Dawn of a New RAMPage

doi:10.1016/j.tips.2020.01.009

Trends in Pharmacological Sciences

Volume 41, Issue 4, April 2020, Pages 249-265

https://doi.org/10.1016/j.tips.2020.01.009 Get rights and content

Highlights

RAMPs interact with GPCRs to regulate receptor function.
RAMP–GPCR coevolution studies suggest that RAMPs globally interact with GPCRs.
Over the past year, two studies expanded the RAMP–GPCR interactome using both multiplexed suspension bead array (SBA) and bioluminescence resonances energy transfer (BRET) methodologies.
Human mutations in RAMP–GPCR pairings have been identified and linked to human disease, including a mutation in calcitonin receptor-like receptor (CLR), associated with hydrops fetalis, and mutations in RAMP2, associated with glaucoma.
For the first time, the US FDA approved a GPCR-directed antibody against RAMP1–CLR, which reduces the number of migraine days patients experience.
The expanded RAMP–GPCR interactome and pivotal success of the first targeted therapy of RAMP–GPCR pairs has ushered in a new RAMPage.

Receptor activity-modifying proteins (RAMPs) interact with G-protein-coupled receptors (GPCRs) to modify their functions, imparting significant implications upon their physiological and therapeutic potentials. Resurging interest in identifying RAMP–GPCR interactions has recently been fueled by coevolution studies and orthogonal technological screening platforms. These new studies reveal previously unrecognized RAMP-interacting GPCRs, many of which expand beyond Class B GPCRs. The consequences of these interactions on GPCR function and physiology lays the foundation for new molecular therapeutic targets, as evidenced by the recent success of erenumab. Here, we highlight recent papers that uncovered novel RAMP–GPCR interactions, human RAMP–GPCR disease-causing mutations, and RAMP-related human pathologies, paving the way for a new era of RAMP-targeted drug development.

Section snippets

Historical Paradigm of RAMP–GPCR Signaling

GPCRs are the most tractable and druggable class of proteins, comprising ~30% of all approved therapeutics [1., 2., 3.]. These seven-transmembrane pass receptors mediate intercellular communication through the binding of endogenous or exogenous ligands, eliciting subsequent receptor conformational changes to release bound G-proteins. Over the past decade, the field of GPCR biology has experienced a dramatic revitalization with the discovery of biased signaling, spawning a new generation of

RAMP–GPCR Coevolution: Emerging Evidence of a Global RAMP–GPCR Interactome

As of 2016, there were only 11 reported RAMP–GPCR interactions [12]. Furthermore, nine of these 11 known RAMP–GPCR pairings involved Class B GPCRs, with the remaining two RAMP–GPCR pairs involving Class A and Class C receptors [13., 14., 15.]. Given that Class B GPCRs only account for ~5% of the non-odorant GPCRs, one can speculate that the breadth of RAMP–GPCR pairings is more extensive than previously thought.

In support of this hypothesis, Barbash et al. [16,17] provided compelling evidence

Expanding the RAMP Repertoire

The early groundwork for RAMP–GPCR interactions focused on Class B GPCR receptors, which revealed that RAMPs interact with calcitonin receptor (CT) [23], CLR [4], corticotropin-releasing factor receptors (CRF) [8], glucagon receptor [7,24], parathyroid hormone receptors [24], secretin receptor [25], and pituitary adenylate cyclase-activating peptide (PACAP) receptors [8,24]. The characterization of these interactions uncovered diverse functions of RAMPs, including alteration of ligand binding,

Physiological and Pathophysiological Roles of RAMPs

The aforementioned bioinformatic and biochemical screening approaches revealed exciting new RAMP–GPCR interactions. However, despite the diverse and widespread tissue expression of RAMPs, the field has been largely unsuccessful in linking specific RAMP–GPCR pairings to physiological and pathological phenotypes [35]. This is due, in large part, to a lack of rigorous in situ detection approaches. To date, much of our current understanding of the physiological role of RAMPs has been gleaned

