The p75 Neurotrophin Receptor Activates Akt (Protein Kinase B) through a Phosphatidylinositol 3-Kinase-dependent Pathway

The Akt kinase plays a crucial role in supporting Trk-dependent cell survival, whereas the p75 neurotrophin receptor (p75NTR) facilitates cellular apoptosis. The precise mechanism that p75NTR uses to promote cell death is not certain, but one possibility is that p75NTR-dependent ceramide accumulation inhibits phosphatidylinositol 3-kinase-mediated Akt activation. To test this hypothesis, we developed a system for examining p75NTR-dependent apoptosis and determined the effect of p75NTR on Akt activation. Surprisingly, p75NTR increased, rather than decreased, Akt phosphorylation in a variety of cell types, including human Niemann-Pick fibroblasts, which lack acidic sphingomyelinase activity. The p75NTR expression level required to elicit Akt phosphorylation was much lower than that required to activate the JNK pathway or to mediate apoptosis. We show that p75NTR-dependent Akt phosphorylation was independent of TrkA signaling, required active phosphatidylinositol 3-kinase, and was associated with increased tyrosine phosphorylation of p85 and Shc and with reduced cytosolic tyrosine phosphatase activity. Finally, we show that p75NTR expression increased survival in cells exposed to staurosporine or subjected to serum withdrawal. These findings indicate that p75NTR facilitates cell survival through novel signaling cascades that result in Akt activation. The Akt kinase plays a crucial role in supporting Trk-dependent cell survival, whereas the p75 neurotrophin receptor (p75NTR) facilitates cellular apoptosis. The precise mechanism that p75NTR uses to promote cell death is not certain, but one possibility is that p75NTR-dependent ceramide accumulation inhibits phosphatidylinositol 3-kinase-mediated Akt activation. To test this hypothesis, we developed a system for examining p75NTR-dependent apoptosis and determined the effect of p75NTR on Akt activation. Surprisingly, p75NTR increased, rather than decreased, Akt phosphorylation in a variety of cell types, including human Niemann-Pick fibroblasts, which lack acidic sphingomyelinase activity. The p75NTR expression level required to elicit Akt phosphorylation was much lower than that required to activate the JNK pathway or to mediate apoptosis. We show that p75NTR-dependent Akt phosphorylation was independent of TrkA signaling, required active phosphatidylinositol 3-kinase, and was associated with increased tyrosine phosphorylation of p85 and Shc and with reduced cytosolic tyrosine phosphatase activity. Finally, we show that p75NTR expression increased survival in cells exposed to staurosporine or subjected to serum withdrawal. These findings indicate that p75NTR facilitates cell survival through novel signaling cascades that result in Akt activation. nerve growth factor p75 neurotrophin receptor phosphatidylinositol 3-kinase phosphatidylinositol 3,4,5-trisphosphate tumor necrosis factor receptor c-Jun N-terminal kinase protein-tyrosine phosphatase bovine calf serum phosphate-buffered saline fluorescence-activated cell sorter multiplicity of infection cAMP-responsive element-binding protein mitogen-activated protein kinase kinase mitogen-activated protein kinase Fas-associated phosphatase-1 tumor necrosis factor receptor-associated factor The neurotrophins are a family of growth factors involved in the survival, development, and death of specific populations of neurons and non-neuronal cells. Nerve growth factor (NGF),1 the prototypic neurotrophin, is the best characterized member of this family, which in mammals, also includes brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 (1Lewin G.R. Barde Y.A. Annu. Rev. Neurosci. 1996; 19: 289-317Crossref PubMed Scopus (1766) Google Scholar). The signal transduction systems that mediate the diverse biological functions of the neurotrophins are initiated by two categories of cell-surface receptors: the Trk receptors and the p75 neurotrophin receptor (p75NTR). One of the main survival pathways for neuronal cell survival is mediated by phosphatidylinositol 3-kinase (PI3K) and involves activation of the Akt serine/threonine kinase (2Dudek H. Datta S.R. Franke T.F. Birnbaum M.J. Yao R. Cooper G.M. Segal R.A. Kaplan D.R. Greenberg M.E. Science. 