A Review of ELTD1, A Pro-Angiogenic Adhesion GPCR

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Biochemical Society Transactions (2014) Volume 42, part 6
A review of ELTD1, a pro-angiogenic adhesion

GPCR
David M. Favara*1 , Alison H. Banham and Adrian L. Harris*
*Department of Oncology, University of Oxford, Oxford, U.K.
Balliol College, University of Oxford, Oxford, U.K.
NDCLS-Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
Biochemical Society Transactions
www.biochemsoctrans.org
Abstract
Epidermal growth factor, latrophilin and seven-transmembrane domain-containing 1 (ELTD1), an orphan
G-protein-coupled receptor (GPCR) belonging to the adhesion GPCR family, has recently been identied
as a potential cancer biomarker and a novel regulator of angiogenesis. In this mini-review, we present
an overview of the current literature on ELTD1 and present bioinformatics data showing ELTD1s sequence
conservation, its expression in cancer cell lines and its mutational frequency in human cancers. Additionally,
we present sequence homology alignment results conrming ELTD1 to be a hybrid comprising motifs shared
with individual members in both adhesion GPCR subfamilies 1 and 2. Finally, we discuss why tumour
endothelial ELTD1 expression may confer a good prognosis yet still represent a therapeutic target.
Introduction
Angiogenesis is the process by which new blood vessels
form from pre-existing vessels. This tightly regulated
process occurs physiologically throughout life during periods
of controlled tissue growth, tissue repair and wound
healing, as well as during the menstrual cycle, during
placental implantation in the uterus and in embryogenesis
[1]. Pathological angiogenesis refers to inappropriate and
excessive angiogenesis and is associated with a spectrum
of diseases, most notably cancer [2]. Cancer-associated
angiogenesis provides the tumour with oxygen and essential
nutrients needed for promoting tumour growth, expansion
and metastasis and is thus an attractive therapeutic target [2].
Since the first association between angiogenesis and
tumour growth over 40 years ago [3], much work has
been invested into the search and development of antiangiogenic therapies. The majority of anti-angiogenic
approaches developed to date target components of either
the vascular endothelial growth factor (VEGF) pathway
or the NOTCH intercellular signalling pathway, which
together make up the two most studied angiogenic pathways
[4]. Translation of these therapies into clinical practice
has, however, proved difficult. For example, despite many
positive results achieved in preclinical models with VEGF
inhibition, its translation into clinical practice has yielded
Key words: adhesion G-protein-coupled receptor (adhesion GPCR), angiogenesis, biomarker,

cancer, epidermal growth factor, latrophilin and seven-transmembrane domain-containing 1
(ELTD1).
Abbreviations: DLL4, Delta-like ligand 4; ECD, extracellular domain; EGF, epidermal growth
factor; ELTD1, epidermal growth factor, latrophilin and seven-transmembrane domain-containing
1; GAIN, GPCR autoproteolysis inducing domain; GPCR, G-protein-coupled receptor; GPS, GPCR
proteolytic site; ICD, intracellular tail; 7TM, seven-transmembrane domain; VEGF, vascular
endothelial growth factor.
1
To whom correspondence should be addressed (email david.favara@balliol.ox.ac.uk).

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Authors Journal compilation
poor overall survival regardless of its broad-spectrum

anti-tumour activity. This may be because of tumour
resistance, either preceding therapy or developing following
prolonged therapy and leading to the restoration of tumour
growth [5]. It can thus be hypothesized that tumours
undergoing selective anti-angiogenic pressure may over time
be able to recruit alternative undiscovered parallel angiogenic
pathways unaffected by the given therapy. The search for
such novel parallel pathways is an active area of current
research.
Recently, epidermal growth factor, latrophilin and seventransmembrane domain-containing 1 (ELTD1) was reported
as a novel and previously largely uncharacterized regulator of
tumour angiogenesis. Cross-talk with VEGF and NOTCH
pathways was identified via either stimulation (VEGF) [6,7]
or repression [Delta-like ligand 4 (DLL4)] [6] of ELTD1
expression. The present mini-review is a summary of current
knowledge regarding ELTD1.
ELTD1 and the adhesion GPCR family

