoma (PC12) cells, it is apoptotic for unprimed PC12 cells when they are deprived of serum. The ratio of tropomyosin-related kinase A to p75 neurotrophin receptor is low in unprimed PC12 cells compared with primed PC12 cells and sympathetic neurons, altering the balance of proNGF-induced signaling to favor apoptosis. We conclude that the relative level of proNGF receptors determines whether this precursor exhibits neurotrophic or apoptotic activity. Nerve growth factor (NGF) is produced as a precursor called pro-nerve growth factor (proNGF), which is secreted by many tissues and is the predominant form of NGF in the central nervous system. In Alzheimer disease brain, cholinergic neurons degenerate and can no longer transport NGF as efficiently, leading to an increase in untransported NGF in the target tissue. The protein that accumulates in the target tissue is proNGF, not the mature form. The role of this precursor is controversial, and both neurotrophic and apoptotic activities have been reported for recombinant proNGFs. Differences in the protein structures, protein expression systems, methods used for protein purification, and methods used for bioassay may affect the activity of these proteins. Here, we show that proNGF is neurotrophic regardless of mutations or tags, and no matter how it is purified or in which system it is expressed. However, although proNGF is neurotrophic under our assay conditions for primary sympathetic neurons and for pheochromocytoma (PC12) cells, it is apoptotic for unprimed PC12 cells when they are deprived of serum. The ratio of tropomyosin-related kinase A to p75 neurotrophin receptor is low in unprimed PC12 cells compared with primed PC12 cells and sympathetic neurons, altering the balance of proNGF-induced signaling to favor apoptosis. We conclude that the relative level of proNGF receptors determines whether this precursor exhibits neurotrophic or apoptotic activity. Nerve growth factor (NGF) 3The abbreviations used are: NGFnerve growth factorproNGFpro-nerve growth factorPC12pheochromocytoma cellsTrkAtropomyosin related kinase AMAPKmitogen-activated protein kinaseWTwild typeHEK 293 cellshuman embryonic kidney 293 cellsFBSfetal bovine serumSCGsuperior cervical ganglionPBSphosphate-buffered salineBSAbovine serum albumin. 3The abbreviations used are: NGFnerve growth factorproNGFpro-nerve growth factorPC12pheochromocytoma cellsTrkAtropomyosin related kinase AMAPKmitogen-activated protein kinaseWTwild typeHEK 293 cellshuman embryonic kidney 293 cellsFBSfetal bovine serumSCGsuperior cervical ganglionPBSphosphate-buffered salineBSAbovine serum albumin. regulates neuronal survival, neurite outgrowth, and differentiation in the peripheral and central nervous systems (1.Huang E.J. Reichardt L.F. Annu. Rev. Neurosci. 2001; 24: 677-736Crossref PubMed Scopus (3333) Google Scholar). The mature form of NGF forms a non-covalent homodimer and binds with high affinity (kd ≈ 10−11m) to tropomyosin-related kinase A (TrkA) and with low affinity (kd ≈ 10−9m) to the common neurotrophin receptor p75NTR (p75 neurotrophin receptor) (2.Bibel M. Barde Y.A. Gene Dev. 2000; 14: 2919-2937Crossref PubMed Scopus (882) Google Scholar). NGF promotes cell survival and growth in cells expressing TrkA through activation of the phosphatidylinositol 3-kinase/AKT pathway and the Ras/mitogen-activated protein kinase (MAPK) pathway (3.Grewal S.S. York R.D. Stork P.J. Curr. Opin. Neurobiol. 1999; 9: 544-553Crossref PubMed Scopus (506) Google Scholar, 4.Kaplan D.R. Miller F.D. Curr. Opin. Neurobiol. 2000; 10: 381-391Crossref PubMed Scopus (1654) Google Scholar). p75NTR plays diverse roles, ranging from cell survival to cell death depending on the cellular context in which it is expressed. Through activation of the NF-κB pathway, p75NTR can contribute to cell survival in sensory neurons (5.Hamanoue M. Middleton G. Wyatt S. Jaffray E. Hay R.T. Davies A.M. Mol. Cell. Neurosci. 1999; 14: 28-40Crossref PubMed Scopus (174) Google Scholar), it is involved in axonal growth via regulation of Rho activity (6.Yamashita T. Tucker K.L. Barde Y.A. Neuron. 