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 identified 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 ELTD1's sequence conservation, its expression in cancer cell lines and its mutational frequency in human cancers. Additionally, we present sequence homology alignment results confirming 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 anti-angiogenic 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 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 seven-transmembrane 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 solely on 7TM sequence homology [10]. Latrophilin 1–3 form the other members of this group and are so named because of their ability to bind α-latrotoxin, a toxin produced by the black widow spider (Latrodectus mactans) [12].

An overview of the GPCR superfamily focusing on the adhesion family

Figure 1
An overview of the GPCR superfamily focusing on the adhesion family

GPCRs can be classified into five 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-β, calnexin-β 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.

Figure 1
An overview of the GPCR superfamily focusing on the adhesion family

GPCRs can be classified into five 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-β, calnexin-β 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.

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).

ELTD1's putative structure and conservation

Figure 2
ELTD1's putative structure and conservation

(A) ELTD1's bioinformatically derived putative structure. (B) Close-up of ELTD1's GPS motif within ELTD1's extracellular GAIN domain. Autoproteolytic cleavage point indicated by dotted red line. (C) ELTD1's 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).

Figure 2
ELTD1's putative structure and conservation

(A) ELTD1's bioinformatically derived putative structure. (B) Close-up of ELTD1's GPS motif within ELTD1's extracellular GAIN domain. Autoproteolytic cleavage point indicated by dotted red line. (C) ELTD1's 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).

In humans, bioinformatic analysis reveals that the 430-amino-acid ELTD1 ECD encodes an epidermal growth factor (EGF) repeat, an EGF–Ca2+ binding repeat and a GAIN domain (Figure 2A). ELTD1's EGF adhesion motifs are not found in other ‘family 1/latrophilin-like’ subfamily members. Ligands to ELTD1's 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 ELTD1's 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 for the majority of adhesion GPCRs, including ELTD1. Other postulated roles for cleavage include involvement in adhesion GPCR ligand–receptor 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 ELTD1's being histidine (position 405), leucine (position 406) and threonine (position 407) (Figure 2B). ELTD1's 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]. ELTD1's signalling ability has yet to be established. ELTD1's 7TM (Figure 2A) 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 ELTD1's ICD. ELTD1's crystal structure remains unsolved.

When comparing homology with human ELTD1 across species, we found that Eltd1 is highly conserved across vertebrates (50–99%) with moderate conservation in non-vertebrates such as Caenorhabditis elegans (16%) (Figure 3). This conservation signifies an evolutionarily important role for ELTD1.

ELTD1 in cancer

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) ELTD1’s 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. Amplification 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.

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) ELTD1’s 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. Amplification 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.

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 reveal that ELTD1's EGF repeats share closest homology with EMR3 (subfamily 2) and that ELTD1's GAIN, 7TM and ICD are closest to LAT3 (subfamily 1). Although ligands to EMR3's 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 α5β1, avβ3 [26] for CD 97. These are not known to associate with ELTD1.

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 β2 (TGF-β2) 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].

ELTD1's 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. VEGF's 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.

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 β-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 ELTD1's 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, ELTD1's 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 ELTD1's 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 ELTD1's 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.

Angiogenesis and Vascular Remodelling: New Perspectives: A Biochemical Society Focused Meeting held at University of Chester, U.K., 14–16 July 2014. Organized and Edited by Roy Bicknell (Birmingham University Medical School, U.K.), Michael Cross (University of Liverpool, U.K.), Stuart Egginton (University of Leeds, U.K.), Victoria Heath (University of Birmingham, U.K.) and Ian Zachary (University College London, U.K.).

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

Funding

D.M.F. is funded by the Rhodes Scholarship. A.H.B. and A.L.H. are funded by Cancer Research UK.