Discovered in 2001, ELTD1 is an orphan member of the
G-protein-coupled receptor (GPCR) superfamily [8]. This
superfamily comprises the largest receptor family in the
human proteome with over 900 members and is divided
into five groups according to the sequence homology of a
domain present in all members, the seven-transmembrane
domain (7TM) [9] (Figure 1). Within the GPCR superfamily,
ELTD1 belongs to the 33 member adhesion family, so named
for their large extracellular domains containing adhesion
motifs, a feature not found in other GPCR families [10].
In general, the adhesion family remains the most poorly
studied and understood of the five GPCR families [11].
Within the adhesion family, ELTD1 is grouped into the
family 1/latrophilin-like subfamily. This grouping is based
Biochem. Soc. Trans. (2014) 42, 16581664; doi:10.1042/BST20140216
Angiogenesis and Vascular Remodelling: New Perspectives
Figure 1 An overview of the GPCR superfamily focusing on the adhesion family

GPCRs can be classied into ve groups according to seven-transmembrane domain sequence homology. The adhesion
family forms the second largest group and is the most poorly understood of the GPCRs. Members of each adhesion subfamily
are listed. Dotted lines surround members with a known ligand. ELTD1 is circled in black. Adhesion motifs expressed by
members from each subfamily are listed. Note that not all motifs listed for each subfamily are expressed by every member
of that group. CAD, cadherin motif; CALX-, calnexin- motif; CUB, Cs1 and Csr/Uegf/BMP1 motif; IG, immunoglobulin
motif; LAM, laminin motif; LRR, leucin-rich repeat; OLF, olfactomedin motif; EGF, epidermal growth factor motif; EEAR,
epitempin/epilepsy-associated repeat; HRM, hormone receptor motif; PTX, pentraxin motif; RBL, rhamnose-binding lectin
motif; SEA, sperm protein, enterokinase, agrin module; TSP, thrombospondin motif.
solely on 7TM sequence homology [10]. Latrophilin 13 form

the other members of this group and are so named because
of their ability to bind -latrotoxin, a toxin produced by the
black widow spider (Latrodectus mactans) [12].
Located on chromosome 1p31.1, ELTD1 encodes a
3527 nucleotide transcript (AT content 64 %) translated
as a 690 amino acid protein [13]. ELTD1 contains 15
exons, expressed as two splice variants: one full-length
and the other a 149 amino acid truncated C-terminal
segment of the transmembrane domain. Like all adhesion
GPCRs, ELTD1 can be topographically divided into three
components (Figure 2A): (i) an extracellular domain (ECD)
containing receptor-specific ecto-domains as well as the
GPCR autoproteolysis inducing domain (GAIN), (ii) a
7TM and (iii) an intracellular tail (ICD).
In humans, bioinformatic analysis reveals that the 430amino-acid ELTD1 ECD encodes an epidermal growth factor
(EGF) repeat, an EGFCa2 + binding repeat and a GAIN
domain (Figure 2A). ELTD1s EGF adhesion motifs are not
found in other family 1/latrophilin-like subfamily members.

Ligands to ELTD1s extracellular domains have yet to be
identified. Adhesion GPCRs are the only GPCRs to contain
GAIN domains. These conserved domains are important
in adhesion GPCR assembly and are found in all but one
adhesion GPCR [14]. Within ELTD1s GAIN domain, a
motif termed the GPCR proteolytic site (GPS) undergoes
autoproteolytic cleavage during protein assembly in the
endoplasmic reticulum before rejoining non-covalently (at
the cleavage site) and being exported to the Golgi complex
and then to the cell membrane [15] (Figure 2B). Although
the GPS motif makes up a small area of the larger GAIN
domain (53 out of 263 amino acids respectively in ELTD1),
the entire GAIN domain itself is required for autoproteolysis
to occur [11]. In some adhesion GPCRs, it is hypothesized
that autoproteolytic cleavage may allow for swapping of
extracellular domain fragments between receptors once at
the cell surface [16]. Although this has been noted with
latrophilin 1, EMR2 and GPR56, [1719] it remains unproven

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Figure 2 ELTD1s putative structure and conservation

(A) ELTD1s bioinformatically derived putative structure. (B) Close-up of ELTD1s GPS motif within ELTD1s extracellular GAIN
domain. Autoproteolytic cleavage point indicated by dotted red line. (C) ELTD1s conservation: ELTD1 exhibits high-level
conservation across vertebrates (black bars) and moderate conservation in C. elegans (white bar), signifying evolutionary
importance. Sequence data obtained from the Ensembl genome browser [13]. His, histidine; Leu, leucine; Thr, threonine;
AA, amino acid(s).
for the majority of adhesion GPCRs, including ELTD1.