1999; 24: 585-593Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar), and it can interact with Trks to enhance neurotrophin affinity (at low concentration of ligand) and specificity of binding to Trks (7.Dechant G. Cell Tissue Res. 2001; 305: 229-238Crossref PubMed Scopus (91) Google Scholar, 8.Roux P.P. Barker P.A. Prog. Neurobiol. 2002; 67: 203-233Crossref PubMed Scopus (593) Google Scholar, 9.Huang E.J. Reichardt L.F. Annu. Rev. Biochem. 2003; 72: 609-642Crossref PubMed Scopus (1953) Google Scholar). High levels of p75NTR expression can induce apoptosis when there are low levels of Trk or when Trk is absent (10.Aloyz R.S. Bamji S.X. Pozniak C.D. Toma J.G. Atwal J. Kaplan D.R. Miller F.D. J. Cell Biol. 1998; 143: 1691-1703Crossref PubMed Scopus (259) Google Scholar, 11.Yoon S.O. Casaccia-Bonnefil P. Carter B. Chao M.V. J. Neurosci. 1998; 18: 3273-3281Crossref PubMed Google Scholar). Apoptosis occurs through increased ceramide production (12.Brann A.B. Tcherpakov M. Williams I.M. Futerman A.H. Fainzilber M. J. Biol. Chem. 2002; 277: 9812-9818Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar), activation of c-Jun N-terminal kinase (JNK1), and p53 (10.Aloyz R.S. Bamji S.X. Pozniak C.D. Toma J.G. Atwal J. Kaplan D.R. Miller F.D. J. Cell Biol. 1998; 143: 1691-1703Crossref PubMed Scopus (259) Google Scholar, 13.Friedman W.J. J. Neurosci. 2000; 20: 6340-6346Crossref PubMed Google Scholar). p75NTR requires a co-receptor called sortilin to induce cell death (14.Nykjaer A. Lee R. Teng K.K. Jansen P. Madsen P. Nielsen M.S. Jacobsen C. Kliemannel M. Schwarz E. Willnow T.E. Hempstead B.L. Petersen C.M. Nature. 2004; 427: 843-848Crossref PubMed Scopus (792) Google Scholar). nerve growth factor pro-nerve growth factor pheochromocytoma cells tropomyosin related kinase A mitogen-activated protein kinase wild type human embryonic kidney 293 cells fetal bovine serum superior cervical ganglion phosphate-buffered saline bovine serum albumin. nerve growth factor pro-nerve growth factor pheochromocytoma cells tropomyosin related kinase A mitogen-activated protein kinase wild type human embryonic kidney 293 cells fetal bovine serum superior cervical ganglion phosphate-buffered saline bovine serum albumin. NGF is produced as a precursor called pro-nerve growth factor (proNGF) (15.Darling T.L. Petrides P.E. Beguin P. Frey P. Shooter E.M. Selby M. Rutter W.J. Cold Spring Harbor Symp. Quant. Biol. 1983; 48: 427-434Crossref PubMed Google Scholar). ProNGF is secreted by many tissues such as prostate cells, spermatids, hair follicles, oral mucosal keratinocytes, sympathetic neurons, cortical astrocytes, heart, and spleen (16.Chen Y. Dicou E. Djakiew D. Mol. Cell. Endocrinol. 1997; 127: 129-136Crossref PubMed Scopus (56) Google Scholar, 17.Delsite R. Djakiew D. Prostate. 1999; 41: 39-48Crossref PubMed Scopus (42) Google Scholar, 18.Yardley G. Relf B. Lakshmanan J. Reinshagen M. Moore G.P. Exp. Dermatol. 2000; 9: 283-289Crossref PubMed Scopus (21) Google Scholar, 19.Hayashi K. Storesund T. Schreurs O. Khuu C. Husvik C. Karatsaidis A. Helgeland K. Martin-Zanca D. Schenck K. Eur. J. Oral Sci. 2007; 115: 344-354Crossref PubMed Scopus (21) Google Scholar, 20.Fahnestock M. Yu G. Coughlin M.D. Prog. Brain Res. 2004; 146: 101-110Crossref PubMed Scopus (113) Google Scholar). ProNGF is the predominant form of NGF in the central and peripheral nervous systems, whereas little or no mature NGF can be detected (21.Fahnestock M. Michalski B. Xu B. Coughlin M.D. Mol. Cell. Neurosci. 2001; 18: 210-220Crossref PubMed Scopus (438) Google Scholar, 22.Bierl M.A. Jones E.E. Crutcher K.A. Isaacson L.G. Neurosci. Lett. 2005; 380: 133-137Crossref PubMed Scopus (52) Google Scholar, 23.Pedraza C.E. Podlesniy P. Vidal N. Arévalo J.C. Lee R. Hempstead B. Ferrer I. Iglesias M. Espinet C. Am. J. Pathol. 2005; 166: 533-543Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 24.Bierl M.A. Isaacson L.G. Neurobiol. Aging. 