Truncated TrkB: Beyond a dominant negative receptor

doi:10.1016/j.cytogfr.2012.01.002

Cytokine & Growth Factor Reviews

Volume 23, Issues 1–2, February–April 2012, Pages 15-24

https://doi.org/10.1016/j.cytogfr.2012.01.002 Get rights and content

Abstract

BDNF activates trkB receptors to regulate neuronal survival, differentiation, and proliferation. Mutations in the BDNF gene, altered BDNF expression, and altered trkB expression are associated with degenerative and psychiatric disorders. The full-length trkB receptor (trkB.tk⁺) undergoes autophosphorylation to activate intracellular signaling pathways. The truncated trkB receptor (trkB.t1) is abundantly expressed in the brain but lacks the catalytic tyrosine kinase domain. TrkB.t1 is a dominant-negative receptor that inhibits trkB.tk⁺ signaling. While this is an important function of trkB.t1, it is only one of its many functions. TrkB.t1 sequesters and translocate BDNF, induces filopodia and neurite outgrowth, stimulates intracellular signaling cascades, regulates Rho GTPase signaling, and modifies cytoskeletal structures. TrkB.t1 is an active signaling molecule with regulatory effects on neurons and astrocytes.

Section snippets

Brain derived neurotrophic factor

BDNF is a neurotrophic factor with diverse, region specific effects. These effects are regulated by spatial and temporal changes in BDNF, trkB isoforms, intracellular signaling molecules, and gene expression. TrkB.tk⁺ mediates the neurotrophic effects of BDNF through PLCγ, PI3K, and Erk/MAPK pathways [1], [29]. The role of trkB.t1 in promoting neuronal survival is unclear, but it has a distinct role in differentiation [25], [30], [31]. This section will provide an overview of BDNF-mediated cell

TrkB receptor isoforms

The trkB gene is located on chromosome 9q22, over 590kbp long, and contains 24 exons [67], [68]. Exons 1-5 contain G/C rich internal initiation entry sites (IRES) and recruit transcription factors to transcription start sites. The start codon for full-length N-terminal receptors is located on exon 5. Four major protein isoforms are derived from translation start sites at the exon 5 start codon. These include: the full-length tyrosine kinase receptor (trkB.tk⁺; gp145), the C-terminal truncated

TrkB.tk⁺ signaling pathways

Three trkB dimers are found in the brain: (1) trkB.tk⁺ homodimer, (2) trkB.t1 homodimer, and (3) trkB.t1-trkB.tk⁺ heterodimer [78]. TrkB.tk⁺ homodimer signaling is complex and mediates the neurotrophic effects of BDNF. The trkB.t1 homodimer regulates cytoskeletal changes in a BDNF-independent manner. When trkB.t1 forms a heterodimer with trkB.tk⁺, it becomes a dominant-negative receptor that inhibits activation of trkB.tk⁺ signaling. Therefore, trkB.t1 negatively regulates PLCγ, PI3K, and

TrkB.t1 protein distribution in the mammalian CNS

In 1990, trkB.t1 was identified as the alternative trkB transcript [13]. The following decade led to the identification of the regional distribution of trkB.tk⁺ and trkB.t1. During this timeframe, trkB.tk⁺ was identified as the signaling isoform of trkB [1] and trkB.t1 was identified as the dominant-negative isoform [17], [18], [19], [78]. Because trkB.tk⁺ was identified as the signaling isoform, it was the focus of most research studies addressing cellular and subcellular receptor localization

The role of trkB.t1 in the brain

TrkB.t1 was identified over 20 years ago [13], yet we are just beginning to understand its function. There is abundant evidence demonstrating trkB.t1-induced inhibition of trkB.tk⁺ and subsequent PLCγ, PI3K, and Erk/MAPK signaling [17], [19], [91], [92], [93]. Dominant-negative inhibition of trkB.tk⁺ by trkB.t1 is so well characterized that many experiments induce trkB.t1 overexpression to verify phenomena that that may be regulated by trkB.tk⁺.

