Neurotrophin signal transduction in the nervous system

doi:10.1016/S0959-4388(00)00092-1

Current Opinion in Neurobiology

Volume 10, Issue 3, 1 June 2000, Pages 381-391

https://doi.org/10.1016/S0959-4388(00)00092-1 Get rights and content

Abstract

Neurotrophins use two types of receptors, the Trk tyrosine kinase receptors and the p75 neurotrophin receptor (p75NTR), to regulate the growth, development, survival and repair of the nervous system. These receptors can either collaborate with or inhibit each other’s actions to mediate neurotrophin effects. The development and survival of neurons is thus based upon the functional interplay of the signals generated by Trk and p75NTR. In the past two years, the signaling pathways used by these receptors, including Akt and MAPK-induced signaling via Trk, and JNK, p53, and NF-κB signaling via p75NTR, have been identified. In addition, a number of novel p75NTR-interacting proteins have been identified that transmit growth, survival, and apoptotic signals.

Introduction

Neurotrophins mediate the survival, differentiation, growth, and apoptosis of neurons by binding to two types of cell surface receptors, the Trk tyrosine kinases and the p75 neurotrophin receptor (p75NTR). These receptors, often present on the same cell, coordinate and modulate the responses of neurons to neurotrophins. The functions of the neurotrophin receptors vary markedly, from the sculpting of the developing nervous system to the regulation of the survival and regeneration of injured neurons. Strikingly, while Trk receptors transmit positive signals such as enhanced survival and growth, p75NTR transmits both positive and negative signals. The signals generated by the two neurotrophin receptors can either augment or oppose each other. Trk and p75NTR thus exist in a paradoxical relationship, each acting to suppress or enhance the other’s actions. How the two neurotrophin receptors act together to regulate the responses of cells to neurotrophins, and the nature of the intracellular signals used by these receptors to exert their effects, are the key questions in neurotrophin signal transduction. In the past two years, several of the intracellular signaling proteins and signal transduction pathways used by these receptors to promote neurotrophin actions have been identified. In this review, we discuss the latest findings in neurotrophin signaling, emphasizing the mechanisms used by the neurotrophin receptors to promote neuronal survival and apoptosis in primary neurons and in vivo systems.

Section snippets

Trk-mediated survival often emanates from Ras

A potent activity of neurotrophins, particularly in sympathetic and sensory neurons, is neuronal survival. Both during development and in culture, the survival of these neurons is absolutely dependent upon a constant exposure to optimal amounts of neurotrophins. The first neurotrophin-activated signaling protein shown to mediate survival of these neurons was the small GTP-binding protein Ras. Inhibition of Ras activity decreased survival of most, but not all, populations of sympathetic neurons 1

The PI-3K/Akt survival pathway

PI-3K was first identified as a regulator of neurotrophin-mediated survival responses by Cooper and colleagues in nerve growth factor (NGF)-dependent PC12 cells [4]. Subsequently, many groups showed that in cerebellar, sympathetic, sensory, cortical and motor neurons, PI-3 kinase activity was responsible for as much as 80% of neurotrophin-regulated cell survival 5, 6, 7, 8, 9•, 10••, 11, 12, 13••, 14, 15, indicating that PI-3K is the major survival-promoting protein for neurons. Not all

PI-3K is a target of Ras

An intimate connection between Ras and PI-3K activity in PC12 cells was first reported by Downward and colleagues [17], who demonstrated that Ras directly interacted with PI-3K and that inhibition of Ras suppressed NGF-mediated PI-3K activity. More recently, Ras was shown to activate PI-3K survival promoting pathways in peripheral neurons using two approaches. First, Ras effector mutants that were selective for activating PI-3K, but not those selective for activating MEK/MAPK or RalGDS

