GO:0033633 negative regulation of cell-cell adhesion mediated by integrin: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0033633 describes any process that stops, prevents, or reduces the frequency, rate, or extent of cell-cell adhesion mediated by integrin [1, 2].
• Integrin-mediated cell-cell adhesion is negatively regulated by soluble factors, matrix-derived peptides, and intracellular signaling pathways [1, 4, 8].
• Key proteins include integrin subunits (ITGA5, ITGB1), PECAM-1, SGK1, Rho/CRIK, and FHL1, which modulate adhesion strength and dynamics [1, 2, 6].
• Dysregulation of this process contributes to cancer progression, vascular permeability, and inflammatory diseases [3, 7].
• Experimental models include knockout, point-mutation, and overexpression cell lines to dissect gene function in adhesion [4, 6].
• CRISPR screening and bioinformatics can identify novel regulators of integrin-mediated cell-cell adhesion [5, 8].
Description
Cell-cell adhesion mediated by integrins is a fundamental process that controls tissue architecture, cell migration, and signaling. Integrins are heterodimeric transmembrane receptors that bind to extracellular matrix ligands and counter-receptors on opposing cells, thereby physically linking cells and transmitting mechanical and biochemical signals [1, 2]. The negative regulation of this adhesion, captured by GO:0033633, encompasses molecular events that weaken or terminate integrin-dependent cell-cell contacts, allowing dynamic remodeling of tissues during development, immune responses, and wound healing [1, 4]. Understanding how this process is controlled is critical because excessive or insufficient adhesion contributes to pathologies such as cancer metastasis, vascular leak, and chronic inflammation [3, 7]. This article integrates authoritative GO annotation with published literature to provide a research-grade overview of the mechanisms, key genes, and experimental approaches for studying negative regulation of integrin-mediated cell-cell adhesion.
negative regulation of cell-cell adhesion mediated by integrin At A Glance
| GO ID | GO:0033633 |
|---|---|
| GO term | negative regulation of cell-cell adhesion mediated by integrin |
| Ontology | biological_process |
| Synonym | negative regulation of cell-cell adhesion mediated by integrin complex |
| Major function | Downregulation or disruption of integrin-dependent cell-cell adhesion |
| Related processes | Cell adhesion, integrin signaling, cytoskeletal reorganization |
| Cellular context | Plasma membrane, focal adhesions, cell-cell junctions |
| Representative regulators | SGK1, PECAM-1, Rho/CRIK, FHL1, ceramides |
| Disease relevance | Cancer, vascular permeability, inflammation |
What Is GO:0033633?
GO:0033633 is a biological process term defined as any process that stops, prevents, or reduces the frequency, rate, or extent of cell-cell adhesion mediated by integrin. In other words, it covers molecular mechanisms that downregulate or disrupt the physical connection between cells that is directly mediated by integrin receptors, as opposed to merely affecting cell-matrix adhesion or general adhesion molecules [1, 2].
Why Is negative regulation of cell-cell adhesion mediated by integrin Important in Cell Biology?
Negative regulation of integrin-mediated cell-cell adhesion is essential for normal physiology, enabling cells to detach and migrate during embryonic development, immune surveillance, and tissue repair [1, 2]. When this regulation fails, cells may remain abnormally adherent or become hyper-adhesive, contributing to cancer cell invasion, metastasis, and resistance to anoikis. Conversely, excessive negative regulation can lead to loss of tissue integrity, as seen in vascular endothelial barrier dysfunction and increased permeability. Thus, understanding the molecular players and signaling pathways that negatively regulate integrin-mediated adhesion is crucial for developing therapeutic strategies targeting adhesion-dependent diseases.
• Controls cell migration and tissue remodeling during development and wound healing.
• Regulates immune cell extravasation and inflammatory responses.
• Modulates vascular endothelial permeability and barrier function.
• Influences cancer cell invasion, metastasis, and survival.
• Involved in keratinocyte differentiation and skin homeostasis.
• Mediated by soluble factors such as ceramides and matrix-derived peptides [4, 8].
• Provides targets for anti-adhesion therapies in oncology and inflammation.
• Requires precise spatiotemporal control to avoid pathological adhesion or detachment [1, 3].
What Happens During negative regulation of cell-cell adhesion mediated by integrin?
Initiation by extracellular or intracellular signals
In simple terms: A signal tells the cell to loosen its grip on its neighbor.
Negative regulation of integrin-mediated cell-cell adhesion can be triggered by extracellular cues such as growth factors, cytokines, or matrix-derived peptides, as well as intracellular signals including kinase cascades and small GTPases [1, 4]. For example, hepatocyte growth factor (HGF) activates SGK1 in a PI-3K-dependent manner, which correlates with reduced integrin-mediated adhesion in MDCK cells. Similarly, the disintegrin elegantin contains a linker region that inhibits integrin alpha5beta1-dependent cell adhesion on fibronectin, demonstrating negative regulation by a soluble peptide.
