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Reverse Signalling

Chapter · September 2016

DOI: 10.1002/9780470015902.a0026897

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Reverse Signalling Advanced article

Emily F Ross⋆ , Department of Biology, University of Virginia, Charlottesville, Vir-

Article Contents
• Introduction
ginia, USA
• Reverse Signalling from TM1 Ligands
Maria F Ali⋆ , Department of Biology, University of Virginia, Charlottesville, Virginia, • Reverse Signalling by TM2 Ligands

USA • GPI-Linked Ligands

Laura A Woo⋆ , Department of Biomedical Engineering, University of Virginia, • Conclusion

• Related Articles
Charlottesville, Virginia, USA
Online posting date: 15th September 2016
Sean R Chadwick, Department of Biology, University of Virginia, Charlottesville,
Virginia, USA
Eunji Lee, Department of Biology, University of Virginia, Charlottesville, Virginia, USA
Ryan M Sangston, Department of Biology, University of Virginia, Charlottesville,
Virginia, USA
Chhavi Sood, Department of Biology, University of Virginia, Charlottesville, Vir-
ginia, USA
Qi Zhang, Department of Biology, University of Virginia, Charlottesville, Virginia, USA
Xiaomu Zhang, Department of Biology, University of Virginia, Charlottesville,
Virginia, USA
Christopher D Deppmann, Department of Biology, University of Virginia,
Charlottesville, Virginia, USA

⋆ These three authors contributed equally to this work.

Cellular signal transduction is defined as the con- differentiation. Here we review reverse signalling
version of an extracellular signal to a response of ligands categorised by how they associate with
within a cell. Commonly referred to as forward the membrane: transmembrane type 1 (TM1),
signalling, this extracellular signal often comes transmembrane type 2 (TM2), or GPI-linked.
in the form of a soluble ligand that binds to a Within this structure we will emphasize the physi-
membrane-spanning receptor. However, many lig- ological and pathological roles of reverse signaling.
ands or their precursors are also transmembrane or
membrane associated. It is now appreciated that
these ligands may also act as receptors in a process
referred to as reverse signalling. There is a grow- Introduction
ing body of evidence that reverse signalling occurs
for several classes of ligands including: ephrins, Signal transduction is defined as the conversion of an extracel-
semaphorins, interleukins, tumour necrosis factor lular cue to a response within a cell. Implicit within this defini-
family members and Notch-associated ligands. tion is communication between cells. Forward signalling is most
This type of signalling has been linked to immune often represented as signalling downstream of receptors such
as ion channels, G-protein-coupled receptors (GPCRs) or recep-
responses, axon guidance, cell proliferation and
tor tyrosine kinases after ligand engagement. However, over the
past 20 years, increased attention has been paid to signalling on
the ligand-bearing cell whereby a membrane-associated ligand
eLS subject area: Cell Biology exhibits receptor-like behaviour. This phenomenon is known as
reverse signalling (Eissner et al., 2004). See also: Signal Trans-
How to cite:
Ross, Emily F; Ali, Maria F; Woo, Laura A; Chadwick, Sean R;
duction: Overview
Lee, Eunji; Sangston, Ryan M; Sood, Chhavi; Zhang, Qi; Zhang, Herein, we examine major classes of ligands known to
Xiaomu; and Deppmann, Christopher D (September 2016) undergo reverse signalling. This article is organised by how
Reverse Signalling. In: eLS. John Wiley & Sons, Ltd: Chichester. the ligands associate with the membrane. In particular, trans-
DOI: 10.1002/9780470015902.a0026897 membrane type 1 (TM1), transmembrane type 2 (TM2) and

eLS © 2016, John Wiley & Sons, Ltd. www.els.net 1

2
Overview of reverse signalling
Transmembrane Transmembrane GPI-linked
Type 1 ligands Type 2 ligands ligands
Reverse Signalling

