Department of Biochemistry and Molecular Biology
University of Chicago
929 E. 57th St.
Chicago, IL 60637
The interplay of extracellular adhesion and intracellular signaling is essential for the development of all organs such as the brain, and is a key phenomenon that is disrupted in many human diseases. Adhesion GPCRs are cell-surface molecules that are believed to mediate intercellular communication via cell-cell and cell-matrix interactions. Genetic studies suggest critical roles for Adhesion GPCRs in development, immunity and especially in neurobiology (such as brain development, synapse maturation/elimination, myelination of neurons, central nervous system angiogenesis and neural tube development); and link them to numerous diseases including neurodevelopmental disorders, deafness, male infertility, schizophrenia, and immune disorders.
We are interested in understanding the mechanisms by which Adhesion GPCRs function in the brain by employing functional, structural, and protein engineering approaches to address major questions in the Adhesion GPCR field. We aim to understand the stepwise mechanical details of Adhesion GPCR activation that is believed to start with adhesion of a ligand to the extracellular region of the Adhesion GPCR, continue with transduction of the signal from the extracellular region to the transmembrane domain via the recently discovered GAIN domain, and end with the activation of the transmembrane domain by the tethered agonist peptide. We believe our structure/function relationship studies will elucidate the mechanistic details about the components that regulate Adhesion GPCR activity and reveal ways of manipulating their function.
Research LaboratoriesCenter of Surgery
University of Leipzig
In 1994, we first described human CD97/ADGRE5, a member of the E (formerly EGF-TM7) subfamily of Adhesion GPCRs. During the next years we showed that, in contrast to the other subfamily E members, CD97 is broadly distributed and not restricted to the hematopoietic system. Especially malignant cells of epithelial and mesenchymal origin highly express CD97, whereas their corresponding normal counterparts often lack this receptor. The main focus of our work is the function of CD97 outside the immune system. Using transgenic mice, selectively expressing CD97 in enterocytes, we identified a role of CD97 in the strengthing of lateral cell contacts. We further showed that during colorectal carcinogenesis, CD97 appears in the cytoplasm.
Our current studies are related to the intracellular signaling of CD97. We defined several intracellular interaction partners of CD97 and are just verifying the functional relevance of their binding to CD97.
Department of Pharmacology
Emory University School of Medicine
Rollins Research Center, Rm 5113
1510 Clifton Road
Atlanta, GA 30322
We are interested in studying the activation and regulation of Adhesion GPCRs, as well as the physiological roles played by these receptors in vivo. In particular, we have an interest in elucidating signaling by Adhesion GPCRs via both G protein-dependent and G protein-independent pathways and understanding how this signaling is controlled by endocytic proteins, such as arrestins and endophilins. Our in vivo studies are focused mainly on the BAI (ADGRB) sub-family and the function of these receptors as regulators of synaptic function. We are also keenly interested in studying disease-associated mutations to human receptors that perturb receptor function.
Department of Experimental Immunology
Academic University Medical Centers
University of Amsterdam
My interest in Adhesion GPCRs started in the mid-90th with the expression cloning of CD97 and the identification of CD55 as its interacting partner. Since then, I have extensively studied the evolution, expression, structure, specificity, and functions of Adhesion GPCRs in immune cells. This work has focussed on the subfamily E members CD97 and EMR1 to 4, and more recently, on the subfamily G cluster GPR56/GPR97/GPR114. Using antibody application and gene targeting, we demonstrated roles of CD97 in granulocyte homeostasis and autoimmune pathogenesis. Moreover, we formally proved the interaction of CD97 with CD55 in vivo and showed that CD97 expression levels on circulating blood cells are regulated upon contact with CD55, possibly to restrict CD97-CD55-mediated cell adhesion to tissue sites. More recently, we reported the specific expression of GPR56 by cytotoxic lymphocytes and microglia and described a role of GPR56 in regulating immediate effector functions of NK cells.
Division of General Biochemistry
Rudolf-Schönheimer-Institute of Biochemistry
University of Leipzig
My group is much interested in the physiological and molecular aspects of Adhesion GPCR signalling. We try to unravel, which stimuli Adhesion GPCR sense, how they are activated and which role proteolytic processing of Adhesion GPCR plays in this process. We primarily use Drosophila melanogaster as a genetic model to investigate these questions under in vivo conditions, but we also employ biochemistry, structural biology, biophysics and bioinformatics to dissect and characterise the physiological and molecular logic of Adhesion GPCR signals.