Therapeutic Targeting of RAMP–GPCRs

Considering the rapidly expanding cohort of GPCRs that functionally interact with RAMPs and the breadth of physiological systems affected by RAMP signaling axes, it stands to reason that the protein–protein interface of a RAMP–GPCR interaction could be exploited for therapeutic benefit. Indeed, the therapeutic tractability of targeting RAMP–GPCR pairs was recently established through the generation of monoclonal antibodies targeting CGRP or its receptor (RAMP1–CLR) for the treatment of

Concluding Remarks and Future Perspectives

The past several years have marked an exciting time for the RAMP–GPCR field, where RAMP–GPCR coevolution studies hypothesized a global RAMP–GPCR interactome. Importantly, in 2019, we witnessed the experimental validation of these bioinformatic studies with the identification of previously unrecognized RAMP–GPCR interactions using two screening platforms (BRET and SBA). These studies effectively expanded the list of RAMP-interacting GPCRs from 11 to 44 receptors that span Class A, B, C, and the

Acknowledgments

We apologize to any in the field whose work is not cited here due to space restrictions. This work was supported by National Institutes of Health (NIH) R01 grants to the National Heart Lung and Blood Institute HL1290986, National Institute of Diabetes and Digestive and Kidney Diseases DK119145, and Eunice Kennedy Shriver National Institute of Child Health and Human Development HD060860 to K.M.C. N.R.N. was supported by a National Heart Lung and Blood Institute F31 HL143836. N.R.H. was supported

Glossary

Adrenomedullin (AM): a 52-amino acid peptide and member of the CGRP family. It is a potent vasodilator with a regulatory role in the cardiovascular and lymphatic systems through activation of CLR paired with RAMP2 or RAMP3.
Adrenomedullin 2 (AM2): also known as intermedin; member of the CGRP family and is expressed in both the peripheral and central nervous systems.
Atypical chemokine receptor 3 (ACKR3): also known as C-X-C chemokine receptor type 7 (CXCR7); a decoy receptor that binds the chemokines

References (90)

S.L. Garland
Are GPCRs still a source of new targets?
J. Biomol. Screen.
(2013)
N. Parameswaran et al.
RAMPs: the past, present and future
Trends Biochem. Sci.
(2006)
C. Weston
Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)
J. Biol. Chem.
(2015)
S. Barbash
Detection of Concordance between Transcriptional Levels of GPCRs and Receptor-Activity-Modifying Proteins
iScience
(2019)
F. Pazos
Assessing protein co-evolution in the context of the tree of life assists in the prediction of the interactome
J. Mol. Biol.
(2005)
J.B. Black
Feedback regulation of G protein-coupled receptor signaling by GRKs and arrestins
(2016)
P. Tsao
Role of endocytosis in mediating downregulation of G-protein-coupled receptors
Trends Pharmacol. Sci.
(2001)
A. Christopoulos
Novel receptor partners and function of receptor activity-modifying proteins
J. Biol. Chem.
(2003)
B. Boldajipour
Control of chemokine-guided cell migration by ligand sequestration
Cell
(2008)
K.R. Klein
Decoy Receptor CXCR7 Modulates Adrenomedullin-Mediated Cardiac and Lymphatic Vascular Development
Dev. Cell
(2014)

J. Bonaventura

L-DOPA-treatment in primates disrupts the expression of A(2A) adenosine-CB(1) cannabinoid-D(2) dopamine receptor heteromers in the caudate nucleus

Neuropharmacology

(2014)

D.O. Borroto-Escuela

G protein-coupled receptor heterodimerization in the brain

Methods Enzymol.

(2013)

C.J. Barrick

Loss of receptor activity-modifying protein 3 exacerbates cardiac hypertrophy and transition to heart failure in a sex-dependent manner

J. Mol. Cell. Cardiol.

(2012)

R. Dackor

Receptor activity-modifying proteins 2 and 3 have distinct physiological functions from embryogenesis to old age

J. Biol. Chem.

(2007)

C. Sternini

Calcitonin gene-related peptide neurons innervating the canine digestive system

Regul. Pept.

(1992)

A.G. Pauza

Alterations in enteric calcitonin gene-related peptide in patients with colonic diverticular disease: CGRP in diverticular disease

Auton. Neurosci.