1997; 275: 661-665Crossref PubMed Scopus (2212) Google Scholar). Increased phosphatidylinositol 3,4,5-trisphosphate (PIP3) production results primarily from relocalization of PI3K from the cytosol to a juxtamembrane location that provides access to PIP substrates. This redistribution of PI3K requires the association of the SH2 domain within the p85 regulatory subunit of PI3K with phosphorylated tyrosines present on activated cell-surface receptors or on receptor-associated adaptor proteins (reviewed in Ref. 3Kaplan D.R. Miller F.D. Curr. Opin. Neurobiol. 2000; 10: 381-391Crossref PubMed Scopus (1630) Google Scholar). Accumulation of PIP3 and its phospholipid phosphatase product, phosphatidylinositol 3,4-bisphosphate, in the plasma membrane creates docking sites for the pleckstrin homology domains of phosphoinositide-dependent kinase-1 and Akt. Phosphorylation of Akt on threonine 308 by phosphoinositide-dependent kinase-1 followed by autophosphorylation on serine 473 activates Akt (4Bellacosa A. Chan T.O. Ahmed N.N. Datta K. Malstrom S. Stokoe D. 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Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). p75NTR activates sphingomyelinase in a we determined p75NTR activation Akt and facilitate apoptosis. results show that p75NTR regulate but to we that p75NTR Akt activation through a pathway that requires PI3K and show that p75NTR expression apoptosis. of p75NTR mediate cell the p75NTR expression level required to elicit Akt phosphorylation is much lower than that required to activate the JNK pathway or to mediate apoptosis. The effect of p75NTR on Akt with increased tyrosine phosphorylation of the p85 regulatory subunit of PI3K and of Shc adaptor that may a role in this with p75NTR expression results in reduced cytosolic tyrosine phosphatase activity. These data indicate that a physiological role of p75NTR is to cell survival through was from cell from and all from or p75NTR M.J. C. Shooter E.M. Nature. PubMed Scopus Google the p75NTR domain M. C. A. R. C. S. A. D. J. Miller F.D. P.A. J. Neurosci. 1997; 17: PubMed Google or the p75NTR domain to N-terminal from kinase J.M. Mol. Cell. Biol. PubMed Scopus Google was with cells. from to cells. p75NTR expression was by and by in on and by in cells. or protein the and for the p75NTR The cell and in in with bovine calf serum and and Niemann-Pick human from the Cell and cells in and C. D. C. P.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). for and phosphorylated proteins was from or from p75NTR was a a protein of the domain of p75NTR M. C. A. R. C. S. A. D. J. Miller F.D. P.A. J. Neurosci. 1997; 17: PubMed Google Scholar, P.A. J. Neurosci. 1999; 19: PubMed Google Scholar). from cell was the and of protein was in Nature. PubMed Scopus Google by and and of in and with in with bovine serum bovine serum was for the or protein was a of to the cells with a or with the p75NTR domain or the p75NTR domain to a cells from in phosphate-buffered saline for and in of and in a with and a was the The was for the was and the was in and for protein and by and of cell survival was which was a of for a The was by the of of and specific and and was and results for by of cells in saline and in and was of of of or of protein which was for and subjected to to protein for followed by and in and by cell death was and cells with and in with the the cells in of and for in the was to and cells on a of cells with cells and in and and on for of of was and cells for in the in of bovine serum and and for on was a of and the was for in and for in with a of and in of with for with was to the for and on a was in and results for by of cells in saline to and in of and and for to and and membrane by for The membrane was for in of with and for to was from membrane and cytosolic by in on the and the was to of protein to a of The was by the of of and was a a was to a of to the of specific tyrosine phosphatase activity. for that not the was was in and results for by of The of p75NTR are and not This is in to the lack of cellular systems in which p75NTR-dependent signaling from M. C. A. R. C. S. A. D. J. Miller F.D. P.A. J. Neurosci. 