2007; 28: 122-134Crossref PubMed Scopus (40) Google Scholar). In Alzheimer disease brain, retrograde transport from the cortex and hippocampus to basal forebrain cholinergic neurons is reduced as these neurons degenerate, with concomitant proNGF accumulation in the cortex and hippocampus (21.Fahnestock M. Michalski B. Xu B. Coughlin M.D. Mol. Cell. Neurosci. 2001; 18: 210-220Crossref PubMed Scopus (438) Google Scholar, 23.Pedraza C.E. Podlesniy P. Vidal N. Arévalo J.C. Lee R. Hempstead B. Ferrer I. Iglesias M. Espinet C. Am. J. Pathol. 2005; 166: 533-543Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). This suggested that proNGF mediates biological activity besides its prodomain function of promoting protein folding and regulation of neurotrophin secretion (25.Edwards R.H. Selby M.J. Garcia P.D. Rutter W.J. J. Biol. Chem. 1988; 263: 6810-6815Abstract Full Text PDF PubMed Google Scholar, 26.Suter U. Heymach Jr., J.V. Shooter E.M. EMBO J. 1991; 10: 2395-2400Crossref PubMed Scopus (129) Google Scholar, 27.Rattenholl A. Lilie H. Grossmann A. Stern A. Schwarz E. Rudolph R. Eur. J. Biochem. 2001; 268: 3296-3303Crossref PubMed Scopus (116) Google Scholar, 28.Farhadi H.F. Mowla S.J. Petrecca K. Morris S.J. Seidah N.G. Murphy R.A. J. Neurosci. 2000; 20: 4059-4068Crossref PubMed Google Scholar). To study the role of proNGF protein in vitro, point mutations were inserted at the cleavage site used by a to proNGF N.G. S. S. D. J. B. J. C. M. Murphy R.A. Biochem. J. PubMed Scopus Google Scholar), to the of proNGF to mature The apoptotic activity R. P. Teng K.K. Hempstead B.L. 2001; PubMed Scopus Google Scholar, Sci. PubMed Scopus Google or neurotrophic activity M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google Scholar, O. M.S. S.J. H. C. K. D. S.J. J. Google Scholar). recombinant in with apoptotic activity at and to and to and a at the This proNGF in cells and purified with apoptotic activity is proNGF mutations at and to and to and and to in a cell system. purified and with neurotrophic activity a at to and no This proNGF in cells a expression system. A proNGF with neurotrophic activity at and to no and in of these may affect the activity of the in such a that is apoptotic and the is To the of proNGF biological these recombinant were in or expression systems and were purified by or from by levels of TrkA and p75NTR receptors of the cells used in these were by of proNGF used in this to and to and to and to and to and to and to cells, cells, from in a proNGF a in from B. Hempstead of the The of by and the by both and were cells to the and a high produced through in protein produced in cells by recombinant at a of of type NGF proNGF with no and no wild type proNGF a M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google Scholar), and wild type were in cells at a of in with protein were in in a at and were by at for on to were at were by assay as M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google Scholar). were by to a of purified NGF by from (21.Fahnestock M. Michalski B. Xu B. Coughlin M.D. Mol. Cell. Neurosci. 2001; 18: 210-220Crossref PubMed Scopus (438) Google Scholar, A. Shooter E.M. PubMed Scopus Google Scholar, P.E. Shooter E.M. J. PubMed Scopus Google Scholar). NGF proNGF as a and from cells with wild type used as a to human embryonic kidney 293 cells were at in with fetal bovine serum were with or at a ratio of to the cells and for the The from the protein expression systems or were at to with for at were with in by with in were and or were both the and NGF the for purified were and by NGF assay as human recombinant proNGF and no in were from cell and protein as A. Lilie H. Grossmann A. Stern A. Schwarz E. Rudolph R. Eur. J. Biochem. 