(2019)

B. Gong

Mutant RAMP2 causes primary open-angle glaucoma via the CRLR-cAMP axis

Genet Med

(2019)

J.M. Bomberger

Novel function for receptor activity-modifying proteins (RAMPs) in post-endocytic receptor trafficking

J. Biol. Chem.

(2005)

J.M. Bomberger

Receptor activity-modifying protein (RAMP) isoform-specific regulation of adrenomedullin receptor trafficking by NHERF-1

J. Biol. Chem.

(2005)

Y. Lv

Adrenomedullin 2 Enhances Beiging in White Adipose Tissue Directly in an Adipocyte-autonomous Manner and Indirectly through Activation of M2 Macrophages

J. Biol. Chem.

(2016)

J. Prakash

Analysis of RAMP3 gene polymorphism with body composition and bone density in young and elderly women

Gene: X 2

(2019)

A. Recober

Induction of multiple photophobic behaviors in a transgenic mouse sensitized to CGRP

Neuropharmacology

(2010)

E. ter Haar

Crystal Structure of the Ectodomain Complex of the CGRP Receptor, a Class-B GPCR, Reveals the Site of Drug Antagonism

Structure

(2010)

M. Udawela

The effects of C-terminal truncation of receptor activity modifying proteins on the induction of amylin receptor phenotype from human CTb receptors

Regul. Pept.

(2008)

K. Sriram et al.

G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs?

Mol. Pharmacol.

(2018)

A.J. Venkatakrishnan

Molecular signatures of G-protein-coupled receptors

Nature

(2013)

L.M. McLatchie

RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor

Nature

(1998)

M. Kadmiel

Understanding RAMPs through genetically engineered mouse models

Adv. Exp. Med. Biol.

(2012)

D. Wootten

Receptor activity modifying proteins (RAMPs) interact with the VPAC2 receptor and CRF1 receptors and modulate their function

Br. J. Pharmacol.

(2013)

M.J. Woolley

The role of ECL2 in CGRP receptor activation: a combined modelling and experimental approach

J. R. Soc. Interface

(2013)

D.L. Hay

CGRP Receptor Biology: Is There More Than One Receptor?

Handb. Exp. Pharmacol.

(2019)

D.L. Hay

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

Br. J. Pharmacol.

(2018)

D.L. Hay et al.

Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles

Annu. Rev. Pharmacol. Toxicol.

(2016)

T. Bouschet

Receptor-activity-modifying proteins are required for forward trafficking of the calcium-sensing receptor to the plasma membrane

J. Cell Sci.

(2005)

A.J. Desai

Role of Receptor Activity Modifying Protein 1 in Function of the Calcium Sensing Receptor in the Human TT Thyroid Carcinoma Cell Line

PLoS One

(2014)

P.M. Lenhart

G-protein-coupled receptor 30 interacts with receptor activity-modifying protein 3 and confers sex-dependent cardioprotection

J. Mol. Endocrinol.

(2013)

S. Barbash

GPCRs globally coevolved with receptor activity-modifying proteins, RAMPs

Proc. Natl. Acad. Sci. U. S. A.

(2017)

K.H. Chen

Spatially resolved, highly multiplexed RNA profiling in single cells

Science

(2015)

R.J. Lefkowitz et al.

Transduction of receptor signals by β-arrestins

(2005)

G. Christopoulos

Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product

Mol. Pharmacol.

(1999)

K.G. Harikumar

Molecular Basis of Association of Receptor Activity-Modifying Protein 3 with the Family B G Protein-Coupled Secretin Receptor

Biochemistry

(2009)

E. Lorenzen

Multiplexed analysis of the secretin-like GPCR-RAMP interactome

Sci Adv

(2019)

D.I. Mackie

RAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis

Proceedings of the National Academy of Sciences

(2019)

J.M. Burns

A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development

J. Exp. Med.

(2006)

U. Naumann

CXCR7 functions as a scavenger for CXCL12 and CXCL11

PLoS One

(2010)

Cited by (23)