Example Cell migration Cytoskeletal Focal Adhesion Neuron Cellular Synapse maturation, Axon growth, Cytokine production, Cell adhesion,
and regulation, migration transcription cell survival guidance proliferation repulsion
Function adhesion axon guidance Legend
Recruitment of CK1 phos leads to Enzyme recruitment Co-receptor SEMA domain
Signal SRC family kinases ATEV adaptor ICD cleaved,
phosphorylation RhoGEF ??? provides PDZ, recruits PDZ effector binds EOS enzyme recruitment, via proline rich regions, recruitment,
activates PI3K pathway MAGUK family proteins protiens transcription factor transient ERK1/2 activates AKT and ERK1/2, acting via Fyn, Akt, pTyrosine, pSerine,
Pathway transcription of NFTA & AP1 MAPK1/2 P
or pThreionine
TACE cut

Reverse G-protein anchor

signalling Ephrin B Sema1A Sema6D tmIL-15 DeltaD Jagged1 NRG1 mTNF FasL Ephrin A DSL domain (RBD)
N N N
C N N N
C Proline rich
ligands C C
C CK1 domain
CK1 domain EGF-like
PDZ binding
ATEV site
P pSerines domain CK1 domain
P
C RS site of Proline rich
C Proline rich
Intracellular P pTyrosine proteolysis

Receptor binding domain

TACE cut site TACE cut site G-protein anchor (RBD)
Extracellular Stem region N
C-terminal stem
region
RBD
Ligand binding domain
(LBD)
N N
N N
N
N N Fibronectin
C C C C C C
type III repeats
N
N DSL Critical EGF- Kinase
domain like repeats domain
11 and 12 ( LBD)
N
N
C C C C C Cystine rich
N
C SAM
Sushi
domain
ATEV site
Furin-like
domain
RS sites of RS sites of
Extracellular proteolysis proteolysis
Plexin domain

RAM domain
Intracellular C
Tyrosine pSerine P P P
P P P
kinase domain N N N pThy P P P PDZ binding domain
Ankryin

eLS © 2016, John Wiley & Sons, Ltd. www.els.net

P repeats pTyrosine P P P P pSerine P
N
PEST domain
P PEST domain pTyrosine P
pTyrosine PlexinA
N N N Ankryin repeats
C
Immunoglobulin
P P SAM domain
Furin-like domain
PDZ binding domain
C RAM domain
C C
Forward
signalling Eph B Eph A
Plexin A1 IL15Ralpha Notch ErbB2 TNFR1 FasR
receptors receptor receptor

Figure 1 Ligands capable of reverse signalling. A small number of ligands and their downstream reverse signalling pathways and cellular functions have been well characterised. Among these are TM1
ligands (EphrinB, Sema1A, Sema6D, tmIL-15, DeltaD, Jagged1 and NRG1), TM2 ligands (mTNF𝛼, FasL) and GPI-linked ligands (Ephrin A). These ligands are involved in a number of cellular functions ranging
from axonal regulation to cell proliferation and migration. A large number of these ligands reverse signal through intracellular domains that contain CK1 phosphorylation sites, PDZ-binding or proline-rich
domains, capable of recruiting adaptor/effector proteins. Other ligands lack these intracellular domains and signal through alternative methods (e.g. recruitment of coreceptors or cleavage).
 Reverse Signalling

