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Signaling by Neuronal Tyrosine Kinase ReceptorsRelevance for Development and Regeneration.

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THE ANATOMICAL RECORD 292:1976–1985 (2009)
Signaling by Neuronal Tyrosine Kinase
Receptors: Relevance for Development
and Regeneration
Division of Neuroanatomy, Medical University Innsbruck, Innsbruck, Austria
Department of Genetics and Bioengineering, Yeditepe University,
Kayisdagi-Istanbul, Turkey
Croatian Institute for Brain Research, School of Medicine University of Zagreb,
Zagreb, Croatia
Receptor tyrosine kinase activation by binding of neurotrophic factors
determines neuronal morphology and identity, migration of neurons to
appropriate destinations, and integration into functional neural circuits
as well as synapse formation with appropriate targets at the right time
and at the right place. This review summarizes the most important
aspects of intraneuronal signaling mechanisms and induced gene expression changes that underlie morphological and neurochemical consequences of receptor tyrosine kinase activation in central and peripheral
C 2009 Wiley-Liss, Inc.
neurons. Anat Rec, 292:1976–1985, 2009. V
Key words: signaling; receptor; neurotrophic
Neurons receive, process, and deliver information to
other neurons and to non-neuronal cells. During development the receiving part of the neuron increases its
surface by extending dendrites and protruding spines;
the outgoing single process, the axon, carries information to distant targets and forms synaptic boutons at its
ending. This morphological level of complexity is brought
about by the influence of neurotrophins, such as nerve
growth factor (NGF), brain derived neurotrophic factor
(BDNF), or neurotrophin 3 (NT3) that are all crucial for
neuronal development, but also for maintenance, adaptation, and plasticity in the adult nervous system (Bibel
and Barde, 2000; Kaplan and Miller, 2000; Huang and
Reichardt, 2001). Neurotrophins and other growth factors are expressed in limiting amounts in the central
and peripheral nervous system, thereby controlling the
Abbreviations used: ABP ¼ actin binding protein; ATF ¼
activating transcription factor; CREB ¼ cAMP response element
binding protein; CGRP ¼ calcitonin gene-related peptide; BDNF
¼ brain derived neurotrophic factor; DRG ¼ dorsal root ganglia;
EGF ¼ epidermal growth factor; ERK ¼ extracellular signalregulated kinase; FGF ¼ fibroblast growth factor; GDNF ¼ glial
cell line-derived neurotrophic factor; GF ¼ growth factor; GSK-3
¼ glycogen synthase 3-kinase; IAP ¼ inhibitor of apoptosis; IEG
¼ immediate-early gene; LMC ¼ Lateral Motor Column; MAP ¼
microtubule associated protein; MAP kinase ¼ mitogen activated
protein kinase; MBP ¼ microtubule binding proteins; MEK ¼
MAPK kinase; MKP ¼ MAP kinase phosphatase; MVBs ¼
multivesicular bodies; NF-H ¼ neurofilament heavy chain; NGF
¼ nerve growth factor; NT3 ¼ Neurotrophin 3; p75NTR ¼ p75
neurotrophin receptor; PDGF ¼ Platelet-derived growth factor;
PI3K ¼ phosphatidylinositol-3 kinase; PLC ¼ phospholipase C;
PS1 ¼ Presenilin 1; RTK ¼ receptor tyrosine kinase; ROCK ¼
Rho-associated kinase; SCG ¼ superior cervical ganglion; SOS ¼
Son of sevenless; SRF ¼ Serum Response Factor; TRAF6 ¼ tumor
necrosis factor receptor-associated factor 6; Trk ¼ tropomyosin
related kinase; VEGF ¼ vascular epithelial growth factor
Grant sponsor: COST (Action B30 ‘‘Neural Regeneration and
Plasticity—NEREPLAS’’), the Daniel-Swarowski-Fonds, the
Austrian Science Foundation (FWF); Grant sponsor: TUBITAK
COST; Grant number: SBAG106S247; Grant sponsor: the
Ministry of Science, Education and Sports of the Republic of
Croatia; Grant number: 108-1081870-1902; Grant sponsor:
International Center for Genetic Engineering and Biotechnology;
Grant number: CRP/CRO06-02.
*Correspondence to: Lars Klimaschewski, Muellerstr 59, Innsbruck 6020, Austria. E-mail:
Received 8 April 2009; Accepted 9 June 2009
DOI 10.1002/ar.20964
Published online in Wiley InterScience (www.interscience.wiley.
number and processes of neurons required for a suitable
density of dendritic fields and target innervation.
Neurotrophins bind to tropomyosinrelated kinases
(Trk) receptors mainly at axonal endings. These subsequently convey a signal to the cell body and to the nucleus (Ginty and Segal, 2002). Together with receptors
for other factors exhibiting neurotrophic activity, e.g.
fibroblast growth factor (FGF) or epidermal growth factor (EGF), they form the receptor tyrosine kinase (RTK)
family which has been demonstrated to be associated
with a plethora of different intraneuronal responses necessary for survival, differentiation, regeneration, and
plasticity (e.g. required for learning). Here, we present a
summary of the most relevant neuronal RTKs (mainly
Trks, FGF, and EGF receptors) with regard to their ability to influence intrinsic neuronal signaling pathways
and gene expression in order to shape neuronal morphology and determine the neurochemical phenotype. For
specific aspects of RTK signaling, we cite recent in-depth
reviews and refer to the literature therein.
The in vivo relevance of RTKs in the nervous system
has been mainly investigated in transgenic animals lacking RTKs in the whole body from fertilization onwards.
From most of these studies it became obvious that inducible and/or conditional mouse mutants would be required
to alter the expression of the respective RTK receptor in
neuronal subpopulations at specific stages of development. Only detailed analyses of the phenotypes of these
mice will provide definite evidence for the specific role of
RTKs in the regulation of neuronal development and regenerative axon growth in the future. Currently, we rely
on studies of conventional knockout mice which suggest
that the neurotrophin receptors play a major role in the
development of peripheral sensory, motor, and sympathetic neurons. It is important to note that, although
sympathetic and sensory neurons depend on neurotrophins during embryogenesis and early postnatal life,
they are not absolutely required for adult peripheral
neurons. Even upon removal of any possible source of
neurotrophic factors, such as non-neuronal cells, about
80% of adult neurons survive and extend long processes
in vitro (Lindsay, 1988).
The specific role of Trk receptors has been investigated
in detail in the superior cervical ganglion (SCG) of
rodents in vivo and in vitro. In this sympathetic neuron
model, TrkC is expressed early in development, before
neurons coalesce to form the SCG. TrkB receptors do not
play a role in postganglionic neuron development, but
are required for preganglionic neurons projecting to the
adrenal gland (Schober et al., 1998). The lack of TrkA
receptors does not influence neurogenesis, neuronal
marker expression, or initial axonal growth in the SCG.
In contrast, TrkA is absolutely necessary for the survival
and target innervation of sympathetic neurons later in
the development (Fagan et al., 1996). Mice lacking TrkA
receptors have not only sympathetic, but also severe sensory neuropathies and most die within 1 month of birth
(Smeyne et al., 1994). Neuronal cell death is detected in
the SCG and in trigeminal and dorsal root ganglia
(DRG) as well. The expression and activity of many survival-related proteins, such as caspase-9, Bax or Bcl-xL,
have been shown to be regulated by Trk signaling. Furthermore, a decrease in cholinergic basal forebrain projections to the hippocampus and cortex is observed in
animals lacking TrkA (Smeyne et al., 1994).
All peripheral sensory neurons exhibit one of the three
Trk receptors at different stages of development. TrkA/
mice are devoid of nociceptive and thermoceptive neurons, whereas TrkC knockout animals lack the largesized proprioceptive neuron subpopulation. TrkA-positive
sensory neurons extend unmyelinated C fibers or thinly
myelinated Ad fibers and are primarily nociceptive.
Their neurochemical phenotype is characterized by the
expression of substance P, calcitonin gene-related peptide (CGRP), the capsaisin receptor and by Naþ channel
gene products suggesting that Trk receptors play not
only a permissive, but also an instructive role during
neuronal development. This is corroborated by the observation that lack of pro-apoptotic Bax has been shown to
rescue dorsal root ganglion neurons in TrkA knockouts,
but the surviving neurons do not make correct peripheral connections and lose their nociceptive markers
(Patel et al., 2000).