Modulation of integrin affinity and clustering
In simple terms: The integrin receptors change shape or group together differently, weakening the connection.
Integrin-mediated adhesion strength depends on the conformational state and clustering of integrin heterodimers. Negative regulators can induce conformational changes that lower ligand-binding affinity or promote dispersal of integrin clusters at cell-cell contacts [2, 5]. Isoaspartate-dependent molecular switches in integrin-ligand recognition have been shown to alter binding specificity and affinity, providing a mechanism for negative regulation. PECAM-1 (CD31) can also modulate integrin function through its cytoplasmic domain and signaling, affecting cell-cell adhesion dynamics.
Cytoskeletal reorganization and junction disassembly
In simple terms: The cell's internal skeleton pulls apart the adhesion site.
Downstream of signaling, the actin cytoskeleton is reorganized to reduce integrin-mediated cell-cell contacts. Rho/CRIK signaling negatively controls keratinocyte differentiation and is coupled with upregulation of FHL1, which can influence cytoskeletal dynamics and adhesion. Ceramides act as novel regulators of U937 cell-cell adhesion mediated by CD29 (integrin beta1), CD98, and CD147, likely through effects on cytoskeletal rearrangement and membrane organization. These events lead to disassembly of integrin-dependent junctions and increased cell motility.
Feedback and cross-talk with other adhesion systems
In simple terms: Other adhesion molecules and signals fine-tune the process.
Negative regulation of integrin-mediated adhesion is integrated with other adhesion and signaling pathways. PECAM-1, a member of the immunoglobulin superfamily, can homophilically interact and modulate integrin-dependent adhesion through inside-out signaling. Endothelial permeability mechanisms involve coordinated changes in integrin adhesion and junctional proteins, highlighting cross-talk between different adhesion systems. Such feedback ensures that cell-cell adhesion is dynamically tuned to environmental cues.
Key Genes Involved in GO:0033633 negative regulation of cell-cell adhesion mediated by integrin
The following genes and proteins have been experimentally linked to the negative regulation of integrin-mediated cell-cell adhesion, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ITGA5 | Integrin alpha-5 subunit; forms alpha5beta1 heterodimer | Target of negative regulation by elegantin linker peptide |
| ITGB1 | Integrin beta-1 subunit; partners with alpha subunits | Mediates cell-cell adhesion regulated by ceramides and other factors |
| SGK1 | Serum/glucocorticoid-regulated kinase 1 | Activated by HGF and Rac1; linked to reduced integrin adhesion |
| PECAM1 | Platelet endothelial cell adhesion molecule-1 (CD31) | Modulates integrin-dependent adhesion and endothelial permeability |
| RHOA | Rho GTPase | Regulates cytoskeletal dynamics and adhesion disassembly |
| CRIK | Citron Rho-interacting kinase | Part of Rho/CRIK signaling that negatively controls keratinocyte differentiation |
| FHL1 | Four and a half LIM domains 1 (KyoT1/2) | Upregulated by Rho/CRIK; influences adhesion and differentiation |
| CD98 | 4F2 cell-surface antigen heavy chain | Involved in U937 cell-cell adhesion regulated by ceramides |
| CD147 | Basigin/EMMPRIN | Participates in ceramide-regulated cell-cell adhesion |
| CD29 | Integrin beta-1 (same as ITGB1) | Mediates U937 cell-cell adhesion modulated by ceramides |
| FN1 | Fibronectin 1 | Extracellular matrix ligand for alpha5beta1; synergy site affected by elegantin |
| RAC1 | Rac1 GTPase | Activates SGK1 in integrin-mediated adhesion pathways |
| HGF | Hepatocyte growth factor | Stimulates SGK1 and modulates integrin adhesion |
| PIK3 | Phosphatidylinositol 3-kinase | Required for HGF-induced SGK1 activation |
| ITGAV | Integrin alpha-V subunit | Potential partner in integrin heterodimers affecting adhesion |
| ITGB3 | Integrin beta-3 subunit | Forms alphaVbeta3; subject to isoaspartate switches |
| CDH5 | VE-cadherin | Endothelial junctional protein cross-talk with integrins |
| ICAM1 | Intercellular adhesion molecule 1 | Inflammatory adhesion molecule interacting with integrins |
How Is negative regulation of cell-cell adhesion mediated by integrin Regulated?