References

References
1
Daly
M.E.
Makris
A.
Reed
M.
Lewis
C.E.
Hemostatic regulators of tumor angiogenesis: a source of antiangiogenic agents for cancer treatment?
J. Natl. Cancer Inst.
2003
, vol. 
95
 (pg. 
1660
-
1673
)
[PubMed]
2
Hanahan
D.
Weinberg Robert
A.
Hallmarks of cancer: the next generation
Cell.
2011
, vol. 
144
 (pg. 
646
-
674
)
[PubMed]
3
Folkman
J.
Tumor angiogenesis: therapeutic implications
N. Engl. J. Med.
1971
, vol. 
285
 (pg. 
1182
-
1186
)
[PubMed]
4
Blanco
R.
Gerhardt
H.
VEGF and Notch in tip and stalk cell selection
Cold Spring Harb. Perspect. Med.
2013
, vol. 
3
 pg. 
a006569
 
[PubMed]
5
Bergers
G.
Hanahan
D.
Modes of resistance to anti-angiogenic therapy
Nat. Rev. Cancer
2008
, vol. 
8
 (pg. 
592
-
603
)
[PubMed]
6
Masiero
M.
Simoes
F.C.
Han
H.D.
Snell
C.
Peterkin
T.
Bridges
E.
Mangala
L.S.
Wu
S.Y.
Pradeep
S.
Li
D.
, et al. 
A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis
Cancer Cell
2013
, vol. 
24
 (pg. 
229
-
241
)
[PubMed]
7
Dieterich
L.C.
Mellberg
S.
Langenkamp
E.
Zhang
L.
Zieba
A.
Salomaki
H.
Teichert
M.
Huang
H.
Edqvist
P.H.
Kraus
T.
, et al. 
Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization
J. Pathol.
2012
, vol. 
228
 (pg. 
378
-
390
)
[PubMed]
8
Nechiporuk
T.
Urness
L.D.
Keating
M.T.
ETL, a novel seven-transmembrane receptor that is developmentally regulated in the heart. ETL is a member of the secretin family and belongs to the epidermal growth factor-seven-transmembrane subfamily
J. Biol. Chem.
2001
, vol. 
276
 (pg. 
4150
-
4157
)
[PubMed]
9
Schioth
H.B.
Fredriksson
R.
The GRAFS classification system of G-protein coupled receptors in comparative perspective
Gen. Comp. Endocrinol.
2005
, vol. 
142
 (pg. 
94
-
101
)
[PubMed]
10
Bjarnadottir
T.K.
Fredriksson
R.
Hoglund
P.J.
Gloriam
D.E.
Lagerstrom
M.C.
Schioth
H.B.
The human and mouse repertoire of the adhesion family of G-protein-coupled receptors
Genomics
2004
, vol. 
84
 (pg. 
23
-
33
)
[PubMed]
11
Promel
S.
Langenhan
T.
Arac
D.
Matching structure with function: the GAIN domain of adhesion-GPCR and PKD1-like proteins
Trends Pharmacol. Sci.
2013
, vol. 
34
 (pg. 
470
-
478
)
[PubMed]
12
Matsushita
H.
Lelianova
V.G.
Ushkaryov
Y.A.
The latrophilin family: multiply spliced G protein-coupled receptors with differential tissue distribution
FEBS Lett.
1999
, vol. 
443
 (pg. 
348
-
352
)
[PubMed]
13
Flicek
P.
Amode
M.R.
Barrell
D.
Beal
K.
Billis
K.
Brent
S.
Carvalho-Silva
D.
Clapham
P.
Coates
G.
Fitzgerald
S.
, et al. 
Ensembl 2014
Nucleic Acids Res.
2014
, vol. 
42
 (pg. 
D749
-
D755
)
[PubMed]
14
Arac
D.
Aust
G.
Calebiro
D.
Engel
F.B.
Formstone
C.
Goffinet
A.
Hamann
J.
Kittel
R.J.
Liebscher
I.
Lin
H.H.
, et al. 
Dissecting signaling and functions of adhesion G protein-coupled receptors
Ann. N.Y. Acad. Sci.
2012
, vol. 
1276
 (pg. 
1
-
25
)
[PubMed]
15
Lin
H.-H.
Chang
G.-W.
Davies
J.Q.
Stacey
M.
Harris
J.
Gordon
S.
Autocatalytic cleavage of the EMR2 receptor occurs at a conserved G protein-coupled receptor proteolytic site motif
J. Biol. Chem.
2004
, vol. 
279
 (pg. 
31823
-
31832
)
[PubMed]
16
Langenhan
T.
Aust
G.
Hamann
J.
Sticky signaling—adhesion class G protein-coupled receptors take the stage
Sci. Signal.
2013
, vol. 
6
 pg. 
re3
 