With regard to other RTKs, it has been demonstrated
that fibroblast growth factor receptors (FGFRs) regulate
neural tube development of the CNS and proliferation of
cortical progenitors (Hasegawa et al., 2004). The latter
require FGFR, in particular FGFR3, for conferring migratory properties on nascent neuronal progeny. Moreover, oligodendrocytes develop under the influence of
FGFR signaling. Epidermal growth factor receptor
(EGFR) null mice reveal massive degeneration in various parts of the brain in the early postnatal period
exhibiting neuronal loss but also delays in GFAP expression (Kornblum et al., 1998). The brains of EGFR knockout mice are smaller but cytoarchitecturally normal at
birth. Therefore, EGFR (ErbB1) expression is critical for
the maintenance of the postnatal mouse forebrain as
well as for the normal development of astrocytes,
whereas ErbB4 has been demonstrated to be required
for myelin formation, neural crest migration, and development of dopaminergic functions (Roy et al., 2007).
These various effects of RTKs have now been analyzed
in detail at the cellular and molecular level in different
cell types in vitro and in vivo.
The major signaling pathways regulated by growth
factor binding have been mostly elucidated and provide
our basic knowledge about the role of RTKs in neurons.
The specific shape of the neuron requires that receptor
signaling information is transported along long distances. Upon binding of the ligand to the receptor, the complex is internalized by endocytosis and transported via
early and late endosomes/multivesicular bodies (MVBs)
toward the lysosomes, where the final degradation of
receptors occurs (Romanelli and Wood, 2008). Alternatively, receptors recycle back to the plasma membrane.
The general function of this vesicular pathway is to control cellular functions by downregulating the signal. The
ligand-receptor complex actually continues signaling
even after internalization by endocytosis, but it stops as
a consequence of increasing acidification of the vesicles
achieved by the activity of the proton pump, vacuolar
Hþ-ATPase (V-ATPase), which finally causes a dissociation of the ligand from its receptor (Nishi and Forgac,
2002; Saroussi and Nelson, 2009).
The signaling endosome hypothesis indicates the ability of endosomes not only to attenuate the signal along
the degradation or recycling pathway, but also, in contrast to carry the signal along considerable distances, in
particular, during retrograde axonal transport in neurons bringing the information to the cell body and the
nucleus (Grimes et al., 1996). The whole complex including the vesicle, the ligand-receptor complex, and eventually the downstream signaling molecules is carried by
the motor protein dynein along microtubules and upon
arrival in the cell body the signaling molecules are
released, pass the nuclear pore, and regulate neuronal
gene expression (Wu et al., 2007).
In case of NGF, signaling starts with binding at the
axon terminal to TrkA receptors or, alternatively, to the
common receptor for all neurotrophins, p75 neurotrophin
receptor (p75NTR), a member of the tumor necrosis factor receptor superfamily. Following endocytosis and
internalization, they could independently be sorted for
recycling or for retrograde transport and subsequent
degradation. Still, it is not clear which type of endosome
travels retrogradely along the axon. It seems that the
early endosomes (marked by small GTPase Rab5) are
located within terminal buttons, where the sorting for
recycling occurs, whereas GTPase Rab7 positive late
endosomes/MVBs are transported retrogradely along the
axon (Deinhardt et al., 2006; Moises et al., 2007). Nevertheless, the other types of endosomes, i.e. early and macroendosomes (the latter resulting from clathrin
independent macropinocytosis) are suggested to carry
cargo along the axon as well (Wu et al., 2008).
Ubiquitination emerged to be crucial for the decision
of how RTKs are sorted along the endosome pathway
(Acconcia et al., 2008). TrkA requires NGF binding to be
both endocytosed and ubiquitinated. It becomes polyubiquitinated by action of tumor necrosis factor receptor-associated factor 6 (TRAF6), which catalyzes the
formation of K63-linked polyubiquitin chains. The action
of TRAF6 and polyubiquitination is necessary for
internalization of the ligand-receptor complex (Geetha
et al., 2005). TRAF6 causes polyubiqutination of
p75NTR as well and together with Presenilin 1 (PS1)
influences its regulated intramembrane proteolysis
(Powell et al., 2009). Multi-monoubiquitination of TrkA
is mediated specifically by Nedd4-2, another E3 ubiquitin ligase, which does not act on other Trks (Arevalo
et al., 2006).
Therefore, both monoubiquitination and polyubiquitination of receptors can occur, but the relation of these
two ways of ubiquitination remains unclear. Moreover,
for the final degradation of TrkA a step involving the
proteasome seems to be necessary prior to its entry into
the lysosome. The involvement of the proteasome in deubiquitination before targeting cargo toward the lysosome
represents a novel concept in receptor trafficking and
degradation (Geetha and Wooten, 2008).
The disturbed trafficking of the signaling complexes
via signaling endosomes is suggested to be one of the
causes for human neurodegenerative diseases. Indeed,
defects of the vesicular transport accompanied by
reduced growth factor signaling were indicated in Alz-
Fig. 1. Receptor tyrosine kinase (RTK) signaling pathways involved
in neuronal survival and neurite outgrowth and its inhibition by negative feedback inhibitors. Ras/Raf/MEK/ERK and PI3K/Akt represent
two major pathways for survival and neurite outgrowth induced by
RTKs. Induction of ERK via Ras/Raf/MEK promotes survival and neurite outgrowth by transcriptional control. The survival pathway of PI3K
includes Akt which phosphorylates BAD and prevents its inhibition of
anti-apoptotic proteins. Inhibition of GSK-3 induces neurite outgrowth
by regulation of microtubule dynamics via microtubule binding proteins (MAPs). Rac and Cdc42 regulate actin dynamics via actin binding proteins (ABP). RhoA influences actin dynamics via actin-based
motor protein myosin II. PI3K transiently inactivates RhoA which
decreases its ability to associate down-stream with ROCK. The negative feedback inhibitors Sprouty and Sef attenuate RTK signalling.
Sprouty specifically inhibits MAP kinase-signalling upstream of Ras at
the level of Grb-2 and downstream of Ras at the level of Raf. Sef-a
blocks phosphorylation of the receptor as a transmembrane protein
and cytoplasmic Sef-b prevents nuclear translocation of ERK by inhibition of the dissociation of the ERK-MEK complex.
heimer’s disease, Down syndrome, Huntington disease,
amyotrophic lateral sclerosis, Niemann Pick disease type
C, and Charcot-Marie-Tooth neuropathies (Bronfman et
al., 2007). Moreover, defective ubiquitination contributes
to neuronal loss, but it is still difficult to distinguish
whether this is due to the inadequate signaling, inadequate degradation, in particular, inadequate autophagic
degradation, or a combination of those (Filimonenko
et al., 2007; Tamai et al., 2008).
Ligand binding induced activation and autophosphorylation results in recruitment of several adapter molecules to tyrosine residues present in the intracellular
domain of RTKs (Kouhara et al., 1997; Meakin et al.,
1999). Adapter proteins like FRS2 or Shc then trigger
the activation of several intracellular signaling pathways. The main cascades activated by RTKs include the
Ras/Raf/MEK/ERK, the PI3K/Akt and the phospholipase
C (PLC) pathway (Fig. 1). ERK- and Akt-signaling is
involved in both, neuronal survival and axon growth.
PLC mainly regulates intracellular Ca2þ-levels and protein kinase C activity via cleavage of PIP2 to DAG and
IP3. This mechanism appears to enhance MEK activity
and is involved in neurotrophin release (Canossa et al.,
The ERK- and PI3K-Pathways are Central for
RTK Signaling
Activation of PI3K/Akt and their downstream targets
represents the major survival promoting pathway in neurons (Dudek et al., 1997; Crowder and Freeman, 1998). In
contrast, the ERK pathway plays a predominant role in
survival following cellular insult (Hetman et al., 1999).
