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.
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.
Our 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, we 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 described a role of the receptor in regulating immediate effector functions.
We suppose that Adhesion GPCRs function fundamentally different from canonical GPCRs. Key to this hypothesis is the observation that known interacting partners facilitate adhesive contacts but do not necessarily initiate receptor signaling. Our current research focuses on the functioning of Adhesion GPCRs in relation to (1) immune responses and (2) constitutive versus agonist-dependent signaling.
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.
– 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
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 PCR 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.
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.
Our team at Uppsala University has a broad interest in membrane bound proteins with large focus on GPCRs and solute carriers. We established the GRAFSs classification for the GPCRs in 2003 (Fredriksson et al., 2003) where we showed that the Adhesion GPCRs are a unique family among GPCRs. We worked with the HUGO nomenclature committee to name several of the human Adhesion GPCRs. Recently we have mined distant genomes and showed that the Adhesion GPCRs are among the most ancient evolutionary branches of the GPCRs. These receptors have expanded in numbers in several species and they have rich numbers of N-terminal domains beyond what seen in mammals. We have proposed that the Secretin family is, in evolutionary terms, a child of the Adhesion family. Further studies relate to the functions and evolution of this family as well as opportunities within drug discovery.
G protein-coupled receptors (GPCRs) from different classes, their structure-function relationships, their signal transduction and physiological functions, and their relevance in inherited diseases are central tropics of the Schöneberg Lab. Specifically, orphan GPCRs of the nucleotide receptor family and the Adhesion class are in the current focus. Investigations include classical receptor pharmacology and animal models, but also evolutionary approaches.
Adhesion GPCRs, as entire class, are considered as orphan GPCRs. Their unique structure suggests specific functions and signal transduction properties. Therefore, unveiling the signal transduction mechanisms of Adhesion GPCRs is of great interest. We identified G protein-coupling for several Adhesion GPCR members and currently test activation scenarios. Several animal models (mouse, C. elegans) addressing in vivo functions of Adhesion GPCR are established in the institute.