Akt is a crucial mediator of PI-3K-induced survival activity

PI-3K, like Ras, stimulates the activities of many signaling proteins. Among these is the serine/threonine kinase Akt (or protein kinase B), a target of NGF-induced PI-3K activity 20, 21. Greenberg and colleagues [6] first reported a role for Akt in neuronal survival, showing that cerebellar neurons required Akt for 20% of IGF-1-induced survival. Subsequently, Akt activity was shown, using dominant-inhibitory Akt, to be necessary for approximately 80% of NGF-induced survival of sympathetic

The targets of Akt

In neurons, Akt has only been shown to regulate survival, and not any other response such as neurite outgrowth or differentation. Thus, all of the proposed direct targets of Akt activity identified in the past year have been proteins that regulate cell survival in many cell systems: these include Bad, an inhibitor of the Bcl-2 anti-apoptotic protein; pro-caspase-9, which is cleaved into the pro-apoptotic caspase-9; and Forkhead, a transcription factor that induces apoptosis by increasing levels

MEK/MAP kinase — a second survival pathway used by neurotrophins?

A second survival-promoting pathway used by neurotrophins consists of the Ras-MEK-MAPK pathway (Figure 1). This pathway has many roles in neurons, including synaptic plasticity, long-term potentiation, and survival (reviewed in [39^•]). The evidence for the contribution of this pathway to neuronal survival is, however, conflicting. While NGF induces a strong and sustained activation of MAPK in sympathetic neurons and PC12 cells, most studies have found that inhibition of MEK has minimal effects

Targets of MEK/MAPK survival activity

Akt induces survival by inhibiting the activity of apoptotic proteins. In contrast, MEK/MAPK induces survival by stimulating the activity or expression of anti-apoptotic proteins, including Bcl-2 and the transcription factor CREB (cAMP response element binding protein). NGF potently increased Bcl-2 levels in sympathetic neurons [48^••], which in turn protected these and other neurons from apoptotic cell death [49]. Inhibition of MEK/MAPK activity in PC12 cells completely blocked NGF’s ability to

p75NTR as a signaling receptor

Although p75NTR was the first-isolated neurotrophin receptor, as well as the first-reported member of the p75NTR/Fas/TNFR1 (tumor necrosis factor receptor 1) family (reviewed in [55]), our understanding of its physiological role and the underlying signaling mechanisms has lagged considerably behind our understanding of the Trk neurotrophin receptors. In particular, studies on p75NTR have been complicated by the fact that it can interact directly with Trk [56], and by the finding that its

p75NTR as an apoptotic receptor independent of Trk

The original finding that p75NTR could mediate neuronal apoptosis in a neural cell line [57] has, over the past several years, been extended to a large number of primary neural cells, both in culture and in vivo. In particular, ligand-dependent activation of p75NTR has been shown to cause the apoptosis of cultured neonatal sympathetic neurons [58^••], motor neurons 59, 60, sensory neurons 61, 62•, oligodendrocytes [63] and Schwann cells [64^•]. Still controversial, however, is the role of p75NTR

p75NTR mediates apoptosis following injury and during development

The past year has also seen a number of studies indicating that the apoptotic function of p75NTR is important following neural injury and during development. The first suggestion that p75NTR might be involved in injury-induced apoptosis originated with studies showing that neuron-specific expression of the p75NTR intracellular domain caused the death of injured facial motor neurons in transgenic mice [70]. More recently, endogenous p75NTR was shown to play a role in the death of injured

p75NTR apoptotic signal transduction

How does p75NTR signal apoptosis? One recently elucidated pathway involves JNK (Jun amino-terminal kinase)-p53-Bax, which is activated by p75NTR activation and following NGF withdrawal ([48^••], Figure 2, Figure 3). p53 appears to be a key death sensor in this pathway, with the levels of this protein determining whether neurons undergo apoptosis in vivo and in culture [48^••]. MEKK and JNK function upstream of p53 in p75NTR-mediated apoptosis, while cdc42/Rac1, Ask1, MKK (mitogen-activated