PI3K and its target Akt are also necessary for NGFdependent survival of sympathetic (Nobes et al., 1996) and
sensory neurons (Klesse and Parada, 1998). Induction of
ERK induces neuronal survival via transcriptional processes by expression of anti-apoptotic proteins like Bcl-2
(Liu et al., 1999). Akt phosphorylates Bcl-2 antagonist of
cell death (BAD) and prevents it from inactivating anti-apoptotic Bcl-2 proteins (Bonni et al., 1999). The transcription factor Forkhead, which induces apoptosis by
increasing the levels of Fas ligand, is inhibited by Akt
(Brunet et al., 1999). Furthermore, Akt indirectly prevents
apoptosis by suppression of glycogen synthase 3-kinase
(GSK-3) (Pap and Cooper, 1998). Besides activation of Akt,
PI3K promotes survival via activation of a group of caspase
inhibitors, the inhibitors of apoptosis (IAPs; LeCasse et al.,
1998), which participate in neurotrophin-mediated survival
in sensory and sympathetic neurons (Wiese et al., 1999).
Enhanced RTK signaling promotes axon elongation not
only by development but also by adult peripheral neurons
as well (Hausott et al., 2008). The ERK- and the PI3Kpathway are both required for neurotrophin-mediated
axon growth (Markus et al, 2002). In PC12 cells, activation of PI3K, Akt, Ras, Raf, Mek, and ERK are necessary
for NGF-induced neurite outgrowth, and overexpression
of Ras, Raf and MEK induces neuritogenesis in the
absence of NGF (Wood et al., 1993; Klesse et al., 1999).
Sustained ERK activation is required for neurite outgrowth by PC12 cells, whereas transient ERK activation
leads to proliferation (Traverse et al., 1992), suggesting
that the duration of the ERK signal determines differentiation of this cell line. In primary cultures, active Ras
induces neurite outgrowth by nodose ganglion neurons in
the absence of neurotrophins (Borasio et al., 1989),
whereas in sympathetic neurons ERK-signaling is
required for BDNF/TrkB-mediated axon elongation
(Atwal et al., 2000). Moreover, ERK phosphorylation is
required for retrograde transport of an ‘‘injury signal’’ as
discussed earlier (Perlson et al., 2005) and for local axon
assembly induced by neurotrophins (Atwal et al., 2000).
ERK regulates polymerization of axonal microtubules
and actin filaments (Goold and Gordon-Weeks, 2005).
Vice versa, inhibition of ERK induces actin depolymerization and growth cone collapse (Atwal et al., 2003).
PI3K is necessary for NGF-induced axon growth by
sympathetic neurons (Kuruvilla et al., 2000) and for the
growth cone response to NGF (Ming et al., 1999). Activated Akt has been shown to accelerate motor axon
regeneration in vivo (Namikawa et al., 2000). Local
assembly of the cytoskeleton which regulates axon morphogenesis is also under the control of PI3K signaling.
PI3K influences the activity of various small GTPases of
the Rho family such as Rac, Cdc42, and RhoA, thereby
regulating actin cytoskeletal dynamics (Higgs and
Pollard, 2001; Smith and Li, 2004).
In fibroblasts, activation of cdc42 induces filopodia and
activation of Rac lamellipodia formation, whereas activation of RhoA results in stress fiber formation (Mackay
et al., 1995; Nobes and Hall, 1995). Neurites can spread
by extension of filopodia and subsequent generation of
lamellipodia between filopodia. In PC12 cells, both Cdc42
and Rac are regulated by PI3K (Yamaguchi et al., 2001;
Aoki et al., 2005) and lamellipodia formation is dependent
on Rac activity (Posern et al., 2000). In primary spinal
cord neurons, overexpression of active Cdc42 promotes
growth cone filopodia formation and axon elongation
(Brown et al., 2000). RhoA activates Rho kinase (ROCK),
which leads to phosphorylation of various target proteins
including myosin light chain that in turn activates myosin
(Zhou and Snider, 2006). In contrast to Rac and Cdc42
which promote neurite outgrowth, Rho causes growth
cone collapse and neurite retraction (Kozma et al., 1997).
Pharmacological inhibition of RhoA induces neurite
outgrowth by PC12 cells (Welsh and Assoian, 2000). Conversely, PC12 cell differentiation is blocked by an active
dominant mutant of RhoA (Sebök et al., 1999). In adult
DRG neurons, inhibition of RhoA stimulates neurite outgrowth even if exposed to inhibitory substrates (Fu et al.,
2007). NGF-induced PI3K activation transiently inactivates RhoA via Rac1, upon which RhoA translocates from
the membrane to the cytoplasm and its ability to associate down-stream with ROCK is decreased (Nusser et al.,
2002). Integrins inactivate RhoA via activation of RhoGAP (Arthur and Burridge, 2001). Activation of PI3K/
Akt inactivates GSK-3ß (Cross et al., 1995), which induces axon growth by stimulating microtubule dynamics
via microtubule binding proteins (MBPs; Zhou et al.,
2004). GSK-3b regulates all aspects of microtubule assembly like microtubule polymerization, plus end binding
and maintenance of microtubule dynamics by different
MBPs. In adult DRG neurons, inhibition of GSK-3b
results in enhanced neurite growth (Jones et al., 2003).
The ERK- and the PI3K-pathway display distinct functions in axon growth. In embryonic DRG cultures (Liu and
Snider, 2001) and in adult DRG explants, which are not
dependent on neurotrophic factors for survival (Edström
and Ekström, 2003), inhibition of PI3K results in diminished axon growth. PI3K inhibitors block spontaneous and
NGF-induced neurite outgrowth. Inhibitors of the Ras/
ERK pathway only transiently arrest spontaneous axonal
outgrowth from DRG explants, while NGF-increased outgrowth is significantly impaired. In Bax knockout mice,
overexpression of Ras and Raf-1 (c-Raf) induces axonal
elongation by embryonic sensory neurons, whereas overexpression of Akt or PI3K increased axon caliber and axonal
branching. Co-transfection with Raf and Akt resulted in
long, thick, and moderately branched axons and the effects
of Raf and Akt appear to be independent of each other
(Markus et al., 2002). In adult DRG neurons, FGF-2 treatment induces prominent ERK phosphorylation, whereas
Akt phosphorylation is slightly increased only. In contrast,
NGF treatment causes phosphorylation of both, ERK and
Akt, to a similar extent (Hausott et al., submitted). It is
therefore not surprising that FGF-2, but not NGF, significantly improves elongative axon growth by adult sensory
neurons in response to a preconditioning sciatic nerve
lesion (Klimaschewski et al., 2004).
Negative Feedback Inhibitors Regulate
RTK Signaling
RTK signaling is attenuated by degradation of the
receptors or by negative feedback inhibitors such as
Sprouty or Sef (Tsang and Dawid, 2004; Mason et al.,
2006). Sprouty proteins were first discovered in 1998
(Hacohen et al., 1998). They represent a major class of
negative feedback inhibitors that limit the intensity and
duration of activation of tyrosine kinases, thereby controlling growth and differentiation processes. Mammals
exhibit four Sprouty isoforms (Sprouty1–4) and their
expression is regulated by growth factors (Ozaki et al.,
2001; Sasaki et al., 2001). Activation of Sprouty specifically inhibits the Ras/Raf/ERK pathway (Yusoff et al.,
2002; Hanafusa et al., 2002; Tefft et al., 2002) induced
by FGF (Impagnatiello et al., 2001), brain-derived neurotrophic factor (BDNF, Gross et al., 2007), glial cell linederived neurotrophic factor (GDNF, Ishida et al., 2007),
platelet-derived growth factor (PDGF, Gross et al.,
2001), or vascular epithelial growth factor (VEGF,
Impagnatiello et al., 2001; Sasaki et al., 2001). In
response to growth factor stimulation, Sprouty1 and 2
bind Grb2 and inhibit the recruitment of the Grb2-SOScomplex to FRS2 or Shp2, thereby preventing downstream Ras/ERK activation (Hanafusa et al., 2002; Tefft
et al., 2002). Sprouty2 and 4 bind Raf and interfere
with the activation of the Ras/ERK pathway downstream of Ras (Yusoff et al., 2002; Sasaki et al., 2003).