The negative regulation of integrin-mediated cell-cell adhesion is itself controlled by multiple signaling pathways. HGF activates SGK1 through PI-3K-dependent and independent pathways, leading to reduced adhesion. Rho/CRIK signaling negatively controls keratinocyte differentiation and is coupled with FHL1 upregulation, which may feed back on adhesion. Ceramides act as novel regulators of U937 cell-cell adhesion mediated by CD29, CD98, and CD147, suggesting lipid signaling in this process. Additionally, PECAM-1 can modulate integrin function through its cytoplasmic domain, providing a regulatory node. These pathways ensure that adhesion is dynamically tuned to physiological needs.
negative regulation of cell-cell adhesion mediated by integrin and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ITGB1 | Cancer metastasis, fibrosis | Knockout in cancer cell lines; adhesion assays |
| PECAM1 | Vascular inflammation, permeability | Endothelial cell knockout; permeability assays |
| SGK1 | Hypertension, cancer | Overexpression in MDCK cells; adhesion assays |
| FHL1 | Keratinocyte differentiation disorders | Knockdown in keratinocytes; differentiation markers |
| ITGA5 | Oral cancer, angiogenesis | Point mutation in integrin alpha5; binding assays [4, 7] |
Cancer progression and metastasis
Loss of negative regulation of integrin-mediated cell-cell adhesion can lead to increased adhesion and survival signals, promoting cancer cell invasion and metastasis. Integrins are widely implicated in oral cancer and other malignancies, where altered adhesion contributes to tumor progression. The disintegrin elegantin inhibits alpha5beta1-dependent adhesion, suggesting that restoring negative regulation could be therapeutic.
Vascular permeability and inflammation
Endothelial barrier function depends on tight regulation of integrin-mediated adhesion. Increased endothelial permeability, as seen in inflammation, involves mechanisms that reduce cell-cell adhesion. PECAM-1 modulates integrin-dependent adhesion and endothelial permeability, making it a key player in inflammatory diseases.
Skin differentiation disorders
Negative control of keratinocyte differentiation by Rho/CRIK signaling coupled with FHL1 expression highlights the importance of adhesion regulation in skin homeostasis. Dysregulation may contribute to hyperproliferative skin diseases.
From negative regulation of cell-cell adhesion mediated by integrin-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X negatively regulate integrin-mediated cell-cell adhesion? | Knockout cell line (e.g., CRISPR-Cas9) followed by adhesion assays [1, 8] |
| Does a specific point mutation in integrin affect negative regulation? | Point-mutation knock-in cell line; ligand-binding assays [4, 5] |
| Can a candidate gene rescue adhesion defects? | Knock-in of wild-type or mutant gene; rescue experiments |
| Where does the protein localize during adhesion disassembly? | Tagged knock-in (e.g., GFP) and live-cell imaging |
| Does overexpression of a regulator reduce adhesion? | Overexpression cell line; functional adhesion assays [1, 6] |
| What genes are required for negative regulation? | CRISPR library screening; bioinformatics analysis [5, 8] |
How to Study the negative regulation of cell-cell adhesion mediated by integrin Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Cell aggregation assay | Frequency and extent of cell-cell adhesion | Quantify negative regulation after gene knockout |
| Flow cytometry-based adhesion assay | Integrin-dependent binding to ligands or cells | Screen for regulators using CRISPR libraries |
| Live-cell imaging | Dynamics of adhesion disassembly | Visualize real-time effects of regulators |
| FRET biosensor | Integrin conformational changes | Detect affinity modulation by negative regulators |
| Phosphoproteomics | Phosphorylation events in adhesion complexes | Identify signaling pathways [1, 6] |
| CRISPR knockout screening | Genes required for negative regulation | Discover novel regulators |
| RNA-seq | Transcriptional changes during adhesion regulation | Identify gene expression signatures |
| Proximity ligation assay | Protein-protein interactions at adhesion sites | Validate complex formation |
Adhesion assays
Cell-cell adhesion assays, such as aggregation assays or dual-color flow cytometry-based adhesion assays, directly measure the frequency and strength of integrin-mediated cell-cell contacts. These are used to quantify negative regulation after genetic manipulation [1, 8].
Live-cell imaging and FRET
Live-cell imaging with fluorescently tagged integrins or junctional proteins allows visualization of adhesion dynamics. FRET-based biosensors can detect conformational changes in integrins associated with negative regulation [2, 5].
CRISPR screening and bioinformatics
Genome-wide CRISPR knockout or activation screens coupled with adhesion readouts can identify novel regulators of integrin-mediated cell-cell adhesion. Bioinformatics analysis of transcriptomic or proteomic data can reveal pathways and networks [5, 8].
Proteomics and phosphoproteomics
Mass spectrometry-based proteomics can identify protein complexes and post-translational modifications that mediate negative regulation, such as phosphorylation of integrin cytoplasmic domains or associated proteins [1, 6].