p75NTR as a signaling receptor in the presence of Trk activation

One of the major conclusions that can be derived from recent studies on the neurotrophin receptors is that the signaling capacity and biological role of p75NTR is a function of cellular Trk activation status. In particular, as discussed above, Trk signaling silences p75NTR-mediated apoptotic pathways such as the JNK-p53 pathway, while leaving other p75NTR pathways ‘intact’. Moreover, emerging evidence indicates that crosstalk between these two receptors is bidirectional, with p75NTR modulating

p75NTR and the regulation of neuronal growth

A second biological function of p75NTR in the presence of Trk activation is the modulation of neuronal growth. Such a role for p75NTR was first suggested by the finding that sympathetic innervation patterns were perturbed in p75NTR^−/− mice [95]. More recent studies led to the conclusion that ligand-mediated p75NTR activation inhibits TrkA-mediated growth and target innervation of sympathetic neurons [96^•]. Remarkably, elimination of p75NTR even led to robust sprouting of adult sympathetic nerve

Conclusions

Neurotrophins regulate neuronal survival and apoptosis at several levels. Trk uses at least two mechanisms, Ras/PI-3K/Akt-induced suppression of apoptotic proteins and pathways, and MEK/MAPK activation of anti-apoptotic proteins, to stimulate survival. p75NTR can potentiate Trk activity through the activation of NF-κB. In most cases, however, p75NTR functions as a ligand-stimulated apoptotic receptor, inducing the activity of the JNK–p53–Bax apoptosis pathway, and of other proteins that

Acknowledgements

We thank Ute Zirrgiebel and Frank Zuhl for generating the figures for this review.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

References (122)

K.S. Vogel et al.
Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons
Cell
(1995)
S.E. Bartlett et al.
In sympathetic but not sensory neurons, phosphoinositide-3 kinase is important for NGF-dependent survival and the retrograde transport of 125I-βNGF
Brain Res
(1997)
K. Virdee et al.
Nerve growth factor-induced PKB/Akt activity is sustained by phosphoinositide 3-kinase dependent and independent signals in sympathetic neurons
Brain Res
(1999)
M. Hetman et al.
Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase
J Biol Chem
(1999)
E.J. Williams et al.
Evidence for and against a pivotal role of PI 3-kinase in a neuronal cell survival pathway
Mol Cell Neurosci
(1999)
J.M. Korhonen et al.
Gab1 mediates neurite outgrowth, DNA synthesis, and survival in PC12 cells
J Biol Chem
(1999)
S.R. Datta et al.
Akt phosphorylation of Bad couples survival signals to the cell-intrinsic death machinery
Cell
(1997)
E. Fujita et al.
Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9
Biochem Biophys Res Commun
(1999)
A. Brunet et al.
Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor
Cell
(1999)
M. Pap et al.
Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway
J Biol Chem
(1998)

S.S. Grewal et al.

Extracellular-signal-regulated kinase signalling in neurons

Curr Opin Neurobiol

(1999)

D.J. Creedon et al.

Mitogen-activated protein kinase-independent pathways mediate the effects of nerve growth factor and cAMP on neuronal survival

J Biol Chem

(1996)

S. Shen et al.

Retinal ganglion cells lose trophic responsiveness after axotomy

Neuron

(1999)

T.M. Michaelidis et al.

Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development

Neuron

(1996)

K. Du et al.

CREB is a regulatory target for the protein kinase Akt/PKB

J Biol Chem

(1998)

T. Morooka et al.

Requirement of p38 mitogen-activated protein kinase for neuronal differentiation in PC12 cells

J Biol Chem

(1998)

F. Davey et al.

TrkB signalling inhibits p75-mediated apoptosis induced by nerve growth factor in embryonic proprioceptive neurons

Curr Biol

(1998)

J.S. Rudge et al.