GPI (glycosylphosphatidiylinositol)-linked will be discussed A common feature of TM1 proteins implicated in reverse sig-
(Figure 1). We will examine the mechanisms of reverse sig- nalling is that they lack intrinsic catalytic activity. Instead, most
nalling and their downstream pathways as well as phenotypes TM1 proteins have very short ICDs and upon ligand binding,
and diseases associated with disrupted reverse signalling. See these ICDs recruit enzymatic activity. There are several examples
also: Ephrins; Semaphorins; First Messengers of this: (1) PDZ binding motifs: Several ligands, including ephrin
B, JAGGED1 and Delta1, have PDZ domain-binding motifs that
recruit effector proteins (Ascano et al., 2003; Wright et al., 2004;
Reverse Signalling from TM1
Bush and Soriano, 2009). For instance, mutations in the PDZ
Ligands binding motif of JAGGED1 failed to induce cellular transforma-
tion, presumably because the ICD of JAGGED1 can no longer
Perhaps the largest class of molecules capable of reverse sig- recruit PDZ domain-bearing effector proteins (Ascano et al.,
nalling are single-pass transmembrane (TM) proteins. TM pro- 2003). In addition, zebrafish delta proteins (DeltaD and DeltaC)
teins contain a plasma membrane-spanning hydrophobic region
bind PDZ domains on MAGI (MAGUK proteins with inverted
as well as extracellular and intracellular hydrophilic regions.
domain arrangement) proteins through an a PDZ binding motif.
These proteins are categorised into two different classes, TM1
and TM2, based on their orientation and topology relative to the Disruption of the ATEV motif on DeltaD results in altered migra-
plasma membrane. tory behaviour of neurons in zebrafish embryos (Wright et al.,
TM1 proteins make up approximately 6% of the coding 2004). (2) Phosphotyrosine: Other TM1 ligands like ephrin B
sequences in the human genome (see also: Signalling via Sin- recruit effector proteins after tyrosine phosphorylation on the
gle-Pass Transmembrane Proteins). By definition, all TM1 ICD by Src family kinases. This creates a docking site for sev-
proteins have an extracellular N-terminus, a single alpha-helical eral SH2 domain bearing adaptor proteins, such as Grb4, which,
TM domain and a cytoplasmic C-terminus. While many of for example, leads to the retraction of axonal growth cones (Xu
these proteins are considered classic receptors, many ligand and Henkemeyer, 2012). (3) Cleavage: Beyond effector protein
precursors start as TM1 proteins and are processed by cleavage recruitment, some TM1 ligands require intracellular cleavage for
events before initiating forward signalling in neighbouring cells. reverse signalling. For example, binding of NRG1 to its recep-
Alternatively, these ligands may remain unprocessed resulting in tor, ErbB2, results in the cleavage and release of the NRG1-ICD.
contact-mediated forward signalling. For example, during axon NRG1-ICD forms a complex with a transcription factor, EOS, to
guidance solubilised or TM semaphorins can bind to neuropilin promote survival and promote synaptic plasticity during develop-
and/or plexin receptors to initiate chemorepulsion or contact ment (Bao et al., 2003, 2004).
repulsion, respectively (Tessier-Lavigne and Goodman, 1996;