Many early experiments approached the potential

Conclusion

TrkB receptor distribution changes throughout development and in regions of the brain affected by neurodegenerative and psychiatric disorders [14], [15], [89]. In the aging brain, there is a relative increase in trkB.t1 expression compared to trkB.tk⁺ [85], [90], [104], [105]. The relative increase in trkB.t1 may result from upregulation of trkB.t1 protein expression or a functional decrease in trkB.tk⁺ expression. Future studies need to address the cellular and subcellular localization of

References (108)

N. Pivac et al.
Brain derived neurotrophic factor Val66Met polymorphism and psychotic symptoms in Alzheimer's disease
Prog Neuropsychopharmacol Biol Psychiatry
(2011)
M.G. Murer et al.
Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease
Prog Neurobiol
(2001)
H. Jourdi et al.
BDNF mediates the neuroprotective effects of positive AMPA receptor modulators against MPP⁺-induced toxicity in cultured hippocampal and mesencephalic slices
Neuropharmacology
(2009)
K. Stahl et al.
Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease
Brain Res
(2011)
R. Klein et al.
The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain
Cell
(1990)
K. Ohira et al.
Change of expression of full-length and truncated TrkBs in the developing monkey central nervous system
Brain Res Dev Brain Res
(1999)
K. Ohira et al.
Expression of TrkB subtypes in the adult monkey cerebellar cortex
J Chem Neuroanat
(2003)
R.H. Fryer et al.
Truncated trkB receptors on nonneuronal cells inhibit BDNF-induced neurite outgrowth in vitro
Exp Neurol
(1997)
R.F. Alderson et al.
Truncated TrkB mediates the endocytosis and release of BDNF and neurotrophin-4/5 by rat astrocytes and schwann cells in vitro
Brain Res
(2000)
K. Ohira et al.
TrkB-T1 regulates the RhoA signaling and actin cytoskeleton in glioma cells
Biochem Biophys Res Commun
(2006)

J. Atkinson et al.

Effects of neurotrophins on embryonic retinal outgrowth

Brain Res Dev Brain Res

(1999)

K. Kawamura et al.

Regulation of preimplantation embryo development by brain-derived neurotrophic factor

Dev Biol

(2007)

H. Staecker et al.

NGF, BDNF and NT-3 play unique roles in the in vitro development and patterning of innervation of the mammalian inner ear

Brain Res Dev Brain Res

(1996)

S. Linnarsson et al.

Cell death in regenerating populations of neurons in BDNF mutant mice

Brain Res Mol Brain Res

(2000)

T. Hagg

Neurotrophins prevent death and differentially affect tyrosine hydroxylase of adult rat nigrostriatal neurons in vivo

Exp Neurol

(1998)

A.K. McAllister et al.

Opposing roles for endogenous BDNF and NT-3 in regulating cortical dendritic growth

Neuron

(1997)

K. Mertz et al.

Brain-derived neurotrophic factor modulates dendritic morphology of cerebellar basket and stellate cells: an in vitro study

Neuroscience

(2000)

C. Finsterwald et al.

Regulation of dendritic development by BDNF requires activation of CRTC1 by glutamate

J Biol Chem

(2010)

E.G. Waterhouse et al.

New insights into the role of brain-derived neurotrophic factor in synaptic plasticity

Mol Cell Neurosci

(2009)

S. Theofilopoulos et al.

Parallel induction of the formation of dopamine and its metabolites with induction of tyrosine hydroxylase expression in foetal rat and human cerebral cortical cells by brain-derived neurotrophic factor and glial-cell derived neurotrophic factor

Brain Res Dev Brain Res

(2001)

N.L. Ward et al.

BDNF is needed for postnatal maturation of basal forebrain and neostriatum cholinergic neurons in vivo

Exp Neurol

(2000)

K.L. Spalding et al.

