Adhesion G Protein Coupled Receptor E2
Introduction
Section titled “Introduction”Background
Section titled “Background”ADGRE2 (Adhesion G Protein Coupled Receptor E2), also known as CD97, is a prominent member of the adhesion G protein-coupled receptor (aGPCR) family. This family of receptors is distinguished by a unique architecture, featuring a large N-terminal extracellular domain that often contains motifs for cell-cell or cell-matrix interactions, coupled to a transmembrane region and an intracellular G protein-coupling domain. This structural design enables aGPCRs to act as crucial intermediaries, translating extracellular signals—particularly those related to mechanical forces or cell contacts—into diverse intracellular signaling cascades.
Biological Basis
Section titled “Biological Basis”At a fundamental biological level, ADGRE2 is integral to processes such as cell adhesion, migration, and the intricate regulation of immune cell activation. It is widely expressed across various immune cell types, including monocytes, macrophages, dendritic cells, and both T and B lymphocytes. The extracellular portion of ADGRE2 specifically interacts with ligands like CD55 (decay-accelerating factor), triggering downstream intracellular signaling pathways that typically involve G proteins. These pathways, in turn, modulate critical cellular functions such such as proliferation, differentiation, and survival, particularly within the dynamic environment of the immune system.
Clinical Relevance
Section titled “Clinical Relevance”Dysregulation of ADGRE2 has been linked to the pathology of several human diseases. Given its established role in immune cell function, alterations in ADGRE2activity or expression are implicated in various inflammatory and autoimmune conditions. Furthermore, research has explored its involvement in the progression of different cancers, where it can influence key processes like tumor cell migration, invasion, and angiogenesis. Genetic variations, such as single nucleotide polymorphisms (SNPs), within theADGRE2 gene could potentially alter its function or expression, thereby influencing an individual’s susceptibility to or the progression of these diseases.
Social Importance
Section titled “Social Importance”The ongoing investigation into the function and genetic variability of ADGRE2significantly advances the understanding of immune system regulation and the underlying mechanisms of disease. This research holds substantial social importance, as it can lead to the identification of novel therapeutic targets for a range of immune-mediated disorders, chronic inflammatory conditions, and various forms of cancer. Developing pharmacological agents that can precisely modulateADGRE2 activity offers promising new avenues for treating conditions where the adhesion or migratory capabilities of immune cells are compromised or dysregulated.
Limitations
Section titled “Limitations”Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”Some studies were conducted with moderate-sized cohorts, which inherently limits the power to detect genetic associations, particularly those with smaller effect sizes, potentially leading to false negative findings. [1] This necessitates larger sample sizes to fully capture the genetic architecture of complex traits. [2] A significant challenge noted across studies is the inconsistent replication of findings; for instance, some reports indicate that only about one-third of examined associations were successfully replicated in subsequent analyses. [1] Reasons for such non-replication include the possibility of initial false positive findings, differences in cohort characteristics that may modify gene-phenotype associations, or insufficient statistical power in replication cohorts. [1] Furthermore, non-replication at the SNP level might occur if different studies identify distinct but strongly linked SNPs to an unknown causal variant, or if multiple causal variants exist within the same gene region. [3]
The comprehensiveness of genetic coverage can also be a limitation, as older genotyping arrays, such as 100K SNP chips, may not adequately cover all relevant gene regions, potentially missing true associations. [4] Additionally, occasional deviations from Hardy-Weinberg equilibrium for certain SNPs, such as rs7258015 (19p13.2), even if visual inspection doesn’t reveal artifacts, warrant careful consideration in interpreting association signals. [5] The choice of significance thresholds in genome-wide scans can also be a pragmatic decision based on prior probabilities and study power, rather than a definitive measure, which can influence the interpretation of findings. [6]
Population Heterogeneity and Phenotypic Precision
Section titled “Population Heterogeneity and Phenotypic Precision”The generalizability of findings is a key limitation, as several studies primarily involved cohorts of individuals who are middle-aged to elderly and predominantly of European descent. [1] This demographic specificity means that the observed genetic associations may not be directly applicable or transferable to younger populations or individuals of diverse ethnic and racial backgrounds. [1] While efforts like principal component analysis and genomic control are applied to correct for population stratification within seemingly homogenous groups [5] the inherent genetic and environmental differences across broader populations remain a barrier to universal applicability.