Endogenous BDNF protein is increased in adult rat hippocampus after a kainic acid induced excitotoxic insult but exogenous BDNF is not neuroprotective

Exp Neurol

(1998)

M. Majdan et al.

Neuronal life and death decisions: functional antagonism between the Trk and p75 neurotrophin receptors

Int J Devl Neurosci

(1999)

D. Schwartz et al.

p53-dependent cell cycle control: response to genotoxic stress

Semin Cancer Biol

(1998)

G. Khursigara et al.

Association of the p75 neurotrophin receptor with TRAF6

J Biol Chem

(1999)

K. Kimpinski et al.

The anti-p75 antibody, MC192, and brain-derived neurotrophic factor inhibit nerve growth factor-dependent neurite growth from adult sensory neurons

Neurosci

(1999)

M. Hamanoue et al.

p75-mediated NF-κB activation enhances the survival response of developing sensory neurons to nerve growth factor

Mol Cell Neurosci

(1999)

B.R. Wong et al.

TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src

Mol Cell

(1999)

X. Ye et al.

TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction

J Biol Chem

(1999)

H. Zhou et al.

Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis

J Biol Chem

(1998)

G.D. Borasio et al.

Involvement of ras p21 in neurotrophin-induced response of sensory but not sympathetic neurons

J Cell Biol

(1993)

C.D. Nobes et al.

Neutralizing anti-p21ras Fabs suppress rat sympathetic neuron survival induced by NGF, LIF, CNTF and cAMP

Eur J Neurosci

(1995)

R. Yao et al.

Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor

Science

(1995)

R.J. Crowder et al.

Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons

J Neurosci

(1998)

H. Dudek et al.

Regulation of neuronal survival by the serine-threonine protein kinase Akt

Science

(1997)

S.R. D’Mello et al.

Insulin-like growth factor and potassium depolarization maintain neuronal survival by distinct pathways: possible involvement of PI 3-kinase in IGF-1 signaling

J Neurosci

(1997)

I.E. Mazzoni et al.

Ras regulates sympathetic neuron survival by suppressing the p53-mediated cell death pathway

J Neurosci

(1999)

A.R. Vaillant et al.

Depolarization and neurotrophins converge on the phosphatidylinositol 3-kinase-Akt pathway to synergistically regulate neuronal survival

J Cell Biol

(1999)

L.J. Klesse et al.

p21 Ras and phosphatidylinositol-3 kinase are required for survival of wild-type and NF1 mutant sensory neurons

J Neurosci

(1998)

X. Dolcet et al.

Activation of phosphatidylinositol 3-kinase, but not extracellular-regulated kinases, is necessary to mediate brain-derived neurotrophic factor-induced motoneuron survival

J Neurochem

(1999)

K.L. Philpott et al.

Activated phosphatidylinositol 3-kinase and Akt kinase promote survival of superior cervical neurons

J Cell Biol

(1997)

P. Rodriguez-Viciana et al.

Phosphatidylinositol-3-OH kinase as a direct target of Ras

Nature

(1994)

M. Holgado-Madruga et al.

Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor

Proc Natl Acad Sci USA

(1997)

M. Andjelkovic et al.

Nerve growth factor promotes activation of the alpha, beta and gamma isoforms of protein kinase B in PC12 pheochromocytoma cells

Eur J Biochem

(1998)

M. Aschroft et al.

The selective and inducible activation of endogenous PI 3-kinase in PC12 cells results in efficient NGF-mediated survival but defective neurite outgrowth

Oncogene

(1999)

L.A. Blair et al.

Akt-dependent potentiation of L channels by insulin-like growth factor-1 is required for neuronal survival

J Neurosci

(1999)

R.J. Crowder et al.

The survival of sympathetic neurons promoted by potassium depolarization, but not by cyclic AMP, requires phosphatidylinositol 3-kinase and Akt

J Neurochem

(1999)

E.C. Le Casse et al.

The inhibitors of apoptosis (IAPs) and their emerging role in cancer

Oncogene

(1998)

S. Wiese et al.

The anti-apoptotic protein ITA is essential for NGF-mediated survival of embryonic chick neurons

Nat Neurosci

(1999)

S.R. Datta et al.