Anterograde transport and trophic actions of BDNF and NT-4/5 in the developing rat visual system

Mol Cell Neurosci

(2002)

P. Stoilov et al.

Analysis of the human TrkB gene genomic organization reveals novel TrkB isoforms, unusual gene length, and splicing mechanism

Biochem Biophys Res Commun

(2002)

D. Barettino et al.

The mouse neurotrophin receptor trkB gene is transcribed from two different promoters

Biochim Biophys Acta

(1999)

M. Haniu et al.

Extracellular domain of neurotrophin receptor trkB: disulfide structure, N-glycosylation sites, and ligand binding

Arch Biochem Biophys

(1995)

M. Haniu et al.

Interactions between brain-derived neurotrophic factor and the TRKB receptor. Identification of two ligand binding domains in soluble TRKB by affinity separation and chemical cross-linking

J Biol Chem

(1997)

N. Ninkina et al.

TrkB variants with deletions in the leucine-rich motifs of the extracellular domain

J Biol Chem

(1997)

T. Yoshimura et al.

GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity

Cell

(2005)

N. Takei et al.

Brain-derived neurotrophic factor enhances neuronal translation by activating multiple initiation processes: comparison with the effects of insulin

J Biol Chem

(2001)

S. Benisty et al.

trkB messenger RNA expression in normal human brain and in the substantia nigra of parkinsonian patients: an in situ hybridization study

Neuroscience

(1998)

M. Silhol et al.

Age-related changes in brain-derived neurotrophic factor and tyrosine kinase receptor isoforms in the hippocampus and hypothalamus in male rats

Neuroscience

(2005)

M.J. Webster et al.

BDNF and trkB mRNA expression in the hippocampus and temporal cortex during the human lifespan

Gene Expr Patterns

(2006)

K. Ohira et al.

Differential expression of the truncated TrkB receptor, T1, in the primary motor and prefrontal cortices of the adult macaque monkey

Neurosci Lett

(2005)

T. Saarelainen et al.

Transgenic mice overexpressing truncated trkB neurotrophin receptors in neurons show increased susceptibility to cortical injury after focal cerebral ischemia

Mol Cell Neurosci

(2000)

M.T. Sommerfeld et al.

Down-regulation of the neurotrophin receptor TrkB following ligand binding. Evidence for an involvement of the proteasome and differential regulation of TrkA and TrkB

J Biol Chem

(2000)

A. Haapasalo et al.

Truncated trkB.T1 is dominant negative inhibitor of trkB.TK⁺-mediated cell survival

Biochem Biophys Res Commun

(2001)

J.K. Atwal et al.

The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase

Neuron

(2000)

T. Numakawa et al.

BDNF function and intracellular signaling in neurons

Histol Histopathol

(2010)

P.F. Buckley et al.

Brain-derived neurotrophic factor: findings in schizophrenia

Curr Opin Psychiatry

(2011)

Pivac N, Kozaric-Kovacic D, Grubisic-Ilic M, Nedic G, Rakos I, Nikolac M, et al. The association between brain-derived...

C. Zuccato et al.

Systematic assessment of BDNF and its receptor levels in human cortices affected by Huntington's disease

Brain Pathol

(2008)

M.B. Spina et al.

Brain-derived neurotrophic factor protects dopamine neurons against 6-hydroxydopamine and N-methyl-4-phenylpyridinium ion toxicity: involvement of the glutathione system

J Neurochem

(1992)

S. Alcantara et al.

TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death

J Neurosci

(1997)

G. Kharebava et al.

Requirement of 3-phosphoinositide-dependent protein kinase-1 for BDNF-mediated neuronal survival

J Neurosci

(2008)

N. Nguyen et al.

Neuroprotection by NGF and BDNF against neurotoxin-exerted apoptotic death in neural stem cells are mediated through Trk receptors, activating PI3-kinase and MAPK pathways

Neurochem Res

(2009)

A.H. Nagahara et al.

Potential therapeutic uses of BDNF in neurological and psychiatric disorders

Nat Rev Drug Discov

(2011)

F.F. Eide et al.

Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling

J Neurosci

(1996)

J. De Wit et al.

Long-term adeno-associated viral vector-mediated expression of truncated TrkB in the adult rat facial nucleus results in motor neuron degeneration

J Neurosci

(2006)

M.P. Armanini et al.

Truncated and catalytic isoforms of trkB are co-expressed in neurons of rat and mouse CNS

Eur J Neurosci

(1995)

R.H. Fryer et al.

Developmental and mature expression of full-length and truncated TrkB receptors in the rat forebrain

J Comp Neurol

(1996)

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Barbara Murray Fenner, PhD is an assistant professor in the Department of Biology at King's College in Wilkes-Barre, PA. She received her PhD in Cellular and Molecular Pathology from the University of Pittsburgh, School of Medicine. Her research specialty is in the field of neuropathology and her dissertation research addressed mechanisms of neurodegeneration. Her dissertation research focused on the role of the truncated trkB receptor in the intracellular sorting of BDNF using quantitative confocal microscopy. Dr. Fenner has received extensive training in microscopy at the Center for Biological Imaging, University of Pittsburgh. Her current research interests include (1) studying the effects of endothelial cells and cytokines on neuronal survival and neurite outgrowth, (2) using quantitative confocal microscopy to analyze intracellular sorting of proteins, and (3) protein function prediction using phylogenomic analyses.

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Mini reviewTruncated TrkB: Beyond a dominant negative receptor

Abstract

Section snippets

Brain derived neurotrophic factor

TrkB receptor isoforms

TrkB.tk+ signaling pathways

TrkB.t1 protein distribution in the mammalian CNS

The role of trkB.t1 in the brain

Conclusion

Prog Neuropsychopharmacol Biol Psychiatry

Prog Neurobiol

Neuropharmacology

Brain Res

Cell

Brain Res Dev Brain Res

J Chem Neuroanat

Exp Neurol

Brain Res

Biochem Biophys Res Commun

Brain Res Dev Brain Res

Dev Biol

Brain Res Dev Brain Res

Brain Res Mol Brain Res

Exp Neurol

Neuron

Neuroscience

J Biol Chem

Mol Cell Neurosci

Brain Res Dev Brain Res

Exp Neurol

Mol Cell Neurosci

Biochem Biophys Res Commun

Biochim Biophys Acta

Arch Biochem Biophys

J Biol Chem

J Biol Chem

Cell

J Biol Chem

Neuroscience

Neuroscience

Gene Expr Patterns

Neurosci Lett

Mol Cell Neurosci

J Biol Chem

Biochem Biophys Res Commun

Neuron

BDNF function and intracellular signaling in neurons

Histol Histopathol

Brain-derived neurotrophic factor: findings in schizophrenia

Curr Opin Psychiatry

Systematic assessment of BDNF and its receptor levels in human cortices affected by Huntington's disease

Brain Pathol

Brain-derived neurotrophic factor protects dopamine neurons against 6-hydroxydopamine and N-methyl-4-phenylpyridinium ion toxicity: involvement of the glutathione system

J Neurochem

TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death

J Neurosci

Requirement of 3-phosphoinositide-dependent protein kinase-1 for BDNF-mediated neuronal survival

J Neurosci

Neuroprotection by NGF and BDNF against neurotoxin-exerted apoptotic death in neural stem cells are mediated through Trk receptors, activating PI3-kinase and MAPK pathways

Neurochem Res

Potential therapeutic uses of BDNF in neurological and psychiatric disorders

Nat Rev Drug Discov

Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling

J Neurosci

Long-term adeno-associated viral vector-mediated expression of truncated TrkB in the adult rat facial nucleus results in motor neuron degeneration

J Neurosci

Truncated and catalytic isoforms of trkB are co-expressed in neurons of rat and mouse CNS

Eur J Neurosci

Developmental and mature expression of full-length and truncated TrkB receptors in the rat forebrain

J Comp Neurol

Mini review
Truncated TrkB: Beyond a dominant negative receptor

TrkB.tk⁺ signaling pathways