[PubMed]
17
Huang
Y.S.
Chiang
N.Y.
Hu
C.H.
Hsiao
C.C.
Cheng
K.F.
Tsai
W.P.
Yona
S.
Stacey
M.
Gordon
S.
Chang
G.W.
Lin
H.H.
Activation of myeloid cell-specific adhesion class G protein-coupled receptor EMR2 via ligation-induced translocation and interaction of receptor subunits in lipid raft microdomains
Mol. Cell. Biol.
2012
, vol. 
32
 (pg. 
1408
-
1420
)
[PubMed]
18
Volynski
K.E.
Silva
J.P.
Lelianova
V.G.
Atiqur Rahman
M.
Hopkins
C.
Ushkaryov
Y.A.
Latrophilin fragments behave as independent proteins that associate and signal on binding of LTX(N4C)
EMBO J.
2004
, vol. 
23
 (pg. 
4423
-
4433
)
[PubMed]
19
Silva
J.P.
Lelianova
V.
Hopkins
C.
Volynski
K.E.
Ushkaryov
Y.
Functional cross-interaction of the fragments produced by the cleavage of distinct adhesion G-protein-coupled receptors
J. Biol. Chem.
2009
, vol. 
284
 (pg. 
6495
-
6506
)
[PubMed]
20
Liu
T.
Qian
W.J.
Gritsenko
M.A.
Camp
D.G.
2nd
Monroe
M.E.
Moore
R.J.
Smith
R.D.
Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry
J. Proteome Res.
2005
, vol. 
4
 (pg. 
2070
-
2080
)
[PubMed]
21
Yona
S.
Lin
H.H.
Siu
W.O.
Gordon
S.
Stacey
M.
Adhesion-GPCRs: emerging roles for novel receptors
Trends Biochem. Sci
2008
, vol. 
33
 (pg. 
491
-
500
)
[PubMed]
22
Kwakkenbos
M.J.
Kop
E.N.
Stacey
M.
Matmati
M.
Gordon
S.
Lin
H.H.
Hamann
J.
The EGF-TM7 family: a postgenomic view
Immunogenetics
2004
, vol. 
55
 (pg. 
655
-
666
)
[PubMed]
23
Stacey
M.
Chang
G.W.
Davies
J.Q.
Kwakkenbos
M.J.
Sanderson
R.D.
Hamann
J.
Gordon
S.
Lin
H.H.
The epidermal growth factor-like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans
Blood
2003
, vol. 
102
 (pg. 
2916
-
2924
)
[PubMed]
24
Hamann
J.
Vogel
B.
van Schijndel
G.M.
van Lier
R.A.
The seven-span transmembrane receptor CD97 has a cellular ligand (CD55, DAF)
J. Exp. Med.
1996
, vol. 
184
 (pg. 
1185
-
1189
)
[PubMed]
25
Wandel
E.
Saalbach
A.
Sittig
D.
Gebhardt
C.
Aust
G.
Thy-1 (CD90) is an interacting partner for CD97 on activated endothelial cells
J. Immunol.
2012
, vol. 
188
 (pg. 
1442
-
1450
)
[PubMed]
26
Wang
T.
Ward
Y.
Tian
L.
Lake
R.
Guedez
L.
Stetler-Stevenson
W.G.
Kelly
K.
CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells
Blood
2005
, vol. 
105
 (pg. 
2836
-
2844
)
[PubMed]
27
Herbert
J.M.
Stekel
D.
Sanderson
S.
Heath
V.L.
Bicknell
R.
A novel method of differential gene expression analysis using multiple cDNA libraries applied to the identification of tumour endothelial genes
BMC Genomics
2008
, vol. 
9
 pg. 
153
 