In PC12 cells, Ras, Raf, Mek, and ERK are required
for neurite outgrowth (Wood et al., 1993; Klesse et al.,
1999). Overexpression of Sprouty1 and 2 blocks PC12
cell neurite outgrowth induced by NGF or FGF-2 (Gross
et al., 2001), conversely, non-phosphorylated dominant
negative Sprouty1, 2 (Hanafusa et al., 2002) or 4
(Sasaki et al., 2001) promote FGF-induced neurite
outgrowth. In cultures of immature cerebellar granule
neurons, overexpression of Sprouty2 blocks neurite formation and inhibition of Sprouty2 by a dominant-negative mutant or by siRNAs promotes neurite outgrowth.
In mature neurons that already exhibit an extensive
neurite network, overexpression of Sprouty2 induces cell
death whereas its inhibition promotes survival (Gross et
al., 2007), which suggests a developmental difference in
the effects of enhanced or reduced Ras/ERK signaling
affecting neurite outgrowth or survival depending on
age. Sprouty2 is highly expressed in adult DRG neurons
and its down-regulation induces elongative axon growth
by adult DRG in vitro through enhanced Ras/ERK signaling (Hausott et al., submitted).
The negative feedback inhibitor Sef (similar expression of FGF genes) was first identified in zebrafish
(Fürthauer et al., 2002; Tsang et al., 2002). Sef is synexpressed with Sprouty2 and Sprouty4 and similarities
between the expression patterns of these genes indicate that they could be co-regulated. The protein interferes with FGFR signaling upstream and downstream
of Ras. Depending on the isoform, it blocks phosphorylation of the receptor (Kovalenko et al., 2003) as a
transmembrane protein by inhibition of FRS2 phosphorylation (Sef-a) or it prevents nuclear translocation of
ERK by inhibition of the dissociation of the ERK–MEK
complex as a cytoplasmatic isoform without influencing
the cytoplasmic activity of ERK (Sef-b, Torii et al.,
2004). Overexpression of Sef inhibits FGF-2- and NGFinduced neurite outgrowth by PC12 cells (Xiong et al.,
2003). Sef is expressed in the brain, the spinal cord,
and in DRGs and it is up-regulated in response to a
sciatic nerve crush at the lesion site (Grothe et al.,
The main function of RTK signaling is to maintain the
level of proteins required for survival, axon growth, and
guidance via changes in gene transcription, protein synthesis, and degradation. The overall effects of Raf-mediated signaling were analyzed using conditional targeting
of B-Raf and C-Raf, two downstream effectors of RTK
signaling. Defects in Raf lead to growth retardation,
partly due to reduced survival, but largely due to
decreased levels of the GDNF Receptor, Ret, as well as
reduced levels of Brn-2 and Klf-7, both transcriptional
regulators of TrkA expression (Zhong et al., 2007). In
these Raf-defective animals, NGF-induced axon growth,
which is under the control of Runx1 and CBF, is also
affected. Runx1/AML1 is involved in axonal outgrowth
by neural crest stem cell-derived nociceptive neurons
and regulates TrkA signaling in combination with an
existing neurogenin2 transcriptional program in these
cells (Marmigere et al., 2006).
In one study, the global effects of RTK signaling during differentiation into neuronal lineages were analyzed
using an Affymetrix microarray involving over 30,000
genes. Pollard et al. (2008) have investigated the transcriptional profile of neural stem cells upon FGF-mediated differentiation. They have identified a set of 64
genes that appears to be a signature for NSC populations, including transcriptional regulators such as
Mef2c, Nkx2.2, Olig1, Pou3, and Sox9, among others.
ERK1/2 and JNK pathways play a role in differentiation
upon NGF stimulation, by regulating either the expression or phosphorylation of various target proteins such
as c-Jun, Elk-1, activating transcription factor (ATF),
neurofilament heavy chain (NF-H), or MAP kinase phosphatase (MKP, Waetzig and Herdegen, 2003).
Elk-1 is a protein that belongs to the ETS domain
superfamily of transcription factors, the founding father
of which is the Ets-1 proto-oncogene initially identified
from the E-26 virus (Sharrocks, 2001). Elk-1 is typically
known as a mitogen-activated transactivator, involved in
the regulation of proliferation in cells (Sharrocks, 2001),
however, Elk-1 has been shown to be localized to axons
and dendrites in largely post-mitotic adult rat brain
(Sgamboto et al., 1998; Demir et al., 2009). Stimulation of
primary neural or neuroblastoma cells results in translocation of the phosphorylated Elk-1 to the neuronal nucleus (Demir et al., 2009) and this was shown to suppress
the expression of pro-apoptotic genes in neuroblastoma
cells (Demir and Aksan Kurnaz, 2008). In mice deficient
for Elk-1, however, there appears to be only a mild neuronal impairment, most probably due to redundancy
(Cesari et al., 2004). Therefore, Elk-1 is likely to serve a
function beyond proliferation in neurons, probably in regulating survival (Ginty and Segal, 2002; Vickers et al.,
2004) or neuronal apoptotis (Barrett et al., 2006a,b).
Another transcription factor regulated by neurotrophins and ERK signaling is CREB (cAMP response element binding protein). In CREB/Bax double null mice
(to prevent apoptosis), DRG and sympathetic neurons
extend much shorter axons than wild type cells in the
presence of NGF (Lonze et al., 2002). Elk-1 and CREB
are phosphorylated in the dentate gyrus upon long-term
potentiation (LTP) induction as a result of RTK activation (Davies et al., 2000).
Fig. 2. Transcriptional regulators influenced by receptor tyrosine kinase (RTK) signalling. RTK signaling pathways mainly operate through
Ras/Raf/MAPK signal transduction or the PI3K signaling pathways,
and create a wide range of responses in the cell, from neuronal survival to motor neuron positioning, from axon extension to learning and
memory. Many transcription factors are targeted by RTKs to mediate
those responses as well as feedback regulation, such as ETS domain
proteins, MADS box proteins, Zn finger or Islet proteins, among many
others. Also targeted by the RTKs are the MAPKAP kinase family
members, most notably RSK2 histone kinase.
Serum response factor (SRF), a transcriptional partner
for Elk-1, plays an important role in neurons as well.
SRF mediates neuronal survival via the PI3K/Akt pathway and was shown to rescue cells from apoptosis on serum withdrawal (Chang et al., 2004). Furthermore, SRF
protects cortical neurons from DNA damage-induced
apoptosis. Whether Elk-1 and SRF cooperate on these
survival functions in neuronal systems is yet to be investigated. SRF is also necessary and sufficient for NGFdependent axonal extension and branching by DRG
sensory neurons (Wickramashinghe et al., 2008). Furthermore, SRF mediates activity-dependent gene expression and possibly morphological plasticity in adult
neurons. Selective depletion of SRF in adult CA1 neurons, for instance, decreases LTP as well as immediateearly gene (IEG) induction upon novelty stimulation
(which normally activates place cells of the hippocampus) without affecting survival of these neurons (Ramanan et al., 2005). Therefore, plasticity in the nervous
system may not necessarily require a different set of
transcriptional programs but rather utilize the existing
survival, axon extension, and related mechanisms to
adapt to changing conditions in the environment.
An interesting group of ETS domain transcription factors regulated by RTK signaling is the Pea3 subfamily
(Fig. 2), comprising Pea3, ERM, and Er81 (Sharrocks,
2001). Er81 is coexpressed with TrkC and Pea3 with
TrkA (Arber et al., 2000). Pea3 is expressed in many
tissues with branching morphogenesis and plays a role in
cell body positioning and axonal connectivity. It is
induced in motor neurons in response to GDNF and thus
modifies motor neuron positioning (Haase et al., 2002).
Met signaling is important for expression of pea3 in
brachial motor neurons and for their recruitment. In
turn met expression is affected by GDNF and Pea3,
thereby providing a positive feedback regulation to the
system (Helmbacher et al., 2003). IGF-1 is yet another
signal that is implicated in the regulation of ERM but
not ER81 in PC12 neuronal differentiation model system.
In proprioceptive sensory neurons, late onset of ETS
and Er81 signaling is crucial for normal development of
sensory afferent projections to the spinal cord, normally
regulated by NGF or NT3-like signals (Hippenmeyer et
al., 2005). However, precocious expression of EWS-Pea3
can lead to axonal projection defects—indicating tightly
regulated temporal control for axonal growth at this
stage of development. Er81 and Pea3 are not crucial for
early stages of neural differentiation, because in Er81
mutant mice motor neurons did develop. However, group
Ia proprioceptice afferents fail to form a discrete termination zone in the ventral spinal cord, thus a defect in
motor coordination developed in mutant mice (Arber et
al, 2000). It was further observed that Er81 and Pea3
expression are mutually exclusive in different motor
neuron subpopulations of the lateral motor column
(LMC) and these subpopulations appear to connect to
developing DRGs that express the same proteins.