1997; 17: PubMed Google Scholar) and M. E. Y. J. D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) that of the domain of superfamily activate downstream signaling To activate p75NTR signaling cascades in a variety of cellular the domain of p75NTR or a of the domain of p75NTR that is to the plasma membrane or protein for all To signaling of p75NTR we on the survival of cells but not that effect on cell survival, whereas p75NTR or a multiplicity of infection of of lower of infection than that of p75NTR or that membrane of the domain may for p75NTR-dependent apoptosis. p75NTR-dependent cell death was not of protein or infection of effect on cell that p75NTR activation to JNK activation J. Kaplan D.R. Miller F.D. J. Cell Biol. 1998; PubMed Scopus Google Scholar, M. D.J. R. J. Miller F.D. J. Cell Biol. 1998; PubMed Scopus Google Scholar, P. B. Chao M.V. J. Neurosci. 1998; PubMed Google and with we that expression of and p75NTR increased phosphorylation of JNK on threonine and tyrosine and increased c-Jun phosphorylation on serine of not JNK or c-Jun phosphorylation not The level of c-Jun protein was also p75NTR expression to of Res. Scholar) the infection To the of the JNK activation initiated by we phosphorylation of the factor which downstream of protein kinase and the phosphorylation of which activates not phosphorylation was by p75NTR expression These results show that p75NTR signaling results in specific activation of the JNK pathway and cell death and that the p75NTR show the signaling that ceramide inhibits PI3K cellular PIP3 and inhibits Akt A. 1998; 12: PubMed Scopus Google Scholar, H. Birnbaum M.J. Pittman R.N. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). p75NTR activates sphingomyelinase neurotrophin Chao M.V. Y.A. Science. 1994; PubMed Scopus Google Scholar, G.M. Y.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and we that p75NTR facilitate apoptosis by PIP3 production and Akt activity. To p75NTR Akt cells with of the p75NTR or and for Akt activation Akt serine 473 Akt autophosphorylation that with Akt kinase A. Newton A.C. J. Biol. Chem. 2000; 275: 8271-8274Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar). 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Shooter E.M. Neuron. 1994; 13: 203-215Abstract Full Text PDF PubMed Scopus (367) Google Scholar) and of J.M. Birren S.J. Ibanez C.F. Persson H. Kaplan D.R. Benedetti M. Chao M.V. Anderson D.J. Neuron. 1994; 12: 733-745Abstract Full Text PDF PubMed Scopus (311) Google Scholar, D. Kaplan Chao M.V. Hempstead J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar) that p75NTR the of TrkA to was that the p75NTR-dependent Akt phosphorylation is to activation of of TrkA that may present in cells. To cells to that activated TrkA was not in cells in which TrkA was in cells. We a specific TrkA for its to Akt phosphorylation and which are of and in this infection level activated Akt but not cell death that Akt phosphorylation in but effect on and Akt phosphorylation in or cells. activation of Akt of TrkA cells and is that p75NTR may mediate in Akt phosphorylation by signaling from To the of p75NTR on Akt phosphorylation determined in a variety of cell that not p75NTR or p75NTR expression in or cells not in increased Akt similar to that in cells. These results indicate that the effect of p75NTR on Akt phosphorylation not of p75NTR on cellular and we to that p75NTR expression Akt activation. is cell in which expression of p75NTR is through the of C. D. C. P.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) and to that p75NTR results in Akt with for the in p75NTR and this with a in Akt phosphorylation two independent of p75NTR expression result in Akt activation in cell The in Akt phosphorylation the that a of cells show p75NTR expression to p75NTR sphingomyelinase and one for the effect of p75NTR on Akt is that p75NTR cellular cellular ceramide and a in PI3K PIP3 and Akt To we the of p75NTR on Akt activation in and Niemann-Pick Niemann-Pick are in acidic which is the of sphingomyelinase activated by p75NTR in cells. T. that p75NTR and Akt phosphorylation in human from and Niemann-Pick that of acidic sphingomyelinase activation is not involved in this p75NTR These data are with the that p75NTR of p75NTR signaling result in JNK c-Jun and cell and lower of p75NTR signaling pathways that include Akt activation and To cells with or and exposed to staurosporine for and of cellular apoptosis determined by by that infection of cells with p75NTR and reduced the of apoptosis with cells or cells with To results to cellular cells for survival cells from the cell which cell death in the of growth cells with of for p75NTR and of serum for was to p75NTR expression and apoptosis. that the that p75NTR was much to cell death by serum that p75NTR survival To to the by p75NTR to activate the effect of PI3K on Akt phosphorylation was and for to Akt phosphorylation by in cells. reduced Akt activation. also Akt phosphorylation by the or or p75NTR not in cells and in human cells. 