Concerns regarding phenotype variability can also impact the reliability of associations, as demonstrated by the variability of serum soluble intercellular adhesion molecule-1 associated with common polymorphisms. [5] Furthermore, the timing of DNA collection, such as in later examinations of a longitudinal cohort, can introduce survival bias, potentially skewing the representation of the study population. [1] The availability of specific phenotype measures can also vary, leading to smaller effective sample sizes for certain traits and thus reduced power for those analyses. [4]
Unaccounted Factors and Remaining Knowledge Gaps
Section titled “Unaccounted Factors and Remaining Knowledge Gaps”The intricate interplay between genetic predispositions and environmental factors, including lifestyle and other biological covariates, represents a complex area that is not always fully captured. While studies often adjust for covariates, such adjustments might inadvertently mediate or mask the effects of certain loci, especially if those effects are intrinsically linked to the adjusted variables.[2] Additionally, ignoring relatedness among sampled individuals can lead to misleading P values and inflated false-positive rates, underscoring the importance of robust statistical modeling of polygenic effects. [7]
Despite the identification of numerous associations, a significant knowledge gap persists in fully understanding the functional implications of many identified SNPs, particularly those located in regions not clearly related to known genes or phenotypes. [2] These findings often represent hypotheses that require extensive further testing and functional validation in independent cohorts [2]. [1] A fundamental challenge remains in prioritizing and functionally characterizing the multitude of genetic associations uncovered by genome-wide scans, highlighting the ongoing need for deeper mechanistic insights beyond statistical correlations. [1]
Variants
Section titled “Variants”Genetic variations play a crucial role in modulating cell adhesion, immune responses, and metabolic pathways, often with implications for the broader cellular environment that includes adhesion G protein-coupled receptors (aGPCRs) such as ADGRE2. The ADGRE5 gene, also known as CD97, is itself an aGPCR involved in cell-cell adhesion, immune cell migration, and inflammation. Variants rs139113505 , rs12973667 , and rs7508244 , located within or near ADGRE5, may influence its expression or functional activity, thereby affecting the strength of cellular interactions or the dynamics of immune responses. Similarly, LINC01841 is a long intergenic non-coding RNA, and its variants rs7259323 , rs58881629 , and rs11667042 , particularly those in close proximity to ADGRE5, could exert regulatory effects on neighboring genes, potentially including other aGPCRs. Such genetic variations are extensively studied through genome-wide association studies to understand their impact on complex biological traits. [8] These regulatory changes might indirectly impact the activity of ADGRE2, another member of the aGPCR family, which plays significant roles in immune cell function and maintaining tissue homeostasis, underscoring the interconnectedness of adhesion receptors in cellular integrity and immune mediation. [4]
Other receptor-related genes also exhibit variations with potential broader biological impacts. ASGR1 encodes the asialoglycoprotein receptor 1, a C-type lectin predominantly expressed in liver cells, responsible for clearing desialylated glycoproteins from the bloodstream. Variants such as rs186021206 (found in the RPL7AP64 - ASGR1 region) and rs55714927 within ASGR1 could alter the efficiency of this receptor, influencing liver function and potentially systemic inflammatory processes. Likewise, MRC1 (mannose receptor C-type 1, or CD206) encodes another C-type lectin expressed on macrophages and dendritic cells, crucial for pathogen recognition and antigen endocytosis. The variant rs56278466 in MRC1 might affect immune cell recognition or antigen presentation, thereby influencing general immune system activity. Both ASGR1 and MRC1 function as cell surface receptors involved in recognizing specific ligands, a mechanism that shares functional parallels with adhesion GPCRs like ADGRE2 in mediating cell-environment interactions and signal transduction. The identification of such genetic loci through genome-wide approaches helps elucidate their contributions to various physiological and pathophysiological conditions. [9]