In TM1 reverse signalling, cytoskeletal rearrangement is
Nakamura et al., 2000; Tamagnone and Comoglio, 2000). See
often downstream of effector protein recruitment. For example,
also: Ephrins; Semaphorins; Interleukins
Sema1a activation by PlexinA ectodomain results in Rho1 acti-
Reverse signalling is initiated when particular TM or
membrane-associated ligands are engaged by the ectodomain vation by recruiting, pebble, a RhoGEF, which promotes axon
of their cognate receptors. The receptor ectodomain can remain defasciculation (Yu et al., 2010; Jeong et al., 2012). Reverse
attached to the cell expressing it or it can be cleaved to initiate signalling via ephrin B3 has also been shown to influence
signalling on the ligand-bearing cell. Perhaps the best charac- cytoskeletal rearrangement by activating Rac and Cdc42 result-
terised examples of TM1 ligands capable of reverse signalling ing in axon retraction and pruning (Xu and Henkemeyer, 2012)
are Semaphorins (sema1a and sema6D), ephrins (ephrin B1, (see also: G Proteins). Inhibition of reverse signalling through
B2 and B3), interleukins (IL-15), neuregulins (TM isoforms of the use of a truncated ligand results in phenotypes including
NRG1) and Notch-associated ligands (Delta1 and JAGGED1) impaired synaptic spine morphogenesis and maturation (Segura
(Ascano et al., 2003; Bao et al., 2003; Toyofuku et al., 2004; et al., 2007) as well as a variety of VACTERL [vertebral (V),
Wright et al., 2004; Khawam et al., 2009; Xu and Henkemeyer, anorectal (A), cardiac (C), tracheoesophageal (TE), renal (R)
2012; Yu et al., 2010). This type of signalling appears to be and limb (L)] abnormalities such as cleft palate and omphalocele
particularly relevant during development, especially in the ner- (Dravis and Henkemeyer, 2011).
vous system. For example, in the Xenopus laevis visual system, Although reverse signalling by TM1 proteins plays a pivotal
ephrin B2 expressing dorsal retinal ganglion cell (RGC) axons role during development, it has also been implicated in dis-
are attracted towards the EphB2 receptor expressing ventral
ease. In colorectal carcinoma, ephrin B2 is overexpressed. Ephrin
tectal region (the dorsoventral retinal axis maps onto ventrodor-
B2 engagement by EphB4 induces several hallmarks of can-
sal tectal axis). Reverse signalling by ephrin B2 is implicated
cer including multiple chemoresistance, epithelial–mesenchymal
in the topographic mapping of axons from the retina onto the
tectum. Loss of the intracellular domain (ICD) of ephrin B2 transition (EMT) and proliferation (Alam et al., 2016). Similarly,
results in erroneous mapping of 30% of dorsal RGCs onto the reverse signalling by mutated membrane bound IL-15 (mIL-15)
tectum (Mann et al., 2003). Importantly, forward signalling via in human renal cancer cells and human prostate carcinoma cells
EphB patterns a different region of axons in the tectum, which is necessary and sufficient to induce EMT (Khawam et al., 2009).
demonstrates how forward and reverse bidirectional signalling Finally, in glioblastoma, ephrin B2 and B3 bidirectional sig-
must cooperate to guide proper nervous system patterning. See nalling with their receptor EphB2 is associated with cancer inva-
also: Axon Guidance siveness (Nakada et al., 2011).