Endosomal signaling via cAMP in parathyroid hormone (PTH) type 1 receptor biology
2024, Molecular and Cellular Endocrinology
Compartmentalization of GPCR signaling is an emerging topic that highlights the physiological relevance of spatial bias in signaling. The parathyroid hormone (PTH) type 1 receptor (PTH₁R) was the first GPCR described to signal via heterotrimeric G-protein and cAMP from endosomes after β-arrestin mediated internalization, challenging the canonical GPCR signaling model which established that signaling is terminated by receptor internalization. More than a decade later, many other GPCRs have been shown to signal from endosomes via cAMP, and recent studies have proposed that location of cAMP generation impacts physiological outcomes of GPCR signaling. Here, we review the extensive literature regarding PTH₁R endosomal signaling via cAMP, the mechanisms that regulate endosomal generation of cAMP, and the implications of spatial bias in PTH₁R physiological functions.
Virtual drug repurposing study for the CGRPR identifies pentagastrin and leuprorelin as putative candidates
2022, Journal of Molecular Graphics and Modelling
Calcitonin gene-related peptide receptor (CGRPR) is a heterodimer consisting of CLR and RAMP1 proteins. Activation of the CGRPR with the endogenous peptide CGRP is known to play a crucial role in migraine pathophysiology. CGRP occupies two regions in the CGRPR upon binding, namely ectodomain and transmembrane sites (sites 1 and 2, respectively). The disruption of the CGRPR heterodimer interface is one of the main strategies to prevent CGRPR activation and its resulting effects. So far, FDA approved monoclonal antibodies and small molecule gepant inhibitors are considered for the treatment of acute or chronic migraine symptoms. However, most of these gepants have severe side effects. Thus, in this study, a virtual drug repurposing approach is applied to CGRPR to find alternative or better molecules that would have a potential to inhibit or block the CLR – RAMP1 interface compared to known gepant molecules. A small molecule library of FDA-approved molecules was screened in these two different binding sites, further simulations were performed and analyzed. The objectives of this study are (i) to repurpose an FDA-approved drug having more potent features for CGRPR inhibition compared to gepants, and (ii) to examine whether the transmembrane binding site (site 2) accepts small molecules or small peptide analogues for binding. As a result of this extensive in silico analysis, two molecules were identified, namely pentagastrin and leuprorelin. It is shown that FDA approved compound rimegepant and the identified pentagastrin molecules form and maintain the interactions through CLR W72 and RAMP1 W74, which are the residues revealed to have an important role in CGRPR antagonism at binding site 1. At binding site 2, the interactions needed to be formed for CGRP binding are not captured by rimegepant nor leuprorelin, yet leuprorelin forms more interactions throughout the simulations, meaning that small molecules are also capable of binding to site 2. Moreover, it is found that the crucial interactions for receptor signaling and heterodimerization occurred between CLR and RAMP1 interface are disrupted more with the ligands bound to ectodomain site, rather than the transmembrane domain. These findings of pentagastrin and leuprorelin molecules are recommended to be considered in further de novo drug development and/or experimental studies related to CGRPR signaling blockade and antagonism.
Structural perspective of class B1 GPCR signaling
2022, Trends in Pharmacological Sciences
Citation Excerpt :
RAMPs are a family of single transmembrane proteins represented by three subtypes (RAMP1, 2, and 3) and can modulate GPCR function in several ways [46]. The simplest way is to act as molecular chaperones for class A, B, and C GPCRs [47]. The functions of RAMPs bound to individual class B1 GPCRs have been reported, covering CLR, CTR, VIP2R, PTH1R, PTH2R, GHRHR, CRF1R, SCTR, GCGR, GIPR, GLP‐1R and GLP‐2R with all three RAMPs [32,48,49], VIP1R with RAMP2 and RAMP3 [49], and CRF2R with RAMP3 [49].
Class B1 G protein-coupled receptors (GPCRs) play important roles in human physiology and disease pathology. Using cryo-electron microscopy (cryo-EM) and X-ray crystallography, the 3D structures of all 15 members of this receptor subfamily have been determined in recent years at the near-atomic level. Although they share many structural commonalities, they show distinct features in terms of ligand recognition and receptor activation. In-depth structural analyses have yielded valuable insights into the N termini of both peptide hormones and cognate receptors, the outward movement of transmembrane helix 6 (TM6), the allosteric modulation sites located in the transmembrane domain (TMD), and the constitutive signaling bias mediated by receptor splice variants. These provide new directions for the design of better therapeutic agents, thereby making these targets more druggable.
G protein-coupled receptor-effector macromolecular membrane assemblies (GEMMAs)
2022, Pharmacology and Therapeutics