Further encompassing broader cellular processes, the region containing ATXN2 and SH2B3 includes the variant rs3184504 , which has been linked to a range of immune and metabolic traits. ATXN2 is involved in RNA processing and stress granule formation, while SH2B3encodes a signaling adaptor protein vital for cytokine signaling and hematopoiesis. The influence of this variant on immune cell development and function could indirectly modulate the cellular contexts in whichADGRE2 operates, affecting cell adhesion and migration during inflammatory responses. ST3GAL4 encodes ST3 beta-galactoside alpha-2,3-sialyltransferase 4, an enzyme critical for synthesizing sialylated glycans on cell surfaces and secreted proteins. The variant rs4055121 could impact the glycosylation patterns of various cell surface receptors, including aGPCRs and their ligands, thereby modulating cell adhesion, recognition, and signaling—functions central to ADGRE2’s role. Lastly, the rs1260326 variant in GCKR(glucokinase regulatory protein) is strongly associated with metabolic traits such as triglyceride levels and glucose homeostasis.[10] While GCKR primarily influences metabolism, metabolic health significantly impacts systemic inflammation and immune cell function, which can, in turn, affect the expression and activity of adhesion molecules like ADGRE2. [11]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs139113505 rs12973667 rs7508244 | ADGRE5 | ADGRE5/ITGB2 protein level ratio in blood ADGRE5/NOTCH1 protein level ratio in blood ADGRE5/PLXNB2 protein level ratio in blood ADGRE5/SEMA7A protein level ratio in blood ADGRE2/ADGRE5 protein level ratio in blood |
| rs186021206 | RPL7AP64 - ASGR1 | ST2 protein measurement alkaline phosphatase measurement low density lipoprotein cholesterol measurement, lipid measurement low density lipoprotein cholesterol measurement low density lipoprotein cholesterol measurement, phospholipid amount |
| rs56278466 | MRC1 | aspartate aminotransferase measurement liver fibrosis measurement ADGRE5/VCAM1 protein level ratio in blood CD200/CLEC4G protein level ratio in blood HYOU1/TGFBR3 protein level ratio in blood |
| rs55714927 | ASGR1 | low density lipoprotein cholesterol measurement total cholesterol measurement serum albumin amount alkaline phosphatase measurement apolipoprotein B measurement |
| rs7259323 | LINC01841 | adhesion G protein-coupled receptor E2 measurement |
| rs58881629 rs11667042 | LINC01841 - ADGRE5 | ADGRE5/VCAM1 protein level ratio in blood adhesion G protein-coupled receptor E2 measurement |
| rs3184504 | ATXN2, SH2B3 | beta-2 microglobulin measurement hemoglobin measurement lung carcinoma, estrogen-receptor negative breast cancer, ovarian endometrioid carcinoma, colorectal cancer, prostate carcinoma, ovarian serous carcinoma, breast carcinoma, ovarian carcinoma, squamous cell lung carcinoma, lung adenocarcinoma platelet crit coronary artery disease |
| rs3829680 | ADGRE2 | adhesion G protein-coupled receptor E2 measurement |
| rs4055121 | ST3GAL4 | transferrin glycosylation measurement immunoglobulin superfamily containing leucine-rich repeat protein 2 measurement level of T-cell-specific surface glycoprotein CD28 in blood CMRF35-like molecule 6 measurement tyrosine-protein kinase receptor TYRO3 measurement |
| rs1260326 | GCKR | urate measurement total blood protein measurement serum albumin amount coronary artery calcification lipid measurement |
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”No information is available in the provided context regarding the classification, definition, or terminology of ‘adhesion g protein coupled receptor e2’.