2001; 268: 3296-3303Crossref PubMed Scopus (116) Google Scholar, O. M.S. S.J. H. C. K. D. S.J. J. Google Scholar). protein purified by protein and in The concentration of purified by at an of for the of NGF and for the of proNGF mutations as Sci. PubMed Scopus Google and by at for the of NGF and for the of ProNGF is to cleavage in the of and were superior cervical ganglion neurons from were as M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google Scholar). cells were in in and for at and cells were with and with or NGF in as with of and for cells were in the with of and unprimed pheochromocytoma cells were in in and for as by J. Cell Biol. PubMed Scopus Google Scholar). were and with NGF or in and for PC12 cells were primed in and NGF for as M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google Scholar). were in of serum and NGF and were and to as for unprimed were with phosphate-buffered and in for at were with in for on and were with and with serum in for at with cells were with a of neuronal at in in a of for at with and with in for at were a at to a The used by this system and the were and for and cells the of cell were as cells a at cells with with were as cells were The assay as M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google Scholar). PC12 were in in serum and for to with no serum for were by of wild type proNGF or proNGF in E. or cells, or NGF for at and were of and of and and on for were at for at and protein concentration the protein assay of protein on for In as with for to cleavage of proNGF by were with proNGF or in for or and as neurite outgrowth, and activation the level of proNGF cleavage in cell as by little to no cleavage in reported which the role of proNGF in as M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google NGF from kinase and from Cell TrkA and p75NTR and neuronal The for and p75NTR primary and for A system used to In the The at the an system were used to the levels of TrkA and p75NTR protein were in primary neurons in for in unprimed PC12 cells in and and in primed PC12 cells in serum NGF for were in of and of and for primary neurons, or in the used in activation for PC12 cells, and by the TrkA and p75NTR The of in were by of a and with of were with were in to for neurite and activation or of with as to proNGF with a and neurotrophic activity in a cell system and used M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google Scholar), whereas with a and apoptotic activity in cells and purified a to R. P. Teng K.K. Hempstead B.L. 2001; PubMed Scopus Google Scholar). To whether these or for the reported in we in a system and its activity and a We an apoptotic proNGF in Sci. PubMed Scopus Google and purified by of in an expression system an at the for an proNGF or the the for and that the protein proNGF a cleavage of detected for NGF proNGF or the which the specificity of the for for wild type of the there is no proNGF production in cells, and the not with protein produced by the cell system not NGF and that and not NGF and were to from neurons in whereas there no detected for The for compared with for NGF with by M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google for compared with no cleavage of the assay proNGF mature NGF as the in promoting neurite neurons with for cells by by the assay not which not from NGF cells M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google Scholar), exhibits neurotrophic and and are not for activities in neurite which to mature NGF whereas cells in the of neurotrophic to the the on neurite and neuronal survival were for and NGF in cells and both TrkA and of PC12 cells the levels of TrkA or The for TrkA activation and for purified and the and for purified proNGF, and proNGF, reported M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google Scholar), proNGF mature NGF for both TrkA and cleavage detected for the assay not proNGF an for proNGF reduced proNGF-induced the role of proNGF in the The proNGF not activation by mature NGF in cells, which to the mature been reported that proNGF requires to TrkA J. C. A. Barker P.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). we a activation assay in the of the no in the of or to the signaling pathway in the of a In of cleavage by the a increase in cleavage of proNGF is not for To the of the we cells to for as by J. C. A. Barker P.