G protein-coupled receptors (GPCRs) are the largest group of receptors involved in cellular signaling across the plasma membrane and a major class of drug targets. The canonical model for GPCR signaling involves three components — the GPCR, a heterotrimeric G protein and a proximal plasma membrane effector — that have been generally thought to be freely mobile molecules able to interact by ‘collision coupling’. Here, we synthesize evidence that supports the existence of GPCR–effector macromolecular membrane assemblies (GEMMAs) comprised of specific GPCRs, G proteins, plasma membrane effector molecules and other associated transmembrane proteins that are pre-assembled prior to receptor activation by agonists, which then leads to subsequent rearrangement of the GEMMA components. The GEMMA concept offers an alternative and complementary model to the canonical collision-coupling model, allowing more efficient interactions between specific signaling components, as well as the integration of the concept of GPCR oligomerization as well as GPCR interactions with orphan receptors, truncated GPCRs and other membrane-localized GPCR-associated proteins. Collision-coupling and pre-assembled mechanisms are not exclusive and likely both operate in the cell, providing a spectrum of signaling modalities which explains the differential properties of a multitude of GPCRs in their different cellular environments. Here, we explore the unique pharmacological characteristics of individual GEMMAs, which could provide new opportunities to therapeutically modulate GPCR signaling.
Molecular simulations reveal the impact of RAMP1 on ligand binding and dynamics of calcitonin gene-related peptide receptor (CGRPR) heterodimer
2022, Computers in Biology and Medicine
Citation Excerpt :
Molecular modeling and simulation methods have become a common tool for visualizing and simulating many physiological systems, as well as studying cellular events in multidimensional approaches. Till date, the role of RAMPs in class B GPCRs are broadly investigated [11,15–18], and there are various experimental studies performed for the neuropeptide-cell signaling and activation mechanisms [15,18–21], as well as the receptor stability and ligand selectivity [9,22,23]. The release of whole structural domains of the human CGRP receptor (CLR + RAMP1) with bound CGRP neuropeptide and in complex with the Gs-protein heterotrimer by Liang et al. is expected to give great momentum to the in silico studies in this area.
Calcitonin gene-related peptide receptor (CGRPR) is a heterodimer protein complex consisting of a class-B G protein-coupled receptor (GPCR) named calcitonin receptor-like receptor (CLR) and an accessory protein, receptor activity modifying protein type 1 (RAMP1). Here in this study, with several molecular modeling approaches and molecular dynamics (MD) simulations, the structural and dynamical effects of RAMP1 on the binding of small molecule CGRPR inhibitors (namely rimegepant and telcagepant) to the CGRPR extracellular ectodomain complex site (site 1) and transmembrane binding site (site 2) are investigated. Results showed that although these molecules stay stable at site 1, they can also bind to site 2, which may be interpreted as non-specificity of the ligands, however, most of these interactions at transmembrane binding site are not sustainable or are weak. Furthermore, to examine the site 2 for gepant binding, different in silico experiments (i.e., alanine scanning mutagenesis, SiteMap, ligand decomposition binding free energy analyses) are also conducted and the results confirmed the putative binding pocket (site 2) of the gepants at the CGRPRs.
Modulating effects of RAMPs on signaling profiles of the glucagon receptor family
2022, Acta Pharmaceutica Sinica B
Citation Excerpt :
This feature would promote the bias of oxyntomodulin towards β-arrestins or ERK1/2 phosphorylation over cAMP relative to GLP-1. Both the glucagon receptor family members and RAMPs are key players of the metabolic and endocrine systems10. They have an overlap organ distribution including the lung, pancreas, kidney, brain, heart and liver45–50.
Receptor activity-modulating proteins (RAMPs) are accessory molecules that form complexes with specific G protein-coupled receptors (GPCRs) and modulate their functions. It is established that RAMP interacts with the glucagon receptor family of GPCRs but the underlying mechanism is poorly understood. In this study, we used a bioluminescence resonance energy transfer (BRET) approach to comprehensively investigate such interactions. In conjunction with cAMP accumulation, Gα_q activation and β-arrestin1/2 recruitment assays, we not only verified the GPCR–RAMP pairs previously reported, but also identified new patterns of GPCR–RAMP interaction. While RAMP1 was able to modify the three signaling events elicited by both glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), and RAMP2 mainly affected β-arrestin1/2 recruitment by GCGR, GLP-1R and glucagon-like peptide-2 receptor, RAMP3 showed a widespread negative impact on all the family members except for growth hormone-releasing hormone receptor covering the three pathways. Our results suggest that RAMP modulates both G protein dependent and independent signal transduction among the glucagon receptor family members in a receptor-specific manner. Mapping such interactions provides new insights into the role of RAMP in ligand recognition and receptor activation.