Cellular survival: a play in three Akts

Genes Dev

(1999)

T.O. Chan et al.

AKT/PKB and other D3 phosphoinositide-regulated kinase: kinase activation by phosphoinositide-dependent phosphorylation

Annu Rev Biochem

(1999)

B. Vanhaesebroeck et al.

The PI3K–PDK1 connection: more than just a road to PKB

Biochem J

(2000)

L. Del Peso et al.

Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt

Science

(1997)

A. Bonni et al.

Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms

Science

(1999)

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ReviewNeurotrophin signal transduction in the nervous system

Abstract

Introduction

Section snippets

Trk-mediated survival often emanates from Ras

The PI-3K/Akt survival pathway

PI-3K is a target of Ras

Akt is a crucial mediator of PI-3K-induced survival activity

The targets of Akt

MEK/MAP kinase — a second survival pathway used by neurotrophins?

Targets of MEK/MAPK survival activity

p75NTR as a signaling receptor

p75NTR as an apoptotic receptor independent of Trk

p75NTR mediates apoptosis following injury and during development

p75NTR apoptotic signal transduction

p75NTR as a signaling receptor in the presence of Trk activation

p75NTR and the regulation of neuronal growth

Conclusions

Acknowledgements

References and recommended reading

Cell

Brain Res

Brain Res

J Biol Chem

Mol Cell Neurosci

J Biol Chem

Cell

Biochem Biophys Res Commun

Cell

J Biol Chem

Curr Opin Neurobiol

J Biol Chem

Neuron

Neuron

J Biol Chem

J Biol Chem

Curr Biol

Exp Neurol

Int J Devl Neurosci

Semin Cancer Biol

J Biol Chem

Neurosci

Mol Cell Neurosci

Mol Cell

J Biol Chem

J Biol Chem

Involvement of ras p21 in neurotrophin-induced response of sensory but not sympathetic neurons

J Cell Biol

Neutralizing anti-p21ras Fabs suppress rat sympathetic neuron survival induced by NGF, LIF, CNTF and cAMP

Eur J Neurosci

Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor

Science

Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons

J Neurosci

Regulation of neuronal survival by the serine-threonine protein kinase Akt

Science

Insulin-like growth factor and potassium depolarization maintain neuronal survival by distinct pathways: possible involvement of PI 3-kinase in IGF-1 signaling

J Neurosci

Ras regulates sympathetic neuron survival by suppressing the p53-mediated cell death pathway

J Neurosci

Depolarization and neurotrophins converge on the phosphatidylinositol 3-kinase-Akt pathway to synergistically regulate neuronal survival

J Cell Biol

p21 Ras and phosphatidylinositol-3 kinase are required for survival of wild-type and NF1 mutant sensory neurons

J Neurosci

Activation of phosphatidylinositol 3-kinase, but not extracellular-regulated kinases, is necessary to mediate brain-derived neurotrophic factor-induced motoneuron survival

J Neurochem

Activated phosphatidylinositol 3-kinase and Akt kinase promote survival of superior cervical neurons

J Cell Biol

Phosphatidylinositol-3-OH kinase as a direct target of Ras

Nature

Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor

Proc Natl Acad Sci USA

Nerve growth factor promotes activation of the alpha, beta and gamma isoforms of protein kinase B in PC12 pheochromocytoma cells

Eur J Biochem

The selective and inducible activation of endogenous PI 3-kinase in PC12 cells results in efficient NGF-mediated survival but defective neurite outgrowth

Oncogene

Akt-dependent potentiation of L channels by insulin-like growth factor-1 is required for neuronal survival

J Neurosci

The survival of sympathetic neurons promoted by potassium depolarization, but not by cyclic AMP, requires phosphatidylinositol 3-kinase and Akt

J Neurochem

Review
Neurotrophin signal transduction in the nervous system