[PubMed]
28
Wallgard
E.
Larsson
E.
He
L.
Hellstrom
M.
Armulik
A.
Nisancioglu
M.H.
Genove
G.
Lindahl
P.
Betsholtz
C.
Identification of a core set of 58 gene transcripts with broad and specific expression in the microvasculature
Arterioscler. Thromb. Vasc. Biol.
2008
, vol. 
28
 (pg. 
1469
-
1476
)
[PubMed]
29
Ghajar
C.M.
Peinado
H.
Mori
H.
Matei
I.R.
Evason
K.J.
Brazier
H.
Almeida
D.
Koller
A.
Hajjar
K.A.
Stainier
D.Y.
, et al. 
The perivascular niche regulates breast tumour dormancy
Nat. Cell Biol.
2013
, vol. 
15
 (pg. 
807
-
817
)
[PubMed]
30
Jain
R.K.
Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy
Science
2005
, vol. 
307
 (pg. 
58
-
62
)
[PubMed]
31
Carmeliet
P.
Jain
R.K.
Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases
Nat. Rev. Drug Discov.
2011
, vol. 
10
 (pg. 
417
-
427
)
[PubMed]
32
Goel
S.
Duda
D.G.
Xu
L.
Munn
L.L.
Boucher
Y.
Fukumura
D.
Jain
R.K.
Normalization of the vasculature for treatment of cancer and other diseases
Physiol. Rev.
2011
, vol. 
91
 (pg. 
1071
-
1121
)
[PubMed]
33
Singh
H.
Tahir
T.A.
Alawo
D.O.
Issa
E.
Brindle
N.P.
Molecular control of angiopoietin signalling
Biochem. Soc. Trans.
2011
, vol. 
39
 (pg. 
1592
-
1596
)
[PubMed]
34
Helfrich
I.
Schadendorf
D.
Blood vessel maturation, vascular phenotype and angiogenic potential in malignant melanoma: one step forward for overcoming anti-angiogenic drug resistance?
Mol. Oncol.
2011
, vol. 
5
 (pg. 
137
-
149
)
[PubMed]
35
Xiao
J.
Jiang
H.
Zhang
R.
Fan
G.
Zhang
Y.
Jiang
D.
Li
H.
Augmented cardiac hypertrophy in response to pressure overload in mice lacking ELTD1
PLoS One
2012
, vol. 
7
 pg. 
e35779
 
[PubMed]
36
Eichstaedt
C.A.
Antao
T.
Pagani
L.
Cardona
A.
Kivisild
T.
Mormina
M.
The Andean adaptive toolkit to counteract high altitude maladaptation: genome-wide and phenotypic analysis of the Collas
PLoS One
2014
, vol. 
9
 pg. 
e93314
 