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This is a longer for this assay and is to proNGF and In this the reduced cleavage of in cell and activation no on activation activation of not reduced by the that cleavage of proNGF is not for activation of by in cells, with no in the level of This activation by is in cells, as by not cleavage detected for the assay human recombinant proNGF in E. the relative activation activity compared with mature NGF as for and in or TrkA the for NGF and for The for activation and for NGF and for the assay its and a on the the assay no cleavage the assay been that PC12 cells primed with NGF apoptosis NGF M. J. PubMed Scopus Google Scholar). we show that both and A and primed PC12 cells NGF with activity that to apoptosis in cells with and PC12 cells are on serum for survival and apoptosis when serum is been that NGF PC12 cells serum J. Cell Biol. PubMed Scopus Google Scholar). we that apoptosis in PC12 cells deprived of serum whereas NGF the cells from The ratio of TrkA to p75NTR plays an role in signaling by NGF A.M. Lee R. Neuron. Full Text PDF PubMed Scopus Google Scholar, D. Kaplan Chao M.V. Hempstead B.L. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Sci. PubMed Scopus Google Scholar). We that the ratio may have a role in by we that the ratio of TrkA to p75NTR in primed PC12 cells compared with unprimed PC12 cells In primary neurons there the level of p75NTR the of the assay proNGF is neurotrophic in neurons and in primed PC12 cells level of TrkA compared with whereas it is apoptotic in the serum assay unprimed PC12 cells level of TrkA compared with ProNGF not increase in Alzheimer disease (21.Fahnestock M. Michalski B. Xu B. Coughlin M.D. Mol. Cell. Neurosci. 2001; 18: 210-220Crossref PubMed Scopus (438) Google and with S. J. E.J. M. J. Exp. 2004; PubMed Scopus Google Scholar). However, the of increased proNGF and its role in Alzheimer is increase in proNGF levels in Alzheimer disease may neuronal proNGF is proNGF is neurons may degenerate to the of neurotrophic when TrkA and retrograde transport of proNGF is Here, we have that proNGF is neurotrophic under conditions for neurons and for primed PC12 However, conditions leading to a ratio of TrkA to such as in unprimed PC12 cells serum to apoptotic activity of To the biological activity of proNGF and its role in cell survival and have produced recombinant mutations that cleavage to the mature form. produced by the and M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google Scholar, O. M.S. S.J. H. C. K. D. S.J. J. Google Scholar, S. J. PubMed Scopus Google neurotrophic whereas produced by the Hempstead and (14.Nykjaer A. Lee R. Teng K.K. Jansen P. Madsen P. Nielsen M.S. Jacobsen C. Kliemannel M. Schwarz E. Willnow T.E. Hempstead B.L. Petersen C.M. Nature. 2004; 427: 843-848Crossref PubMed Scopus (792) Google Scholar, R. P. Teng K.K. Hempstead B.L. 2001; PubMed Scopus Google Scholar, Sci. PubMed Scopus Google are Differences in the of of a expression systems, and methods of bioassay were to the biological activities M. Yu G. Coughlin M.D. Prog. Brain Res. 2004; 146: 101-110Crossref PubMed Scopus (113) Google Scholar). may the of a to to its receptor T. G. J. T.L. H. Cell. Full Text PDF PubMed Scopus Google Scholar), whereas the of may the site of a protein P. C. M. A. E. P. I. G. B. B. J. J. Lett. 1997; PubMed Scopus Google Scholar), protein P. R. B. J. M.J. M. S. Sci. 2002; Scholar, I. 2005; PubMed Scopus Google Scholar), or such as Lee M. C. S. C. Nature. 