Other postulated roles for cleavage include involvement in
adhesion GPCR ligandreceptor interactions, signalling and
protection of receptor/membrane integrity during periods
of mechanical stress [16]. The amino acids involved in
this autoproteolytic cleavage have been identified [16]
in all cleaved GPCRs with ELTD1s being histidine (position
405), leucine (position 406) and threonine (position 407)
(Figure 2B). ELTD1s cleavage occurs between the leucine
and threonine residues. Although a mass spectrometry based
study of the human plasma N-glycoproteome has identified
a circulating N-terminal ELTD1 peptide [20], it remains
unknown whether ELTD1 commonly disassociates at its
proteolytic cleavage site once it is expressed on the cell
surface.
Canonical GPCR signalling involves ligands binding to
extracellular regions of the 7TM which initiate G-protein
signalling. Whether this also occurs in members of the
adhesion family remains unclear [16]. ELTD1s signalling
ability has yet to be established. ELTD1s 7TM (Figure 2A)

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comprises 237 amino acids and its ICD comprises 22 amino

acids, the shortest ICD among members of the family
1/latrophilin-like subfamily. Bioinformatic analysis reveals
only a single predicted phosphorylation site on ELTD1s
ICD. ELTD1s crystal structure remains unsolved.
When comparing homology with human ELTD1 across
species, we found that Eltd1 is highly conserved across
vertebrates (5099 %) with moderate conservation in nonvertebrates such as Caenorhabditis elegans (16 %) (Figure 3).
This conservation signifies an evolutionarily important role
for ELTD1.
When compared with other adhesion family GPCRs,
ELTD1 appears to be a hybrid comprising motifs from
adhesion subfamilies 1 and 2 and lacking the adhesion
motifs found in other subfamily 1 members. Interestingly,
ELTD1 expression does not follow the tissue distribution of
other subfamily 1 members {predominantly expressed in the
central nervous system (CNS) [21]} or subfamily 2 members
(predominantly expressed by cells of the immune system
[22]). We performed sequence homology comparisons which
Figure 3 ELTD1 in cancer

(A) ELTD1 expression levels in 1036 cancer cell lines: ELTD1 is poorly expressed in the majority of cancer cell lines. Data
obtained from the Cancer Cell Line Encyclopedia [39]. (B) ELTD1s alteration frequency in 48 curated cancer-genome datasets
obtained from cBioPortal for Cancer Genomics [41]. The number of altered cases and total cases per dataset is listed above
each column. ELTD1 is mutated in 10 % of melanoma and lung squamous cell carcinoma cases. Amplication without
other ELTD1 alterations occurs in bladder carcinoma, sarcoma and uterine carcinosarcoma datasets. ACyC, adenoid cystic
carcinoma; adeno, adenocarcinoma; AML, acute myeloid leukaemia; ccRCC, kidney renal clear cell carcinoma; CCLE, Cancer
Cell Line Encyclopedia; CML, chronic myeloid leukaemia; DLBC lymphoma, diffuse large B-cell lymphoma; GBM, glioblastoma
multiforme; MM, multiple myeloma; NCI60, National Cancer Institute 60 human tumour cell line screen; pRCC, renal papillary
cell carcinoma; SC, squamous carcinoma.
reveal that ELTD1s EGF repeats share closest homology

with EMR3 (subfamily 2) and that ELTD1s GAIN, 7TM
and ICD are closest to LAT3 (subfamily 1). Although ligands
to EMR3s EGF motifs remain unknown, the EGF motif
ligands of other subfamily 2 members are known, namely:

dermatan sulfate [23] for both CD97 and EMR2; and CD55
[24], CD90 [25] and integrins 51, av3 [26] for CD 97.
These are not known to associate with ELTD1.