eLS © 2016, John Wiley & Sons, Ltd. www.els.net 3

 Reverse Signalling

Reverse Signalling by TM2 Ligands Another major role of TNFSF reverse signalling is mediating
immune and inflammatory responses. One example of reverse
TM2 ligands are similar to TM1 proteins in that they span the signalling in the immune system occurs through the Fas lig-
and (FasL). The cytoplasmic domain of FasL contains both a
membrane once, but with a cytoplasmic N-terminus and an extra-
CK1 binding site and a proline-rich domain, which allow for the
cellular C-terminus. TM2 proteins are also capable of undergoing
recruitment of adaptor proteins that result in the stimulation of
reverse signalling, with the most prominent examples residing in
both the PI3K and MAPK pathways. Stimulation of these path-
the tumour necrosis factor superfamily (TNFSF).
ways activates the transcription factors NFAT and AP-1, leading
The TNFSF and tumour necrosis factor receptor superfam-
to the production of cytokines and proliferation of FasL-bearing
ily (TNFRSF) are involved in proinflammatory cytokine pro-
cells. Several other examples of TNFSF reverse signalling have
duction and apoptosis (Wajant et al., 2003). To understand been shown to induce expansion of particular immune cell pop-
TNFSF reverse signalling, it is important to appreciate the mem- ulations, which is critical for rapidly defending against invading
brane topology of these ligands. TNFSF members can exist as pathogens (Sun et al., 2006; Eissner et al., 2004).
both a trimeric membrane-embedded ‘pro’ form, as well as a TNF𝛼 signalling has been implicated in a number of inflamma-
cleaved, soluble ‘mature’ form. The mature trimer binds to recep- tory diseases such as rheumatoid arthritis (RA) and Crohn disease
tors to influence several processes ranging from immune cell (CD). Two drugs have been developed to suppress TNF𝛼 activ-
function to nervous system development. Forward signalling of ity in RA and CD: Infliximab (Ifx) and Etanercept (Eta). The
the TNFSF induces major pathways including NF-kB (nuclear two drugs have different efficacies towards each disease, which
factor-kappaB), Caspase-8 and JNK. See also: Tumour Necrosis is likely due to structural differences. Ifx is a monoclonal anti-
Factors body capable of dimerising to bind two TNF𝛼 molecules, while
While mechanisms of forward signalling for TNFSF and their Eta is a fusion protein containing a portion of the TNFR which
receptors are well documented, there is evidence that the pro can bind only one molecule of TNF𝛼. While both drugs are effec-
form of these ligands can also reverse signal to the ligand-bearing tive in the treatment of RA, only Ifx is effective in the treatment
cell (Hildt and Oess, 1999). Importantly, reverse signalling from of CD. It has been suggested that Eta is ineffective in the treat-
these ligands activates pathways distinct from forward signalling ment of CD because it is unable to induce reverse signalling
resulting in the induction of distinct cellular responses. However, through mTNF𝛼 causing a subsequent failure to induce apoptosis
all TNFSF members capable of reverse signalling do not initiate in immune helper cells that are a hallmark of this inflammatory
identical pathways. This is perhaps not surprising given the sig- disorder (Kirchner et al., 2004).
nificant heterogeneity between the intracellular portions of these
ligands, which are often short, some having as few as 22 amino
acids (Sun and Fink, 2007). GPI-Linked Ligands
As with reverse signalling via TM1 ligands, the ICDs of
TNFSF lack enzymatic activity. Therefore, the mechanisms Another class of ligands that can transduce bidirectional signals
by which these ligands promote reverse signalling are likely is the GPI-anchored proteins. Unlike TM ligands mentioned ear-
through recruitment of adaptor and effector proteins (Eissner lier, GPI-linked proteins lack both a TM and cytoplasmic domain.
et al., 2004). A proposed mechanism of enzymatic recruitment A phosphoethanolamine linker connects GPI-linked ligands to an
is through casein kinase 1 (CK1) binding and phosphorylation evolutionarily conserved glycolipid core, which enables anchor-
ing of the protein to the extracellular leaflet of the plasma mem-
motifs present in the ICD of 6 TNFSF members (Sun and Fink,
brane. The soluble proteins that are linked to the GPI anchor
2007). Importantly, these CK1 motifs are conserved across
include enzymes, adhesion molecules, receptors, regulatory pro-
several species (Horiuchi et al., 2010).
teins and surface antigens; this diversity contributes to the wide
A well-characterised example of TNFSF reverse signalling
range of biological functions associated with this class of ligands
comes from the developing nervous system. The soluble
(Brennan, 2001). See also: Protein Association with Membrane
ectodomain of TNFR1 is generated by the calcium-dependent
Rafts
complex of ARTS-1 (aminopeptidase regulator of TNFR1 shed- While the GPI anchor has long been known to stably anchor
ding) and NUCB2 (nucleobindin 2) (Islam et al., 2006). Upon proteins to the plasma membrane, it has been postulated to medi-
engagement by the soluble ectodomain of TNFR1, mTNF𝛼 ate more complex biological roles in the host cell, such as, asso-
reverse signalling promotes axon growth and branching in sym- ciating proteins with lipid rafts, inducing conformational changes
pathetic neurons via transient activation of ERK1/ERK2 as well in proteins, targeting proteins to the apical membrane of polarised
as Ca2+ influx. In the absence of this signalling, neuronal target cells, regulating protein solubility via phospholipase cleavage and
innervation is impaired (Kisiswa et al., 2013). intracellular signal transduction (Paulick and Bertozzi, 2008).
As described earlier, mTNF𝛼 reverse signalling has been shown This mode of membrane attachment is not synonymous with a
to increase intracellular calcium, an effect that is ablated when TM domain. In fact, mice with the GPI anchor of GDNF receptor
CK1 is inhibited (Watts et al., 1999). Whether this phospho- 𝛼1 replaced by a TM domain demonstrated dramatically altered
rylation event is required for other aspects of mTNF𝛼, reverse signalling, resulting in developmental defects reminiscent of the
signalling remains an open question. It will also be important to knockout animal (Tsui et al., 2015).
determine whether other members of the TNFSF that contain a Perhaps the best example of GPI-linked protein reverse sig-
putative CK1 motif on their ICD reverse signal in a similar way. nalling is from the ephrin A class of ligands. In this case, reverse