The LIM homeodomain proteins Islet-1 and 2 (Fig.
2) that comprise functional partners for Pea3 proteins
are expressed in different subsets of motor and interneurons, essentially regulating axonal pathfinding of
motor neurons as well as neurotransmitter production.
Interestingly, mice lacking Isl-1 exhibit a loss of neurons
due to apoptosis (Thor and Thomas, 1997). Apoptosis
and survival are two sides of the same coin, and many
survival proteins such as Bcl2, Mcl2, Elk-1, ATF3 protect neurons against apoptotic stimuli during development. C-Jun itself participates in neuronal apoptosis
upon NGF withdrawal, with c-Jun activation resulting
in cytochrome release and subsequent apoptosis (Whitfield et al., 2001).
The POU (Pit-Oct-Unc) domain family member Brn-3
was shown to be required not for the initial specification
of sensory neurons, but rather for their normal differentiation and survival (Wang et al., 2002, and references
therein). In Brn-3b/-3c double knockout mice, defects in
axon growth go along with the elimination of optic
fibers; very few correctly routed fibers were detected,
and cell numbers were reduced in the ganglion cell layer
(Wang et al., 2002), indicating that apoptotic stimuli
could not be bypassed in the absence of Brn-3 transcription factors. In differentiated PC12 cells as well as in
medullablastoma cells Brn-3a regulates the expression
of TrkA receptors (Valderrama and Misra, 2008), providing a feedback control to the system (Fig. 2).
Thus, a range of different transcriptional regulators
work in concert to regulate differentiation, migration,
cell body positioning, axonal growth, and survival of
neurons during development. Some of them are crucial
in the adult neuron as well, for example, CREB acts as
an integration point for many GPCRs, Trks, NMDA
receptors, and L-type calcium channels, and thus is
implicated in a variety of different processes including
learning, memory, addiction, depression, anxiety, and
many other higher cognitive functions, as well as plasticity associated with these processes (for a detailed review
on CREB, Carlezon et al., 2005). CREB also regulates
the expression of proteins such as c-Fos, BDNF, or glutamate receptor GluR1, thereby providing yet another
feedback control to the system. Similarly, another target
of MAPK signaling implicated in LTP, learning and
memory is the ribosomal S6 kinase, RSK2 (Sharma and
Carew, 2004). RSK2 is a histone kinase (Merienne et al.,
2001), and mutations in the rsk2 gene result in CoffinLowry syndrome (CLS), an X-linked disorder with mild
mental retardation and facial abnormalities (Delaunoy
et al., 2001).
In summary, although each neuronal subtype is unique
in its function, there are common themes in all of those
subtypes both during embryonic development as well as
in adult plasticity, and similar groups of transcriptional
regulators and other proteins act as effectors of RTK signaling in almost all types of neurons to generate a plethora of responses and higher cognitive abilities.
Despite significant progress in our understanding of
the molecular and cellular events induced by RTK activation, several key issues remain to be addressed before
we can claim a comprehensive understanding of the neuronal functions of RTKs. Different cellular levels are
now in the focus of many laboratories, aiming to elucidate the activation and recycling of RTKs, the binding
and modification of signaling molecules, and the regulation of nuclear events leading to changes in gene
Many of these studies finally aim at developing clinical treatments based on activation of RTKs to promote
neuronal survival and axonal regeneration. In fact, neuroprotective effects could be achieved by treating traumatic or ischemic lesions, neurodegenerative diseases
such as amyotrophic lateral sclerosis (ALS), Huntington’s or Parkinson’s disease and various peripheral neuropathies with large amounts of RTK ligands in animal
models. As soon as neurotrophins and other growth factors became available in recombinant form, immediate
therapeutic success was expected similar to the success
seen with erythropoietin in the hematopoietic system.
However, early clinical trials with neurotrophins given
to patients with neurodegenerative diseases did not fulfill the promise (Thoenen and Sendtner, 2002).
Consequently, based on more detailed knowledge of
the signal transduction pathways and transcriptional
changes induced by RTK activation, a new effort to
search for endogenous or pharmacological modulators of
RTK signaling has been started. Exciting results of
recent preclinical studies suggest a promising therapeutic potential of these small molecules activating RTK signaling in slowing the progression of neurodegenerative
Authors apologize to all contributors to the field whose
work has not been cited due to space limitations.
Acconcia F, Sigismund S, Polo S. 2009. Ubiquitin in trafficking: The
network at work. Exp Cell Res 315:1610–1618.
Aoki K, Nakamura T, Fujikawa K, Matsuda M. 2005. Local phosphatidylinositol 3,4,5-trisphosphate accumulation recruits Vav2
and Vav3 to activate Rac1/Cdc42 and initiate neurite outgrowth
in nerve growth factor-stimulated PC12 cells. Mol Biol Cell 16:
Arber S, Ladle DR, Lin JH, Frank E, Jessell TM. 2000. ETS gene
Er81 controls the formation of functional connections between
Group Ia sensory afferents and motor neurons. Cell 101:485–498.
Arévalo JC, Waite J, Rajagopal R, Beyna M, Chen ZY, Lee FS, Chao
MV. 2006. Cell survival through Trk neurotrophin receptors is differentially regulated by ubiquitination. Neuron 50:549–559.
Arthur WT, Burridge K. 2001. RhoA inactivation by p190RhoGAP
regulates cell spreading and migration by promoting membrane
protrusion and polarity. Mol Biol Cell 12:2711–2720.
Atwal JK, Massie B, Miller FD, Kaplan DR. 2000. The TrkB-Shc
site signals neuronal survival and local axon growth via MEK
and PI3-kinase. Neuron 27:265–277.
Atwal JK, Singh KK, Tessier-Lavigne M, Miller FD, Kaplan DR.
2003. Semaphorin 3F antagonizes neurotrophin-induced phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase
signaling: a mechanism for growth cone collapse. J Neurosci 23:
Barrett LE, Sul JY, Takano H, Van Bockstaele EJ, Haydon PG,
Eberwine JH. 2006a. Region-directed phototransfection reveals
the functional significance of a dendritically synthesized transcription factor. Nat Methods 3:455–460.
Barrett LE, Van Bockstaele EJ, Sul JY, Takano H, Haydon PG,
Eberwine JH. 2006b. Elk-1 associates with the mitochondrial permeability transition pore complex in neurons. Proc Natl Acad Sci
USA 103:5155–5160.
Bibel M, Barde YA. 2000. Neurotrophins: key regulators of cell fate
and cell shape in the vertebrate nervous system. Genes Dev 14:
Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg
ME. 1999. Cell survival promoted by the Ras-MAPK signaling
pathway by transcription-dependent and -independent mechanisms. Science 286:1358–1362.
Borasio GD, John J, Wittinghofer A, Barde YA, Sendtner M, Heumann R. 1989. Ras P21-Protein promotes survival and fiber outgrowth of cultured embryonic neurons. Neuron 2:1087–1096.
Bronfman FC, Escudero CA, Weis J, Kruttgen A. 2007. Endosomal
transport of neurotrophins: roles in signaling and neurodegenerative diseases. Dev Neurobiol 67:1183–1203.
Brown MD, Cornejo BJ, Kuhn TB, Bamburg JR. 2000. Cdc42 stimulates neurite outgrowth and formation of growth cone filopodia
and lamellipodia. J Neurobiol 43:352–364.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson
MJ, Arden KC, Blenis J, Greenberg ME. 1999. Akt promotes cell
survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 96:857–868.
Canossa M, Griesbeck O, Berninger B, Campana G, Kolbeck R,
Thoenen H. 1997. Neurotrophin release by neurotrophins: implications for activity-dependent neuronal plasticity. Proc Natl Acad
Sci USA 94:13279–13286.
Carlezon WA, Jr, Duman RS, Nestler EJ. 2005. The many faces of
CREB. Trends Neurosci 28:436–445.