Cellular Adhesion and Intercellular Communication
Section titled “Cellular Adhesion and Intercellular Communication”Cellular adhesion molecules are critical for mediating interactions between cells and their extracellular environment, influencing processes from tissue integrity to immune responses. Intercellular Adhesion Molecule-1 (ICAM-1) serves as a prominent example, with soluble ICAM-1levels linked to the development of symptomatic peripheral arterial disease and increased risk of diabetes[12]. [13] The genetic regulation of ICAM-1 is evident, as its gene cluster on chromosome 19 contains quantitative trait loci (QTL) that influence circulating ICAM-1 concentrations [14]. [15] Furthermore, inflammatory cytokines are known to transcriptionally regulate the ICAM-1 gene, involving essential roles of NF-kappa B sites [16] highlighting the interplay between inflammation, gene expression, and adhesion.
Beyond direct adhesion molecules, other biomolecules contribute to cellular interaction and recognition. The ABO histo-blood group antigens, for instance, are covalently linked to human plasma alpha2-macroglobulin and von Willebrand factor (vWF) in individuals with corresponding ABO phenotypes, suggesting a role in broader biological recognition and hemostasis. [17] This connection is further underscored by the association of ABO blood group antigens with soluble ICAM-1 levels [5]indicating a complex network of interactions that modulate cellular adhesion and communication, impacting systemic health and disease susceptibility.
Receptor Signaling and Molecular Pathways
Section titled “Receptor Signaling and Molecular Pathways”Cellular functions are largely dictated by intricate receptor-mediated signaling pathways that transduce external stimuli into intracellular responses. A key example is the high affinity IgEreceptor found on mast cells, which, even upon weak stimulation, can induce the production of allergy-promoting lymphokines.[18] This receptor also plays a role in stimulating the synthesis and secretion of monocyte chemotactic protein-1 (MCP-1), a potent chemokine involved in inflammatory responses. [19] Such receptor activation illustrates how specific biomolecules initiate cascades that profoundly affect cellular behavior and immune modulation.
The precise regulation of cell motility and other cellular functions often involves small GTPases, which act as molecular switches. For example, the neuronal chemorepellent Slit2has been shown to inhibit vascular smooth muscle cell migration by suppressing the activation ofRac1, a small GTPase. [20] This mechanism highlights the importance of GTPase signaling in controlling cellular dynamics relevant to vascular health and development. Moreover, broader signaling networks, such as the Mitogen-activated protein kinase (MAPK) pathway, are integral to various cellular processes, with their activation being influenced by factors like age and acute exercise in human skeletal muscle[21] demonstrating the widespread impact of these molecular pathways.
Genetic and Regulatory Control of Cellular Function
Section titled “Genetic and Regulatory Control of Cellular Function”Genetic mechanisms underpin the diversity and regulation of cellular functions, with variations in the genome influencing gene expression patterns and protein activity. Genome-wide association studies (GWAS) have identified numerous genetic variants, or single nucleotide polymorphisms (SNPs), that are associated with a wide range of traits, including global gene expression levels [8], [22]and protein quantitative trait loci (pQTLs). [23] For instance, SNPs within the TF(transferrin) gene and theHFEgene significantly explain genetic variation in serum-transferrin levels[24] and some of these SNPs are also linked to the mRNA expression levels of the SRPRB gene (signal recognition particle receptor, B subunit). [24]
Beyond direct transcriptional regulation, post-transcriptional mechanisms like alternative splicing introduce further complexity to gene expression. Common variants in the HMGCR gene, associated with LDL-cholesterol levels, have been observed to affect the alternative splicing of exon 13. [25] This highlights how genetic variation can modulate protein isoform diversity, impacting cellular functions. Transcription factors, such as MEF2C (Myocyte Enhancer Factor 2C), are crucial in developmental processes, controlling cardiac morphogenesis and myogenesis [26] dysregulation, such as overexpression of MEF2C, can lead to severe conditions like dilated cardiomyopathy[27]demonstrating the critical role of these regulatory proteins in tissue development and disease.