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ELTD1 as an angiogenic regulator

When first discovered, ELTD1 expression was noted only in
rat bronchiolar and vascular smooth muscle cells and in both
rat and human cardiomyocytes [8]. In 2008, two separate
studies found ELTD1 to be part of the normal endothelial
transcriptome in humans [27] and mice [28] respectively. In
2012, a study aiming to characterize the transcriptome of
blood vessels associated with grade IV glioblastoma found
ELTD1 to be one of 95 genes up-regulated in these vessels
[7]. The same study found that VEGF-A and transforming
growth factor 2 (TGF-2) up-regulated ELTD1 expression
in these vessels but did not specifically associate ELTD1
as a regulator of angiogenesis [7]. In 2013, ELTD1 was
characterized as a novel regulator of both physiological and
tumour angiogenesis [6].
ELTD1s association as a regulator of tumour angiogenesis
was identified using a bioinformatic screen for previously
uncharacterized genes associated with tumour angiogenesis
[6]. This was performed by analysing the expression profile
of approximately 1000 primary human tumour samples from
three different tumour types and comparing expression with a
core signature of well-recognized angiogenic and endothelial
cell associated seed genes. ELTD1 was found to be the
highest ranked non-seed gene which was not an established
regulator of angiogenesis. This role was then functionally
validated both in vitro and in vivo [6].
ELTD1 was found to be highly expressed in vascular
endothelial cells and vascular smooth muscle cells, with
higher endothelial expression being observed in peri-tumoral
vessels (across a range of tumours) than in vessels from
matched normal tissues. ELTD1 was also found to be
regulated by two key angiogenic ligands, namely VEGF,
up-regulating ELTD1, and DLL4, down-regulating ELTD1.
VEGFs effect on ELTD1 validated previous findings in
glioblastoma-associated vessels [7]. ELTD1 and DLL4 were
also found to antagonize each other. A separate study focusing
on the breast cancer perivascular niche further validated
this antagonism by showing that NOTCH1 silencing of
neovascular sprouts increased extracellular ELTD1 protein
enrichment [29].
ELTD1 silencing in human umbilical vein endothelial
cells demonstrated its important role in tip cell function
during sprouting angiogenesis. Additionally, through use
of the zebrafish (Danio rerio) embryo, Eltd1 was shown
to be important in vasculogenesis. In this model, Eltd1
silencing using morpholinos caused severe vascular defects
and prevented effective intersegmental vessel formation from
the dorsal aorta.
When human ovarian and colorectal tumour xenografts
were implanted in mice, systemic anti-mouse Eltd1 silencing
in the murine stroma was found to substantially inhibit
tumour growth. In addition to having smaller and fewer
tumours, Eltd1 silenced mice survived longer and had far
fewer sites of metastasis when compared with controls. No
significant toxicity was observed as body weight and heart to
body weight ratios were unaffected.

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Finally, high endothelial cell ELTD1 expression was found

to correlate with improved overall survival in a number of
cancer types, namely renal cancer, colorectal cancer, head
and neck squamous cell carcinoma and ovarian cancer. These
findings implicate ELTD1 as a putative prognostic marker
of favourable outcome for these cancers when treated with
chemotherapy.
The ELTD1 vessel maturity hypothesis

Tumour-associated vessels are functionally and structurally
abnormal, being immature, tortuous and very leaky [30].
These factors all result in poor drug delivery to the tumour
site. In contrast, mature vessels are less leaky and tortuous,
which facilitates better drug delivery to the tumour site. This
is the principle behind vascular maturation/normalization as
a strategy for the treatment of cancer [31].
In the light of the findings that higher vascular
ELTD1 expression correlates with improved survival in
numerous cancer types, we hypothesize that ELTD1 may
be important in regulating tumour vessel maturation, with
higher expression promoting higher microvessel density,
more mature and differentiated and/or less leaky vessels.
This is analogous to vascular normalization after anti-VEGF
therapy [32]. The consequence of this is improved perfusion,
thus aiding drug delivery to the tumour, as well as producing
a less aggressive tumour (through a reduction in tumour
hypoxia which acts as a driver of metastasis).
Previously, propanolol (a non-specific -adrenergic
receptor inhibitor) was shown to be selectively toxic
to malignant vascular endothelial tumour cells versus
normal endothelial cells when administered to the SVR
angiosarcoma-forming cell line in mice. In this context,
transcriptional profiling revealed that propanolol similarly
increased endothelial expression of both Eltd1 and Tek, a gene
encoding the Tie2 angiogenic receptor which promotes vessel
quiescence, stability and maturation [33,34]. This association
adds further weight to ELTD1s vessel maturity hypothesis.
Should our hypothesis be proven correct, therapies which
increase endothelial ELTD1 expression (like propanolol) may
become important in the management of certain cancers.
In summary, ELTD1s roles in sprouting angiogenesis and
its putative association with vessel maturity may explain
why higher endothelial ELTD1 expression correlates with
improved survival in numerous tumour types and yet also
represents a therapeutic target.
Other roles for ELTD1