4 eLS © 2016, John Wiley & Sons, Ltd. www.els.net

 Reverse Signalling

Box 1 Logic of Bidirectional Signalling

What is the advantage of forward and reverse signalling? Perhaps the most parsimonious explanation is that a single
receptor–ligand interaction may be able to elicit distinct responses in neighbouring cells (Eissner et al., 2004). This is critical
within tissues that require coordinated function or patterning of distinct cell types. Antagonistic Response: Reverse signalling
can trigger independent or opposing pathways relative to forward signalling. For example, while tyrosine phosphorylation
occurs on ICDs of both EphB and ephrin B, downstream forward or reverse signalling results in attraction and repulsion,
respectively (Xu and Henkemeyer, 2012). In this way, bidirectional signalling patterns the nerve during development by
signalling separation of distinct axon populations. Coordinated response: In other examples, bidirectional signalling leads to
a coordinated response within tissues. In bone remodeling, reverse signalling via ephrin B2 expressing osteoclast precursors
prevents osteoclast formation, while forward signalling in EphB4 expressing osteoblasts enhances differentiation (Zhao et al.,
2006). Therefore, forward and reverse signalling in both bone cell types inhibit bone resorption and enhance new bone formation
in order to maintain bone homeostasis. In these two examples, bidirectionality has antagonistic or coordinated roles; however,
it is likely that there are several other ways in which bidirectional signalling is used to coordinate development and function
(e.g. mutually exclusive differentiation and axon fasciculation).