[PubMed]
37
Towner
R.A.
Jensen
R.L.
Colman
H.
Vaillant
B.
Smith
N.
Casteel
R.
Saunders
D.
Gillespie
D.L.
Silasi-Mansat
R.
Lupu
F.
, et al. 
ELTD1, a potential new biomarker for gliomas
Neurosurgery
2013
, vol. 
72
 (pg. 
77
-
90
)
[PubMed]
38
Pekow
J.
Dougherty
U.
Huang
Y.
Gometz
E.
Nathanson
J.
Cohen
G.
Levy
S.
Kocherginsky
M.
Venu
N.
Westerhoff
M.
, et al. 
Gene signature distinguishes patients with chronic ulcerative colitis harboring remote neoplastic lesions
Inflamm. Bowel Dis.
2013
, vol. 
19
 (pg. 
461
-
470
)
[PubMed]
39
Barretina
J.
Caponigro
G.
Stransky
N.
Venkatesan
K.
Margolin
A.A.
Kim
S.
Wilson
C.J.
Lehár
J.
Kryukov
G.V.
Sonkin
D.
, et al. 
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
Nature
2012
, vol. 
483
 (pg. 
603
-
607
)
[PubMed]
40
Lawrence
M.S.
Stojanov
P.
Mermel
C.H.
Robinson
J.T.
Garraway
L.A.
Golub
T.R.
Meyerson
M.
Gabriel
S.B.
Lander
E.S.
Getz
G.
Discovery and saturation analysis of cancer genes across 21 tumour types
Nature
2014
, vol. 
505
 (pg. 
495
-
501
)
[PubMed]
41
Cerami
E.
Gao
J.
Dogrusoz
U.
Gross
B.E.
Sumer
S.O.
Aksoy
B.A.
Jacobsen
A.
Byrne
C.J.
Heuer
M.L.
Larsson
E.
, et al. 
The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data
Cancer Discov.
2012
, vol. 
2
 (pg. 
401
-
404
)
[PubMed]
42
Bettegowda
C.
Agrawal
N.
Jiao
Y.
Sausen
M.
Wood
L.D.
Hruban
R.H.
Rodriguez
F.J.
Cahill
D.P.
McLendon
R.
Riggins
G.
, et al. 
Mutations in CIC and FUBP1 contribute to human oligodendroglioma
Science
2011
, vol. 
333
 (pg. 
1453
-
1455
)
[PubMed]
43
Willis
T.G.
Jadayel
D.M.
Du
M.Q.
Peng
H.
Perry
A.R.
Abdul-Rauf
M.
Price
H.
Karran
L.
Majekodunmi
O.
Wlodarska
I.
, et al. 
Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types
Cell
1999
, vol. 
96
 (pg. 
35
-
45
)
[PubMed]
44
Agrawal
A.
Pergadia
M.L.
Saccone
S.F.
Lynskey
M.T.
Wang
J.C.
Martin
N.G.
Statham
D.
Henders
A.
Campbell
M.
Garcia
R.
, et al. 
An autosomal linkage scan for cannabis use disorders in the nicotine addiction genetics project
Arch. Gen. Psychiatry
2008
, vol. 
65
 (pg. 
713
-
721
)
[PubMed]
45
Walter
S.
Atzmon
G.
Demerath
E.W.
Garcia
M.E.
Kaplan
R.C.
Kumari
M.
Lunetta
K.L.
Milaneschi
Y.
Tanaka
T.
Tranah
G.J.
, et al. 
A genome-wide association study of aging
Neurobiol. Aging
2011
, vol. 
32
 (pg. 
2109.e15
-
2109.e28
)
[PubMed]
46
Lee
K.T.
Byun
M.J.
Kang
K.S.
Park
E.W.
Lee
S.H.
Cho
S.
Kim
H.
Kim
K.W.
Lee
T.
Park
J.E.
, et al. 
Neuronal genes for subcutaneous fat thickness in human and pig are identified by local genomic sequencing and combined SNP association study
PLoS One
2011
, vol. 
6
 pg. 
e16356
 
[PubMed]
47
Harkensee
C.
Oka
A.
Onizuka
M.
Middleton
P.G.
Inoko
H.
Nakaoka
H.
Gennery
A.R.
Ando
K.
Morishima
Y.
Japan Marrow Donor Programme (JMDP)
Microsatellite scanning of the immunogenome associates MAPK14 and ELTD1 with graft-versus-host disease in hematopoietic stem cell transplantation
Immunogenetics
2013
, vol. 
65
 (pg. 
417
-
427
)
[PubMed]
48
Porto Neto
L.R.
Bunch
R.J.
Harrison
B.E.
Barendse
W.
DNA variation in the gene ELTD1 is associated with tick burden in cattle
Anim. Genet.
2011
, vol. 
42
 (pg. 
50
-
55
)
[PubMed]