Cesari F, Brecht S, Vintersten K, Vuong LG, Hofmann M, Klingel
K, Schnorr JJ, Arsenian S, Schild H, Herdegen T, Wiebel FF,
Nordheim A. 2004. Mice deficient for the Ets transcription factor
Elk-1 show normal immune responses and mildly impaired neuronal gene activation. Mol Cell Biol 24:294–305.
Chang SH, Poser S, Xia Z. 2004. A novel role for serum response
factor in neuronal survival. J Neurosci 24:2277–2285.
Cross DAE, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA.
1995. Inhibition of glycogen-synthase kinase-3 by insulin-mediated by protein-kinase-B. Nature 378:785–789.
Crowder RJ, Freeman RS. 1998. Phosphatidylinositol 3-kinase and
Akt protein kinase are necessary and sufficient for the survival of
nerve growth factor-dependent sympathetic neurons. J Neurosci
Davies S, Vanhoutte P, Pages C, Caboche J, Laroche S. 2000. The
MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent
gene expression in the dentate gyrus in vivo. J Neurosci 20:
Deinhardt K, Salinas S, Verastegui C, Watson R, Worth D, Hanrahan S, Bucci C, Schiavo G. 2006. Rab5 and Rab7 control endocytic
sorting along the axonal retrograde transport pathway. Neuron
Delaunoy J, Abidi F, Zeniou M, Jacquot S, Merienne K, Pannetier
S, Schmitt M, Schwartz C, Hanauer A. 2001. Mutations in the
X-linked RSK2 gene (RPS6KA3) in patients with Coffin-Lowry
syndrome. Hum Mut 17:103–116.
Demir O, Aksan Kurnaz I. 2008. Wildtype Elk-1, but not a SUMOylation mutant, represses egr-1 expression in SH-SY5Y neuroblastomas. Neurosci Lett 437:20–24.
Demir O, Korulu S, Yildiz A, Karabay A, Aksan Kurnaz I. 2009.
Elk-1 interacts with neuronal microtubules and relocalizes to the
nucleus upon phosphorylation. Mol Cell Neurosci 40:111–119.
Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao RJ, Cooper GM,
Segal RA, Kaplan DR, Greenberg ME. 1997. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science
Edström A, Ekström PAR. 2003. Role of phosphatidylinositol 3-kinase in neuronal survival and axonal outgrowth of adult mouse
dorsal root ganglia explants. J Neurosci Res 74:726–735.
Fagan AM, Zhang H, Landis S, Smeyne RJ, Silossantiago I, Barbacid M. 1996. TrkA, but not TrkC, receptors are essential for survival of sympathetic neurons in vivo. J Neurosci 16:6208–6218.
Filimonenko M, Stuffers S, Raiborg C, Yamamoto A, Malerød L,
Fisher EM, Isaacs A, Brech A, Stenmark H, Simonsen A. 2007.
Functional multivesicular bodies are required for autophagic
clearance of protein aggregates associated with neurodegenerative
disease. J Cell Biol 179:485–500.
Fu Q, Hue J, Li SX. 2007. Nonsteroidal anti-inflammatory drugs
promote axon regeneration via RhoA inhibition. J Neurosci 27:
Fürthauer M, Lin W, Ang SL, Thisse B, Thisse C. 2002. Sef is a
feed back-induced antagonist of Ras/MAPK-mediated FGF signalling. Nat Cell Biol 4:170–174.
Geetha T, Jiang J, Wooten MW. 2005. Lysine 63 polyubiquitination
of the nerve growth factor receptor TrkA directs internalization
and signaling. Mol Cell 20:301–312.
Geetha T, Wooten MW. 2008. TrkA receptor endolysosomal degradation is both ubiquitin and proteasome dependent. Traffic 9:
Ginty D, Segal RA 2002. Retrograde neurotrophin signaling: Trking along the axon. Curr Opin Neurobiol 12:268–274.
Goold RG, Gordon-Weeks PR. 2005. The MAP kinase pathway is
upstream of the activation of GSK3 beta that enables it to phosphorylate MAP1B and contributes to the stimulation of axon
growth. Mol Cell Neurosci 28:524–534.
Grimes ML, Zhou J, Beattie EC, Yuen EC, Hall DE, Valletta JS,
Topp KS, LaVail JH, Bunnett NW, Mobley WC. 1996. Endocytosis
of activated TrkA: evidence that nerve growth factor induces formation of signaling endosomes. J Neurosci 16:7950–7964.
Gross I, Bassit B, Benezra M, Licht JD. 2001. Mammalian Sprouty
proteins inhibit cell growth and differentiation by preventing Ras
activation. J Biol Chem 276:46460–46468.
Gross I, Armant O, Benosman S, de Aguilar JLG, Freund JN,
Kedinger M, Licht JD, Gaiddon C, Loeffler JP. 2007. Sprouty2
inhibits BDNF-induced signaling and modulates neuronal differentiation and survival. Cell Death Differ 14:1802–1812.
Grothe C, Claus P, Haastert K, Lutwak E, Ron D. 2008. Expression
and regulation of Sef, a novel signaling inhibitor of receptor tyrosine kinases-mediated signaling in the nervous system. Acta Histochem 110:155–162.
Haase G, Dessaud E, Garces A, de Bovis B, Birling MC, Filippi P,
de Lapeyriere O. 2002. GDNF acts through PEA3 to regulate cell
body positioning and muscle innervation of specific motor neuron
pools. Neuron 35:893–905.
Hacohen N, Kramer S, Sutherland D, Hiromi Y, Krasnow MA. 1998.
Sprouty encodes a novel antagonist of FGF signaling that patterns
apical branching of the Drosophila airways. Cell 92:253–263.
Hanafusa H, Torii S, Yasunaga T, Nishida E. 2002. Sprouty1 and
Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol 4:850–858.
Hasegawa H, Ashigaki S, Takamatsu M, Suzuki-Migishima R,
Ohbayashi N, Itoh N, Takada S, Tanabe Y. 2004. Laminar patterning in the developing neocortex by temporally coordinated
fibroblast growth factor signaling. J Neurosci 24:8711–8719.
Hausott B, Schlick B, Vallant N, Dorn R, Klimaschewski L. 2008.
Promotion of neurite outgrowth by fibroblast growth factor receptor 1 overexpression and lysosomal inhibition of receptor degradation in pheochromocytoma cells and adult sensory neurons.
Neuroscience 153:461–473.
Helmbacher F, Dessaud E, Arber S, de Lapeyriere O, Henderson
CE, Klein R, Maina F. 2003. Met signaling is required for recruitment of motor neurons to PEA3-positive motor pools. Neuron 39:
Hetman M, Kanning K, Cavanaugh JE, Xia ZG. 1999. Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase.
J Biol Chem 274:22569–22580.
Higgs HN, Pollard TD. 2001. Regulation of actin filament network
formation through Arp2/3 complex: activation by a diverse array
of proteins. Annu Rev Biochem 70:649–676.
Hippenmeyer S, Vrieseling E, Sigrist M, Portmann T, Laengle C,
Ladle DR, Arber S. 2005. A developmental switch in the response
of DRG neurons to ETS transcription factor signaling. PLoS Biol
Huang EJ, Reichardt LF. 2001. Neurotrophins: Roles in neuronal
development and function. Annu Rev Neurosci 24:677–736.
Impagnatiello MA, Weitzer S, Gannon G, Compagni A, Cotten M,
Christofori G. 2001. Mammalian sprouty-1 and-2 are membraneanchored phosphoprotein inhibitors of growth factor signaling in
endothelial cells. J Cell Biol 152:1087–1098.
Ishida M, Ichihara M, Mii S, Jijiwa M, Asai N, Enomoto A, Kato T,
Majima A, Ping J, Murakumo Y, Takahashi M. 2007. Sprouty2
regulates growth and differentiation of human neuroblastoma
cells through RET tyrosine kinase. Cancer Sci 98:815–821.
Jones DM, Tucker BA, Rahimtula M, Mearow KM. 2003. The synergistic effects of NGF and IGF-1 on neurite growth in adult
sensory neurons: convergence on the PI 3-kinase signaling pathway. J Neurochem 86:1116–1128.