signalling is initiated upon binding to the ectodomain of their (Leyton et al., 2001; Peles et al., 1995). Bidirectional signalling
cognate Eph receptor tyrosine kinase (RTK). Reverse signalling involving GPI-linked CD48 expressed on T cells and NK cell
from five ephrin A ligands has been implicated in regulating receptor 2B4 (CD244) have been implicated in regulating pro-
diverse biological processes including receptor-mediated apop- liferation (Chlewicki et al., 2008). Additional studies hint at
tosis, insulin secretion, cell branching, attraction, repulsion and GPI-linked CD59 and CD160 ligands regulating T-cell activa-
adhesion (Konstantinova et al., 2007; Coate et al., 2009; Holen tion by interacting with CD2 and herpesvirus entry mediator,
et al., 2008; Lim et al., 2008). Several methodologies have respectively (Liversidge et al., 1996; Cheung et al., 2009). More
enabled delineation of ephrin A reverse signalling including (1) focused studies are necessary to elucidate molecular mechanisms
soluble fusion proteins that mimic the soluble ectodomain of Eph of reverse signalling via this unique class of GPI-linked ligands
receptors, (2) small molecule inhibitors against ephrin A and (3) and further explore other possible GPI-linked proteins that may
ephrin A-specific knockout models. Ephrin A reverse signalling undergo reverse signalling.
has been shown to activate downstream pathways including Src,
FAK, Fyn, Akt and MAPK1/2 (Coate et al., 2009; Holen et al.,
2008; Lim et al., 2008).
How can a protein with no TM domain propagate a signal?
Several mechanisms have been proposed including endocytic Conclusion
pathways and the recruitment of coreceptors or chaperones
to facilitate signalling across the membrane (Brennan, 2001; The structure and function of ligands involved in reverse sig-
Lakhan et al., 2009; Li et al., 2015; Bonanomi et al., 2012). Sev- nalling can be effectively divided into three groups based on
eral coreceptors have been shown to mediate ephrin A reverse membrane topology: TM (type 1 and type 2) and GPI linked.
signalling including the Ret RTK and neurotrophin receptors These ligands can signal through a variety of mechanisms, includ-
p75NTR and TrkB (Bonanomi et al., 2012; Lim et al., 2008; ing recruitment of effector or adaptor proteins through pro-
Marler et al., 2008). In some cases, the forward and reverse sig- tein domains or interactions with coreceptors on the same cell.
nals activated by EphA–ephrin A interactions can lead to opposite Reverse signalling has been shown to be involved in many critical
effects on cell function. For example, EphA forward signalling in cellular processes including axon guidance, apoptosis, prolifera-
motor neurons induces repulsion in ventral limb axons express- tion and differentiation. Despite growing knowledge of reverse
ing ephrin A ligands, while reverse signalling through ephrin signalling mechanisms, this remains an immature field. The lack
A and coreceptor Ret promote attraction towards EphA recep- of knowledge is partly due to the use of conventional ligand or
tor expressing cells in the dorsal limb (Bonanomi et al., 2012). receptor knockout animals that disrupt both forward and reverse
In addition, ephrin A-mediated reverse signalling also induces a signalling, which display phenotypes that are largely attributed
variety of distinct effects in different cell types (i.e. motor and to forward signalling. In the future, more sophisticated knock-in
retinal ganglion neurons); however, this is likely attributed to a strategies, through mutations and truncations in the ligand ICD, or
difference in ephrin A coreceptors (Lim et al., 2008; Bonanomi isolation of downstream reverse signalling through the use of sol-
et al., 2012; Rashid et al., 2005). uble receptors, which selectively induce reverse signalling, will
Beyond ephrin A reverse signalling, several other GPI-linked allow us to parse out the role of forward and reverse signalling in
ligands may participate in reverse signalling. GPI-linked Thy-1 development, function and disease. These strategies will lead to a
and contactin expressed in neurons have been proposed to stimu- more comprehensive list of ligands capable of reverse signalling,
late bidirectional signals upon binding to integrin 𝛽3 on astrocytes which may reveal that this mode of cell–cell communication is
and receptor type protein tyrosine phosphatase 𝛽 on glial cells not an exception but may in fact be a rule.

eLS © 2016, John Wiley & Sons, Ltd. www.els.net 5

 Reverse Signalling

Related Articles Holen HL, Shadidi M, Narvhus K, et al. (2008) Signaling through
ephrin-A ligand leads to activation of Src-family kinases, Akt
phosphorylation, and inhibition of antigen receptor-induced apop-
Axon Guidance
tosis. Journal of Leukocyte Biology 84 (4): 1183–1191.
Ephrins Horiuchi T, Mitoma H, Harashima S, Tsukamoto H and Shimoda T
First Messengers (2010) Transmembrane TNF-𝛼: structure, function and interaction
G Proteins with anti-TNF agents. Rheumatology (Oxford, England) 49 (7):
Interleukins 1215–1228.
Protein Association with Membrane Rafts Islam A, Adamik B, Hawari FI, et al. (2006) Extracellular TNFR1
Semaphorins release requires the calcium-dependent formation of a nucle-
Signal Transduction: Overview obindin 2-ARTS-1 complex. Journal of Biological Chemistry 281
Signalling via Single-Pass Transmembrane Proteins (10): 6860–6873.
Tumour Necrosis Factors Jeong S, Juhaszova K and Kolodkin AL (2012) The control of
semaphorin-1a-mediated reverse signaling by opposing pebble and
RhoGAPp190 functions in drosophila. Neuron 76 (4): 721–734.
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