Previous experimental results have connected latrophilin, an evolutionarily old member of the Adhesion GPCR class, to synaptic function. In contrast, our recent studies on latrophilins demonstrated that latrophilin signalling is important for tissue polarity implicating latrophilin function in concerting developmental activities of large cell populations. We thus currently focus our investigations on the role of Adhesion GPCR in the nervous system, but we are also interested in their functions in other organs such as heart and kidney.
Division of General Biochemistry
Rudolf-Schönheimer-Institute of Biochemistry
University of Leipzig
My group aims to unravel the function of aGPCRs on a molecular as well as on a physiological level. We have solved the signal transduction of several aGPCRs and described a tethered agonist activation mechanism, which allows now for in vitro and in vivo manipulation of this orphan receptor group through derived synthetic peptides. We could show that several aGPCRs can be activated through mechanical stimuli and/ or the interaction with the surrounding extracellular matrix components. We want to identify the G protein-dependent and -independent signaling cascades of aGPCRs and search for ways to specifically activate certain pathways at a time. We further employ receptor-deficient animal models to study the impact of aGPCR-deficiency on metabolism, cardiac and bone function.
Department of Microbiology and Immunology
Chang Gung University
259 Wen-Hwa 1st Road, Kwei-Shan
(P) +886 3 2118800-ext3321
– The role of EMR2 receptor in the cellular functions of macrophages
– The role of CD97 receptor in tumorigenesis
– Functional characterization of GPS auto-proteolysis in Adhesion GPCRs
– The role of GPR56 in NK cell function
– The role of GPR56 receptor in tumorigenesis
– Functional characterization of GPR56–ligand interaction
Oregon Health & Science University, L474
3181 SW Sam Jackson Park Road
Portland, OR 97239
We are interested in the function of Adhesion GPCRs in glial cell development and myelination, with a specific focus on myelinating glia. Myelin is the insulating membrane that surrounds neuronal projections called axons. Myelin is generated by specialized glial cells called Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system. The importance of myelin is underscored in diseases in which it is disrupted, including numerous peripheral neuropathies and multiple sclerosis.
We became interested in the biology of Adhesion GPCRs through our discovery that GPR126 is essential for Schwann cell myelination in the peripheral nervous system. Using zebrafish and mouse models, and in collaboration with other members of the Adhesion GPCR Consortium, we are currently working to define domain-specific and cell type-specific functions of GPR126 in the peripheral nervous system as well as activating ligands and downstream signaling events. Excitingly, beyond GPR126, there are several Adhesion-GPCRs expressed in myelinating glia in both the central and peripheral nervous systems. Another major focus of the Monk lab, therefore, is to define the function of these Adhesion GPCRs in glial cell development, myelination, myelin maintenance, and regeneration.
Newborn Brain Research Institute
University of California, San Francisco
35 Medical Center Way, RMB, PodD, 1036
San Francisco, CA 94143
We are interested in the role of adhesion GPCRs in brain development and malformation. Genetic studies have identified mutations in a specific adhesion GPCR, GPR56, which is the underlying cause of a severe human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Our subsequent studies revealed that GPR56 interacts with its ligand, collagen III, in the developing brain to regulate the integrity of the pial basement membrane and the proper positioning of the migrating neurons.
In parallel, we are examining how GPR56 signaling regulates myelination. Brain MRIs of patients with BFPP reveal associated myelination defects in the region of periventricular white matter. Oligodendrocytes are largely responsible for the development of myelin in those areas. It is possible that GPR56 signaling affects the interaction of oligodendrocytes and the axons, thus regulating myelination in the central nervous system.
We are also investigating the functional domains of the GPR56 molecule, the ligand(s) that activate GPR56, and the signal transduction events that are triggered by GPR56 activation. Ultimately, we hope that our work will delineate novel signaling pathways that control the development of the mammalian brain and shed light on the intrinsic causes of brain malformations.