Kaplan DR, Miller FD. 2000. Neurotrophin signal transduction in
the nervous system. Curr Opin Neurobiol 10:381–391.
Klesse LJ, Meyers KA, Marshall CJ, Parada LF. 1999. Nerve
growth factor induces survival and differentiation through
two distinct signaling cascades in PC12 cells. Oncogene 18:2055–
Klesse LJ, Parada LF. 1998. p21 Ras and phosphatidylinositol-3
kinase are required for survival of wild type and NF1 mutant
sensory neurons. J Neurosci 18:10420–10428.
Klimaschewski L, Nindl W, Feurle J, Kavakebi P, Kostron H. 2004.
Basic fibroblast growth factor isoforms promote axonal elongation
and branching of adult sensory neurons in vitro. Neuroscience
Kornblum HI, Hussain R, Wiesen J, Miettinen P, Zurcher SD, Chow
K, Derynck R, Werb Z. 1998. Abnormal astrocyte development
and neuronal death in mice lacking the epidermal growth factor
receptor. J Neurosci Res 53:697–717.
Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi
D, Lax I, Schlessinger J. 1997. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 89:693–702.
Kovalenko D, Yang XH, Nadeau RJ, Harkins LK, Friesel R. 2003.
Sef inhibits fibroblast growth factor signaling by inhibiting
FGFR1 tyrosine phosphorylation and subsequent ERK activation.
J Biol Chem 278:14087–14091.
Kozma R, Sarner S, Ahmed S, Lim L. 1997. Rho family GTPases
and neuronal growth cone remodelling: Relationship between
increased complexity induced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoA and lysophosphatidic acid. Mol
Cell Biol 17:1201–1211.
Kuruvilla R, Ye HH, Ginty DD. 2000. Spatially and functionally distinct roles of the PI3-K effector pathway during NGF signaling in
sympathetic neurons. Neuron 27:499–512.
LeCasse EC, Baird S, Korneluk RG, MacKenzie AE. 1998. The
inhibitors of apoptosis (IAPs) and their emerging roles in cancer.
Oncogene 17:3247–3259.
Lindsay RM. 1988. Nerve growth-factors (NGF, BDNF) enhance
axonal regeneration but are not required for survival of adult
sensory neurons. J Neurosci 8:2394–2405.
Liu RY, Snider WD. 2001. Different signaling pathways mediate
regenerative versus developmental sensory axon growth. J Neurosci 21:RC164.
Liu YZ, Boxer LM, Latchman DS. 1999. Activation of the Bcl-2 promoter by nerve growth factor is mediated by the p42/p44 MAPK
cascade. Nucleic Acids Res 27:2086–2090.
Lonze BE, Riccio A, Cohen S, Ginty DD. 2002. Apoptosis, axonal
growth defects, and degeneration of peripheral neurons in mice
lacking CREB. Neuron 34:371–385.
Mackay DJG, Nobes CD, Hall A. 1995. The Rho progress—a potential role during neuritogenesis for the Rho family of GTPases.
Trends Neurosci 18:496–501.
Markus A, Zhong J, Snider WD. 2002. Raf and akt mediate distinct
aspects of sensory axon growth. Neuron 35:65–76.
Marmigere F, Montelius A, Wegner M, Groner Y, Reichardt LF,
Ernfors P. 2006. The Runx1/AML1 transcription factor selectively
regulates development and survival of TrkA nociceptive sensory
neurons. Nat Neurosci 9:180–187.
Mason JM, Morrison DJ, Basson MA, Licht JD. 2006. Sprouty
proteins: multifaceted negative-feed back regulators of receptor
tyrosine kinase signaling. Trends Cell Biol 16:45–54.
Meakin SO, MacDonald JIS, Gryz EA, Kubu CJ, Verdi JM. 1999.
The signaling adapter FRS-2 competes with Shc for binding to
the nerve growth factor receptor TrkA—a model for discriminating proliferation and differentiation. J Biol Chem 274:9861–9870.
Merienne K, Pannetier S, Harel-Bellan A, Sassone-Corsi P. 2001.
Mitogen-regulated RSK2-CBP interaction controls their kinase
and acetylase activities. Mol Cell Biol 21:7089–7096.
Ming GI, Song HJ, Berninger B, Inagaki N, Tessier-Lavigne M,
Poo MM. 1999. Phospholipase C-gamma and phosphoinositide
3-kinase mediate cytoplasmic signaling in nerve growth cone
guidance. Neuron 23:139–148.
Moises T, Dreier A, Flohr S, Esser M, Brauers E, Reiss K, Merken
D, Weis J, Krüttgen A. 2007. Tracking TrkA’s trafficking: NGF
receptor trafficking controls NGF receptor signaling. Mol Neurobiol 35:151–159.
Namikawa K, Honma M, Abe K, Takeda M, Mansur K, Obata T,
Miwa A, Okado H, Kiyama H. 2000. Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal
regeneration. J Neurosci 20:2875–2886.
Nishi T, Forgac M. 2002. The vacuolar (Hþ)-ATPases—nature’s
most versatile proton pumps. Nat Rev Mol Cell Biol 3:94–103.
Nobes CD, Hall A. 1995. Rho, Rac, and Cdc42 GTPases regulate the
assembly of multimolecular focal complexes associated with actin
stress fibers, lamellipodia, and filopodia. Cell 81:53–62.
Nobes CD, Reppas JB, Markus A, Tolkovsky AM. 1996. Active
p21Ras is sufficient for rescue of NGF-dependent rat sympathetic
neurons. Neuroscience 70:1067–1079.
Nusser N, Gosmanova E, Zheng Y, Tigyi G. 2002. Nerve growth factor signals through TrkA, phosphatidylinositol 3-kinase, and Rac1
to inactivate RhoA during the initiation of neuronal differentiation of PC12 cells. J Biol Chem 277:35840–35846.
Ozaki K, Kadomoto R, Asato K, Tanimura S, Itoh N, Kohno M.
2001. ERK pathway positively regulates the expression of Sprouty
genes. Biochem Biophys Res Commun 285:1084–1088.
Pap M, Cooper GM. 1998. Role of glycogen synthase kinase-3 in the
phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol
Chem 273:19929–19932.
Patel TD, Jackman A, Rice FL, Kucera J, Snider WD. 2000. Development of sensory neurons in the absence of NGF/TrkA signaling
in vivo. Neuron 25:345–357.
Perlson E, Hanz S, Ben Yaakov K, Segal-Ruder Y, Seger R, Fainzilber M. 2005. Vimentin-dependent spatial translocation of an
activated MAP kinase in injured nerve. Neuron 45:715–726.
Pollard SM, Wallbank R, Tomlinson S, Grotewold L, Smith A. 2008.
Fibroblast growth factor induces a neural stem cell phenotype in
fetal forebrain progenitors and during ES cell differentiation. Mol
Cell Neurosci 38:393–403.
Posern G, Saffrich R, Ansorge W, Feller SM. 2000. Rapid lamellipodia formation in nerve growth factor-stimulated PC12 cells is
dependent on Rac and P13K activity. J Cell Phys 183:416–424.
Powell JC, Twomey C, Jain R, McCarthy JV. 2009. Association
between Presenilin-1 and TRAF6 modulates regulated intramembrane proteolysis of the p75NTR neurotrophin receptor. J Neurochem 108:216–230.
Ramanan N, Shen Y, Sarsfield S, Lemberger T, Schuetz G, Linden
DJ, Ginty DD. 2005. SRF mediates activity-induced gene expression and synaptic plasticity but not neuronal viability. Nat Neurosci 8:759–767.
Romanelli RJ, Wood TL. 2008. Directing traffic in neural cells:
determinants of receptor tyrosine kinase localization and cellular
responses. J Neurochem 105:2055–2068.
Roy K, Murtie JC, El-Khodor BF, Edgar N, Sardi SP, Hooks BM,
Benoit-Marand M, Chen C, Moore H, O’Donnell P, Brunner D,
Corfas G. 2007. Loss of erbB signaling in oligodendrocytes alters
myelin and dopaminergic function, a potential mechanism for
neuropsychiatric disorders. Proc Natl Acad Sci USA 104:8131–
Saroussi S, Nelson N. 2009. Vacuolar H(þ)-ATPase-an enzyme for
all seasons. Pflugers Arch 457:581–587.