View all citing articles on Scopus

²: These authors contributed equally.

View full text

Trends in Pharmacological Sciences

ReviewDawn of a New RAMPage

Highlights

Section snippets

Historical Paradigm of RAMP–GPCR Signaling

RAMP–GPCR Coevolution: Emerging Evidence of a Global RAMP–GPCR Interactome

Expanding the RAMP Repertoire

Physiological and Pathophysiological Roles of RAMPs

Therapeutic Targeting of RAMP–GPCRs

Concluding Remarks and Future Perspectives

Acknowledgments

Glossary

J. Biomol. Screen.

Trends Biochem. Sci.

J. Biol. Chem.

iScience

J. Mol. Biol.

Trends Pharmacol. Sci.

J. Biol. Chem.

Cell

Dev. Cell

Neuropharmacology

Methods Enzymol.

J. Mol. Cell. Cardiol.

J. Biol. Chem.

Regul. Pept.

Auton. Neurosci.

Genet Med

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Gene: X 2

Neuropharmacology

Structure

Regul. Pept.

G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs?

Mol. Pharmacol.

Molecular signatures of G-protein-coupled receptors

Nature

RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor

Nature

Understanding RAMPs through genetically engineered mouse models

Adv. Exp. Med. Biol.

Receptor activity modifying proteins (RAMPs) interact with the VPAC2 receptor and CRF1 receptors and modulate their function

Br. J. Pharmacol.

The role of ECL2 in CGRP receptor activation: a combined modelling and experimental approach

J. R. Soc. Interface

CGRP Receptor Biology: Is There More Than One Receptor?

Handb. Exp. Pharmacol.

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

Br. J. Pharmacol.

Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles

Annu. Rev. Pharmacol. Toxicol.

Receptor-activity-modifying proteins are required for forward trafficking of the calcium-sensing receptor to the plasma membrane

J. Cell Sci.

Role of Receptor Activity Modifying Protein 1 in Function of the Calcium Sensing Receptor in the Human TT Thyroid Carcinoma Cell Line

PLoS One

G-protein-coupled receptor 30 interacts with receptor activity-modifying protein 3 and confers sex-dependent cardioprotection

J. Mol. Endocrinol.

GPCRs globally coevolved with receptor activity-modifying proteins, RAMPs

Proc. Natl. Acad. Sci. U. S. A.

Spatially resolved, highly multiplexed RNA profiling in single cells

Science

Transduction of receptor signals by β-arrestins

Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product

Mol. Pharmacol.

Molecular Basis of Association of Receptor Activity-Modifying Protein 3 with the Family B G Protein-Coupled Secretin Receptor

Biochemistry

Multiplexed analysis of the secretin-like GPCR-RAMP interactome

Sci Adv

RAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis

Proceedings of the National Academy of Sciences

A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development

J. Exp. Med.

CXCR7 functions as a scavenger for CXCL12 and CXCL11

PLoS One

Review
Dawn of a New RAMPage