Other groups have shown ELTD1 expression to be important
in rodent cardiomyocyte development [8], and in protecting
against pathological hypertrophy in response to increased
major vessel pressure loading in mice [35]. This study also
found that failed hypertrophied human hearts in patients
awaiting cardiac transplantation had significantly lower
cardiac ELTD1 expression than healthy controls [35]. In
this context, ELTD1 polymorphisms have been found to be
positively selected in a cohort of high-altitude living Andean

people, possibly as a cardioprotective measure against lifelong
low oxygen induced increased cardiac effort [36]. This cohort
was also found to have an additional muscle layer in their
pulmonary arteries [36]. Thus, in some contexts, there may
be benefits derived from increasing ELTD1 expression.
In addition to its angiogenic role in cancer, ELTD1 has also
been found up-regulated in the tumour vasculature of high
grade gliomas [37] and has been found to be part of a panel
of nine genes up-regulated in patients with ulcerative colitis
harbouring an occult colorectal cancer [38].
Using publically available bioinformatic data, we note that
the majority of cancer cell lines do not highly express ELTD1
[39] (Figure 3A). We found that ELTD1 mutations occur in a
wide range of human cancers. These mutations do not cluster
in any specific region but rather occur randomly across all of
ELTD1s domains [40]. The frequency of ELTD1 mutations,
however, is low, with only melanoma and lung squamous
carcinoma having a mutational frequency of 10 % or more
in 48 curated cancer genome datasets [41] (Figure 3B). These
mutations are thus unlikely to be relevant functionally.
We reviewed genes in the vicinity of ELTD1 for the
presence of known cancer driver genes and found that
the known cancer gene FUBP1 (a causative gene for both
oligodendrogliomas and oligoastrocytomas [42]) is present
in the same band as ELTD1 (1p31.1). Looking within 10gb of
either side of ELTD1, we found an additional cancer driver,
BCL10 (a causative gene in mucosa-associated lymphoid
tissue lymphoma [43]). Analysis of ELTD1, FUBP1 and
BCL10 in a range of cancer genome datasets reveals that
mutations in these three genes occur mostly in ELTD1 and
that amplifications or deletions usually affect all three genes
when present in a patient. This suggests that ELTD1 may
function as a passenger gene in these circumstances or be a
novel cancer driver.
Other associations include ELTD1 polymorphisms conferring vulnerability to cannabis dependence [44] and
increased event-free longevity [from a meta-analysis of nine
genome-wide association studies (GWAS) on aging] [45].
ELTD1 has also been described as one of eight genes
responsible for subcutaneous fat thickness in humans and pigs
[46]. Finally, ELTD1 polymorphisms have been identified
in patients at risk of developing graft-versus-host disease
following haemopoietic stem cell transplants [47], and in
cattle who are resistant to therapy against tick parasites
[48]. In all these cases, however, the mechanisms underlying
ELTD1s association remain to be identified.
Conclusion
ELTD1 is an adhesion GPCR with roles which include
the regulation of physiological and tumour angiogenesis,
involvement in cardiac development and cardioprotection,
and regulation of expression in certain cancers. In all these
varied roles, ELTD1 warrants further investigation as both a
biomarker and therapeutic target.
Funding
D.M.F. is funded by the Rhodes Scholarship. A.H.B. and A.L.H. are
funded by Cancer Research UK.
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Received 6 August 2014

doi:10.1042/BST20140216

A Review of ELTD1, A Pro-Angiogenic Adhesion GPCR

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Biochemical Society Transactions (2014) Volume 42, part 6