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M. 1997; PubMed Scopus Google Scholar). also to the p85 subunit of PI3K a similar p75NTR-dependent in tyrosine that but not increased tyrosine phosphorylation of These results indicate that p75NTR activates a pathway by tyrosine phosphorylation of adaptor proteins that PI3K to the plasma To the of cell-surface proteins is by p75NTR cells with and cell-surface and for by that p75NTR expression increased tyrosine phosphorylation of a in cells with results show that p75NTR expression increased tyrosine phosphorylation of in the of a p75NTR and its effect on phosphorylation to regulatory with proteins of kinase or of the p75NTR and the S. T. S. J. Y. 1999; PubMed Scopus Google the possibility that cellular tyrosine phosphatase by To test cells with or subjected to and for cytosolic and that expression of p75NTR or in a in cytosolic whereas was by p75NTR These results indicate that p75NTR is of cytosolic and suggest that in the mediated by p75NTR may to in activity. We that p75NTR expression to Akt of p75NTR expression JNK and c-Jun phosphorylation and promote lower p75NTR expression are associated with activation of Akt and of apoptosis by p75NTR expression that Akt phosphorylation and survival the of cellular including p85 and that p75NTR the of tyrosine or with we that p75NTR expression is associated with a in cytosolic activity. that p75NTR facilitate apoptosis. M. C. A. R. C. S. A. D. J. Miller F.D. P.A. J. Neurosci. 1997; 17: PubMed Google Scholar) that of the p75NTR domain within neurons of results in of and and Barde and J.M. A. Barde Y.A. Nature. 1996; PubMed Scopus Google Scholar, J.M. Barde Y.A. Neuron. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) that cells that p75NTR cell death that by the of or the p75NTR p75NTR or show in apoptosis within the and J.M. Barde Y.A. 1999; Google and p75NTR facilitate apoptosis of P. Chao M.V. Nature. 1996; PubMed Scopus Google Scholar) and neurons M. D.J. R. J. Miller F.D. J. 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The activation of Akt by p75NTR requires active PI3K and with in the of including the adaptor protein the p85 regulatory subunit of and a cell-surface The increased of proteins with reduced cytosolic in the of of a cytosolic may a in the signaling that may a to with the and PIP3 required to specific by but one is which with p75NTR in cells S. T. S. J. Y. 1999; PubMed Scopus Google Scholar). also binds human T. S. S. Science. PubMed Scopus Google and apoptosis by Y. H. T. T. S. J. T. J. 2000; PubMed Scopus Google Scholar, J. M. H. H. T. E. T. M. E. S. T. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar) through mechanism that may for Akt activation involves a proteins and The receptor is a member of the superfamily that activates survival pathways in in by and a that a of kinase and is required for this effect D. N. M. H. Y. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). p75NTR with of the family, including Chao M.V. J. Biol. 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Full Text PDF PubMed Google with the possibility that p75NTR may also and a that specific signaling but not the of the receptor the role of is to the receptor to a signaling p75NTR in Akt activation expression but much of expression required for We the that signaling p75NTR signaling and that p75NTR in two signaling in the p75NTR activate survival pathways that and by activates signaling pathways that result in cellular apoptosis. we a novel p75NTR signaling pathway that results in phosphorylation of Akt and that cell These data suggest that the signaling role of p75NTR may than with p75NTR of signaling pathways that survival and death cellular We are to and for with for phosphatase and Kaplan for the and and and for of the

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