Department of Neurosurgery
NYU School of Medicine
530 First Avenue – Skirball 8R-303
New York, NY 10016
Dimitris Placantonakis is a neurosurgeon-scientist at NYU Grossman School of Medicine. His laboratory investigates the role of Adhesion GPCRs in glioblastoma, an aggressive brain malignancy. Areas of interest include activation mechanisms, extracellular ligands and intracellular interactors, signaling mechanisms and oncologic phenotypes. Besides the basic mechanistic studies, the laboratory is also interested in the clinical translation of Adhesion GPCRs as therapeutic targets in oncology.
Institute for Cell Biology
Heinrich Heine University
We are interested in understanding how Adhesion GPCR signals are translated into physiological functions in different biological contexts. In order to delineate the molecular mechanisms that underlie Adhesion GPCR activation and activity, we use a broad range of cell biological, biochemical, and pharmacological methodologies. We further aim to link these molecular mechanisms to physiological functions in vivo by employing different model organisms as well as cell culture models.
Using the evolutionary conserved Adhesion GPCRs Latrophilins as prototypic members of the receptor class, our previous analyses have shown that the extraordinarily large N terminus of the receptors is a linchpin for different receptor functions. Thereby, an Adhesion GPCR does not only transduce classical G protein signals into cells, but also acts completely independently of its 7TM and C terminus, for instance to mediate signals on opposing cells. One main focus of our current research is to understand how and by which mechanisms different Adhesion GPCRs distinguish and integrate their different modes of function.
Laboratory for Molecular Pharmacology
Department of Neuroscience and Pharmacology
Faculty of Health Sciences
University of Copenhagen
Institute for Biochemistry
University of Leipzig
In the Scholz lab, we aim to understand physiological rationale of the vivid alternative splicing activities of Adhesion GPCR mRNAs and investigate if and how Adhesion GPCRs ‘talk’ to other cell surface molecules to enable neuronal mechanophysiology. Building on the knowledge of Adhesion GPCR function in physiological settings, we are also aiming to understand cellular processes that go wrong when Adhesion GPCRs fail to perform and especially if that entails faulty mechanical signature of cells and tissues contributing to mechanopathologies.
Departments of Neuroscience and
Biochemistry and Molecular Biology
Baylor College of Medicine
One Baylor Plaza
Houston, TX 77030
We are interested in the function of Adhesion GPCRs in neuronal development and plasticity. The organization of neurons into complex brain circuits involves highly regulated steps including axon and dendritic growth and the formation and refinement of synapses, which mediate communication between neurons. Synapses continue to remodel throughout life, which is important for processes like learning and memory. Failure to properly form or maintain these synaptic connections and neural circuits underlies a wide array of neuropsychiatric disorders. We previously identified the Adhesion GPCR BAI1 (ADGRB1) as a critical regulator of dendritic arbor and excitatory synapse development and showed that BAI1 coordinates these processes through the differential activation of multiple Rho GTPase signaling pathways. We are continuing to investigate the specific roles BAI Adhesion GPCRs play in neuronal development, synaptic plasticity and behavior and to elucidate the mechanisms by which BAIs mediate their effects on these processes. Our long-term goal is to provide mechanistic insight into BAI1 Adhesion GPCR biology, which has potential implications for human health as BAIs are linked to autism spectrum disorder, schizophrenia, bipolar disorder, cognitive performance, and brain cancers.
Department of Physiology
School of Medicine
Johns Hopkins University
205 Wood Basic Science Building
725 North Wolfe Street
Baltimore, MD 21205
My introduction to Adhesion GPCRs came during my postdoctoral training in Jennifer Pluznick’s lab at Johns Hopkins University, where her group investigates understudied GPCRs in the kidney. My research in her lab is focused on ADGRF5/GPR116, and specifically identifying its significance in renal physiology. We discovered that Gpr116 is localized to acid secreting A-type intercalated cells of the collecting ducts and is a critical regulator of vacuolar-type H+-ATPase (V-ATPase) surface expression. Genetic deletion of GPR116 in mice causes a physiologically inappropriate distribution of proton pumps on the luminal membrane of A-type cells, leading to urine acidification and a subtle metabolic alkalosis. Furthermore, we revealed that in situ GPR116 activation with a synthetic agonist peptide inhibits proton flux in A-type cells, demonstrating that GPR116 is a critical negative regulator of V-ATPase proton pumps. My future research will continue our investigation of GPR116 and expand into other aGPCRs to determine their roles in renal physiology. I am also interested in transcriptional regulators of Adhseion GPCRs as well as identifying the endogenous activators of these receptors in the kidney.