2004; 427: PubMed Scopus Google Scholar). we show that proNGF and a R. P. Teng K.K. Hempstead B.L. 2001; PubMed Scopus Google Scholar), and no O. M.S. S.J. H. C. K. D. S.J. J. Google Scholar), or and no Sci. PubMed Scopus Google neurite or TrkA and with activity to with and no M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google Scholar). the that or the biological activity of recombinant can and protein or protein P. R. B. J. M.J. M. S. Sci. 2002; Scholar, I. 2005; PubMed Scopus Google Scholar, Jones D. 2007; PubMed Scopus Google Scholar). we show that a not the neurotrophic activity of proNGF with apoptotic activity in cells R. P. Teng K.K. Hempstead B.L. 2001; PubMed Scopus Google Scholar). We show that proNGF in E. or cells activity. We that proNGF can neurotrophic activity no matter in which expression system it is of these are purified it is that or from the expression systems be for neurotrophic activity. we have that cleavage of proNGF is not for its neurotrophic activity. The of proNGF to when a is used to a for proNGF reduced the activity of proNGF, whereas there no in the activity of NGF for activation of the role of proNGF in the the activation of that occurs M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google Scholar, S. J. PubMed Scopus Google is to proNGF whereas proNGF to mature NGF is for the activity with longer J. C. A. Barker P.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google NGF of from the cell is although it is that proNGF is and secreted to as by and S. J. PubMed Scopus Google Scholar). ProNGF exhibits neurotrophic activity for primary neurons and for primed PC12 cells M. Yu G. Michalski B. S. A. Coughlin M.D. J. 2004; PubMed Scopus Google Scholar). However, in unprimed PC12 cells deprived of serum Sci. PubMed Scopus Google Scholar, J. Cell Biol. PubMed Scopus Google we that proNGF apoptosis. there a ratio of TrkA to p75NTR in unprimed PC12 cells compared with primed PC12 cells or This that of proNGF with apoptotic activity were in cells under conditions low TrkA high p75NTR In favor of this apoptotic activity of proNGF been in unprimed PC12 cells or PC12 cells with low levels of TrkA Sci. PubMed Scopus Google Scholar), neurons and expressing little or no TrkA M.S. Lee R. J.C. Hempstead B.L. S.O. Neuron. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, B. C. J.C. Lee R. K. M. Hempstead B.L. S.O. Sci. 2004; PubMed Scopus Google Scholar), and in and neurons expressing increased levels of p75NTR B. C. J.C. Lee R. K. M. Hempstead B.L. S.O. Sci. 2004; PubMed Scopus Google Scholar, M. C. A. R.S. M. Hempstead B.L. Carter W.J. J. Neurosci. 28: PubMed Scopus Google Scholar). been that the ratio of TrkA to p75NTR is of the that can the signaling pathway or by NGF A.M. Lee R. Neuron. Full Text PDF PubMed Scopus Google Scholar, D. Kaplan Chao M.V. Hempstead B.L. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Sci. PubMed Scopus Google Scholar). proNGF affinity NGF for p75NTR (14.Nykjaer A. Lee R. Teng K.K. Jansen P. Madsen P. Nielsen M.S. Jacobsen C. Kliemannel M. Schwarz E. Willnow T.E. Hempstead B.L. Petersen C.M. Nature. 2004; 427: 843-848Crossref PubMed Scopus (792) Google Scholar, R. P. Teng K.K. Hempstead B.L. 2001; PubMed Scopus Google Scholar), it is not that proNGF apoptosis NGF when p75NTR levels are high compared with we conclude that the ratio of TrkA to p75NTR plays a role in the signaling pathway by proNGF, and its biological activity. In increased proNGF promotes apoptotic activity in of p75NTR is or M.S. Lee R. J.C. Hempstead B.L. S.O. Neuron. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, B. C. J.C. Lee R. K. M. Hempstead B.L. S.O. Sci. 2004; PubMed Scopus Google Scholar, M. C. A. R.S. M. Hempstead B.L. Carter W.J. J. Neurosci. 28: PubMed Scopus Google Scholar), whereas proNGF is neurotrophic in the with of TrkA to p75NTR H. M.D. M. Exp. 2007; PubMed Scopus Google Scholar). We have that the ratio of TrkA to p75NTR is for proNGF activity. We that in Alzheimer neurons degenerate to of proNGF neurotrophic and that they proNGF-induced apoptosis as TrkA is In we have that the biological activity of proNGF is not by the expression or the system. However, bioassay conditions may the ratio of TrkA to in neurotrophic or apoptotic activity of assay or disease may levels of TrkA compared with p75NTR altering the balance of proNGF-induced signaling to favor apoptosis. We conclude that relative levels of TrkA to p75NTR receptors whether proNGF exhibits neurotrophic or apoptotic activity.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.