Pathophysiological Implications and Systemic Effects
Section titled “Pathophysiological Implications and Systemic Effects”Disruptions in molecular and cellular pathways can lead to a spectrum of pathophysiological processes affecting various tissues and organs, often with systemic consequences. In the cardiovascular system, cardiac hypertrophy, a maladaptive response to stress, is characterized by parallel gene expression patterns ofIL-6 and BNP and can be complicated by diastolic dysfunction. [28] Furthermore, specific genetic mutations, such as those in the cardiac Ryanodine receptor gene (hRyR2), underlie channelopathies that manifest as serious arrhythmias like catecholaminergic polymorphic ventricular tachycardia [29], [30]illustrating how defects in key ion channels can severely impair heart function.
Vascular health is significantly influenced by cellular interactions and inflammatory mediators. Subclinical atherosclerosis, a precursor to cardiovascular disease, is a focus of genome-wide association studies investigating major arterial territories.[4] Molecules like monocyte chemoattractant protein-1 (MCP-1 or CCL2) are implicated in these processes, with polymorphisms in CCL2 associated with serum MCP-1 concentrations, and MCP-1itself linked to carotid atherosclerosis[31]. [1]Beyond cardiovascular disease, genetic variations also impact metabolic homeostasis, as demonstrated bySLC2A9influencing serum urate concentration and gout[32] and genetic loci affecting plasma levels of liver enzymes like AKP2 [33] underscoring the broad systemic impact of genetic and cellular dysregulation.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Cellular Signaling and Intracellular Transduction
Section titled “Cellular Signaling and Intracellular Transduction”G protein-coupled receptors often initiate complex intracellular signaling cascades that translate extracellular stimuli into specific cellular responses. For instance, the activation of Rac1, a small GTPase, is a key event in cell migration and cytoskeletal rearrangement, with its activity notably inhibited by the neuronal chemorepellent Slit2, demonstrating a mechanism for regulating cellular motility. [20]Concurrently, the Mitogen-Activated Protein Kinase (MAPK) pathway represents a fundamental signaling cascade, activated by diverse stimuli and influencing cellular processes such as responses to age and acute exercise in human skeletal muscle.[21] Furthermore, the regulation of ion channel activity, such as cAMP-dependent chloride transport mediated by the CFTR channel, highlights the critical role of second messengers, which are frequently modulated by G protein-coupled receptor activation, in maintaining cellular fluid balance and function. [34] These interconnected cascades collectively process external cues, leading to specific intracellular responses and often impacting the activity of downstream transcription factors.
Transcription factor regulation is a pivotal mechanism for controlling gene expression in response to cellular signals. The ICAM-1 gene, which is vital for intercellular adhesion, undergoes transcriptional regulation by inflammatory cytokines via a specific variant NF-kappa B site and p65 homodimers. [16] Similarly, the transcription factor MEF2Cis essential for governing cardiac morphogenesis and myogenesis, where its dysregulation can result in serious cardiac conditions such as dilated cardiomyopathy.[27] Another example is HNF-1, which synergistically trans-activates the human C-reactive protein promoter, illustrating a key regulatory step in the acute phase response. [35] These intricate regulatory mechanisms ensure precise gene expression patterns, enabling cells to adapt and respond appropriately to various physiological and pathological stimuli.