Sasaki A, Taketomi T, Kato R, Saeki K, Nonami A, Sasaki M,
Kuriyama M, Saito N, Shibuya M, Yoshimura A. 2003. Mammalian Sprouty4 suppresses Ras-independent ERK activation by
binding to Raf1. Nat Cell Biol 5:427–432.
Sasaki A, Taketomi T, Wakioka T, Kato R, Yoshimura A. 2001. Identification of a dominant negative mutant of sprouty that potentiates fibroblast growth factor-but not epidermal growth factorinduced ERK activation. J Biol Chem 276:36804–36808.
Schober A, Wolf N, Huber K, Hertel R, Krieglstein K, Minichiello L,
Kahane N, Widenfalk J, Kalcheim C, Olson L, Klein R, Lewin
GR, Unsicker K. 1998. TrkB and neurotrophin-4 are important
for development and maintenance of sympathetic preganglionic neurons innervating the adrenal medulla. J Neurosci 18:
Sebök A, Nusser N, Debreceni B, Guo Z, Santos MF, Szeberenyi J,
Tigyi G. 1999. Different roles for RhoA during neurite initiation,
elongation, and regeneration in PC12 cells. J Neurochem 73:949–
Sgamboto V, Vanhoutte P, Pages C, Rogard M, Hipskind R, Besson
MJ, Caboche J. 1998. In vivo expression and regulation of Elk-1,
a target of the ERK signaling pathway, in the adult rat brain.
J Neurosci 18:214–226.
Sharma SK, Carew TJ. 2004. The roles of MAPK cascades in synaptic plasticity and memory in Aplysia : facilitatory effects and
inhibitory constraints. Learn Mem 11:373–378.
Sharrocks AD. 2001. The ETS-domain transcription factor family.
Nat Rev Mol Cell Biol 2:827–837.
Smeyne RJ, Klein R, Schnapp A, Long LK, Bryant S, Lewin A, Lira
SA, Barbacid M. 1994. Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature
Smith LG, Li R. 2004. Actin polymerization: riding the wave. Curr
Biol 14:109–111.
Tamai K, Toyoshima M, Tanaka N, Yamamoto N, Owada Y, Kiyonari H, Murata K, Ueno Y, Ono M, Shimosegawa T, Yaegashi N,
Watanabe M, Sugamura K. 2008. Loss of hrs in the central nervous system causes accumulation of ubiquitinated proteins and
neurodegeneration. Am J Pathol 173:1806–1817.
Tefft D, Lee M, Smith S, Crowe DL, Bellusci S, Warburton D. 2002.
mSprouty2 inhibits FGF10-activated MAP kinase by differentially
binding to upstream target proteins. Am J Physiol Lung Cell Mol
Physiol 283:700–706.
Thoenen H, Sendtner M. 2002. Neurotrophins: from enthusiastic
expectations through sobering experiences to rational therapeutic
approaches. Nat Neurosci Suppl 5:1046–1050.
Thor S, Thomas JB. 1997. The Drosophila islet gene governs axon
pathfinding and neurotransmitter identity. Neuron 18:397–409.
Torii S, Kusakabe M, Yamamoto T, Maekawa M, Nishida E. 2004.
Sef is a spatial regulator for Ras/MAP kinase signaling. Dev Cell
Traverse S, Gomez N, Paterson H, Marshall C, Cohen P. 1992. Sustained activation of the mitogen-activated protein (MAP) kinase
cascade may be required for differentiation of PC12 cells—comparison of the effects of Nerve Growth Factor and Epidermal
Growth Factor. Biochem J 288:351–355.
Tsang M, Friesel R, Kudoh T, Dawid IB. 2002. Identification of Sef,
a novel modulator of FGF signalling. Nat Cell Biol 4:165–169.
Tsang M, Dawid IG. 2004. Promotion and attenuation of FGF Signaling through the Ras-MAPK pathway. Sci STKE 2004:1–5.
Valderrama X, Misra V. 2008. Novel Brn3a cis-acting sequences
mediate transcription of human trkA in neurons. J Neurochem
Vickers ER, Kazsa A, Aksan Kurnaz I, Seifert A, Zeef L, O’Donnell
A, Hayes A, Sharrocks AD. 2004. Ternary TCF-SRF complexregulated gene activity is required for cellular proliferation and
inhibition of apoptotic cell death. Mol Cell Biol 24:10340–10351.
Waetzig V, Herdegen T. 2003. The concerted signaling of ERK1/2
and JNKs is essential for PC12 neuritogenesis and converges at
the level of target proteins. Mol Cell Neurosci 24:238–249.
Wang SW, Mu X, Bowers WJ, Kim D-S, Plas DJ, Crair MC, Federoff
HJ, Gan L, Klein WH. 2002. Brn3b/Brn3c double knockout mice
reveal and unsuspected role for Brn3c in retinal ganglion cell
axon outgrowth. Development 129:467–477.
Welsh CF, Assoian RK. 2000. A growing role for Rho family
GTPases as intermediaries in growth factor- and adhesiondependent cell cycle progression. Biochim Biophys Acta 1471:
Whitfield J, Neame SJ, Paquet L, Bernard O, Ham J. 2001. Dominant negative c-Jun promotes neuronal survival by reducing BIM
expression and inhibiting mitochondrial cytochrome C release.
Neuron 29:629–643.
Wickramashinghe SR, Alvania RS, Ramanan N, Wood JN, Mandai
K, Ginty DD. 2008. Serum response factor mediates NGF-dependent target innervation by embryonic DRG sensory neurons. Neuron 58:532–545.
Wiese S, Digby MR, Gunnersen JM, Gotz R, Pei G, Holtmann B,
Lowenthal J, Sendtner M. 1999. The anti-apoptotic protein ITA is
essential for NGF-mediated survival of embryonic chick neurons.
Nat Neurosci 2:978–983.
Wood KW, Qi HQ, Darcangelo G, Armstrong RC, Roberts TM, Halegoua S. 1993. The cytoplasmic raf oncogene induces a neuronal
phenotype in PC12 cells—a potential role for cellular Raf kinases
in neuronal growth factor signal transduction. Proc Natl Acad Sci
USA 90:5016–5020.
Wu C, Cui B, He L, Chen L, Mobley WC. 2009. The coming of
age of axonal neurotrophin signaling endosomes. J Proteomics 72:
Wu C, Ramirez A, Cui B, Ding J, Delcroix JD, Valletta JS, Liu JJ,
Yang Y, Chu S, Mobley WC. 2007. A functional dynein-microtubule network is required for NGF signaling through the Rap1/
MAPK pathway. Traffic 8:1503–1520.
Xiong SQ, Zhao QH, Rong ZL, Huang GR, Huang YL, Chen PL,
Zhang SP, Liu L, Chang ZJ. 2003. hSef inhibits PC-12 cell differentiation by interfering with Ras-mitogen-activated protein
kinase MAPK signaling. J Biol Chem 278:50273–50282.
Yamaguchi Y, Katoh H, Yasui H, Mori K, Negishi M. 2001. RhoA
inhibits the nerve growth factor-induced Rac1 activation through
Rho-associated kinase-dependent pathway. J Biol Chem 276:
Yusoff P, Lao DH, Ong SH, Wong ESM, Lim J, Lo TL, Leong HF,
Fong CW, Guy GR. 2002. Sprouty2 inhibits the Ras/MAP kinase
pathway by inhibiting the activation of raf. J Biol Chem 277:
Zhong J, Li X, McNamee C, Chen AP, Baccarini M, Snider WD.
2007. Raf kinase signaling functions in sensory neuron differentiation and axon growth in vivo. Nat Neurosci 10:598–607.
Zhou FQ, Snider WD. 2006. Intracellular control of developmental
and regenerative axon growth. Philos Trans R Soc Lond B Biol
Sci 361:1575–1592.
Zhou FQ, Zhou J, Dedhar S, Wu YH, Snider WD. 2004. NGFinduced axon growth is mediated by localized inactivation of
GSK-30 and functions of the microtubule plus end binding protein
APC. Neuron 42:897–912.
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development, receptorsrelevance, tyrosine, neuronal, regenerative, signaling, kinases
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