Metabolic Regulation and Homeostasis
Section titled “Metabolic Regulation and Homeostasis”Metabolic pathways are meticulously controlled to ensure cellular and systemic homeostasis. The facilitative glucose transporterSLC2A9 (GLUT9) is a crucial component of urate transport, significantly influencing serum urate concentration and excretion, which directly impacts the pathophysiology of gout.[36]The activity of this transporter is vital for maintaining uric acid balance, a key metabolite, and genetic variants withinSLC2A9are associated with variations in uric acid levels.[36]Beyond urate metabolism, the broader scope of energy metabolism involves components like thePRKAG2 gene, which encodes a gamma2 subunit of 5’-AMP-activated protein kinase, a central sensor and regulator of cellular energy status. [37]
Lipid and glucose metabolism are also subject to sophisticated regulatory mechanisms. Membrane lipid biosynthesis is a fundamental biological process[38] and genetic variants within the FADS1/FADS2 gene cluster are linked to the fatty acid composition in phospholipids, highlighting the genetic influences on individual lipid profiles. [39]In glucose metabolism, genes such asGCKR and HK1are associated with fasting glucose levels and glycated hemoglobin, respectively, withGCKR polymorphisms specifically linked to elevated fasting serum triacylglycerol, reduced insulinemia, and a decreased risk of type 2 diabetes. [5]The functional analysis of human glucokinase gene mutations reveals essential regulatory mechanisms of its activity, which are critical for glucose phosphorylation and maintaining overall glucose homeostasis.[40] Dysregulation in these interconnected pathways is a significant contributor to various metabolic disorders.
Molecular Control of Gene and Protein Function
Section titled “Molecular Control of Gene and Protein Function”The regulation of gene expression and protein function involves multiple layers of molecular control. Genetic variants that influence protein quantitative trait loci (pQTLs) can affect protein levels, suggesting a critical regulatory dimension beyond simple transcriptional control. [23] For instance, the regulation of the ICAM-1 gene by inflammatory cytokines through NF-kappa B involves specific DNA-protein interactions that dictate the cellular inflammatory response. [16] This precise transcriptional control ensures that gene products are produced appropriately in response to external environmental cues or internal physiological signals.
Post-translational modifications and allosteric control serve to fine-tune protein activity and cellular responses. While specific examples for a particular receptor may not be extensively detailed, the functional analysis of human glucokinase gene mutations highlights intrinsic regulatory mechanisms governing enzyme activity, which can involve allosteric modulation or various post-translational modifications.[40]Similarly, the activity of enzymes such as glycosylphosphatidylinositol-specific phospholipase D is subject to regulation, impacting critical lipid metabolism pathways and potentially contributing to conditions like nonalcoholic fatty liver disease.[41] These molecular control mechanisms are indispensable for enabling dynamic cellular responses and maintaining overall physiological equilibrium.
Systems-Level Pathway Integration and Disease Relevance
Section titled “Systems-Level Pathway Integration and Disease Relevance”Biological pathways rarely operate in isolation, instead exhibiting extensive crosstalk and intricate network interactions that integrate various cellular functions. A notable example is how angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells, providing a clear mechanism by which it antagonizes cGMP signaling, illustrating a critical regulatory interplay in cardiovascular function.[42] Furthermore, the parallel gene expressions of IL-6 and BNPduring cardiac hypertrophy complicated with diastolic dysfunction suggest a coordinated inflammatory and structural response in pathological cardiac remodeling.[28] The association of metabolic syndrome pathways, including those involving LEPR, HNF1A, IL6R, and GCKR, with plasma C-reactive protein levels further demonstrates how diverse metabolic and inflammatory pathways are interconnected at a systemic level.[43]
Dysregulation within these highly integrated networks is a fundamental cause of numerous disease states. Genetic variants influencing urate transport, specifically in genes likeSLC2A9 and GLUT9, are directly linked to elevated serum uric acid levels and the pathogenesis of gout.[44] Similarly, common genetic variants in the FTOgene are strongly associated with body mass index and predispose individuals to childhood and adult obesity, highlighting a clear genetic basis for metabolic disorders.[45]The identification of such genetic loci and their associated mechanisms provides crucial insights for developing therapeutic targets, where interventions could aim to modulate specific pathway components or bolster compensatory mechanisms to restore physiological balance and mitigate disease progression. For instance, understanding the regulatory mechanisms of glucokinase activity offers insights into potential therapeutic strategies for type 2 diabetes[40] and the role of ICAM-1 in type 1 diabetes points to targets for immune modulation. [46]
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