How CRISPR Can Be Used to Study GO:0033633 negative regulation of cell-cell adhesion mediated by integrin
Knockout
CRISPR-Cas9 knockout of candidate genes (e.g., SGK1, PECAM1, FHL1) in cell lines such as MDCK, endothelial cells, or U937 can test whether they are required for negative regulation of integrin-mediated cell-cell adhesion. Knockout cells are then subjected to adhesion assays to measure changes in adhesion strength [1, 2, 6].
Point Mutation
Point mutations can be introduced into integrin genes (e.g., ITGA5, ITGB1) to mimic or disrupt regulatory phosphorylation sites or ligand-binding residues. These knock-in cell lines help dissect the precise molecular determinants of negative regulation, such as the isoaspartate switch in integrin-ligand recognition [4, 5].
Knock-in
Knock-in of tagged versions of integrins or regulatory proteins (e.g., GFP-tagged PECAM1) allows visualization and biochemical isolation of adhesion complexes. This approach can reveal dynamic localization and interactions during negative regulation.
Overexpression
Overexpression of negative regulators (e.g., SGK1, FHL1, or disintegrin peptides) can suppress integrin-mediated cell-cell adhesion. Overexpression cell lines are useful for gain-of-function studies and for testing therapeutic potential of enhancing negative regulation [1, 4, 6].
How EDITGENE Supports negative regulation of cell-cell adhesion mediated by integrin Research
Researchers studying negative regulation of cell-cell adhesion mediated by integrin-related genes often need to determine whether a candidate gene is causally involved in adhesion dynamics or merely correlated with changes in expression. EDITGENE provides comprehensive CRISPR-based services to generate precisely engineered cell models, enabling functional validation of genes in this pathway.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of cell-cell adhesion mediated by integrin research.
Frequently Asked Questions About negative regulation of cell-cell adhesion mediated by integrin
What is GO:0033633?
GO:0033633 is a Gene Ontology biological process term defined as any process that stops, prevents, or reduces the frequency, rate, or extent of cell-cell adhesion mediated by integrin [1, 2].
What genes are involved in negative regulation of cell-cell adhesion mediated by integrin?
Key genes include SGK1, PECAM1, RHOA, CRIK, FHL1, ITGA5, ITGB1, and CD98, among others, as reported in published studies [1, 2, 4, 6, 8].
How is integrin-mediated cell-cell adhesion negatively regulated?
It can be negatively regulated by extracellular factors like HGF and ceramides, intracellular kinases such as SGK1, and cytoskeletal regulators like Rho/CRIK, which alter integrin affinity or promote junction disassembly [1, 4, 6, 8].
What diseases are associated with dysregulation of this process?
Dysregulation is linked to cancer metastasis, vascular permeability, inflammation, and skin differentiation disorders [2, 3, 6, 7].
What experimental models are used to study GO:0033633?
Common models include CRISPR knockout, point-mutation knock-in, and overexpression cell lines, combined with adhesion assays, imaging, and proteomics [1, 4, 5, 8].
Which integrins are most studied in this context?
Integrin alpha5beta1 (ITGA5/ITGB1) and beta1-containing integrins are frequently studied, along with beta2 and beta3 integrins in immune and endothelial cells [4, 5, 8].
How can CRISPR screening help identify regulators of this process?
Genome-wide CRISPR screens with adhesion readouts can uncover novel genes that negatively regulate integrin-mediated cell-cell adhesion, followed by bioinformatics analysis [5, 8].
What is the role of PECAM-1 in this process?
PECAM-1 (CD31) modulates integrin-dependent adhesion and endothelial permeability, acting as a negative regulator in certain contexts.
Can ceramides regulate integrin-mediated cell-cell adhesion?
Yes, cell-permeable ceramides act as novel regulators of U937 cell-cell adhesion mediated by CD29, CD98, and CD147.
What methods measure negative regulation of integrin-mediated adhesion?
Cell aggregation assays, flow cytometry-based adhesion assays, live-cell imaging, FRET biosensors, and phosphoproteomics are commonly used [1, 2, 5, 6].
Conclusion
GO:0033633, negative regulation of cell-cell adhesion mediated by integrin, is a critical biological process that ensures dynamic control of tissue architecture and cell migration. Dysregulation of this process contributes to cancer, vascular disease, and inflammatory conditions. By leveraging CRISPR-based models and advanced screening technologies, researchers can dissect the molecular mechanisms and identify therapeutic targets. EDITGENE provides end-to-end services to support these investigations, from knockout and knock-in cell line generation to library screening and bioinformatics.
References
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- 2. Jackson DE. 2003. The unfolding tale of PECAM-1.. FEBS Lett 540(1-3):7-14 PMID: 12681475
- 3. Lum H et al.. 1996. Mechanisms of increased endothelial permeability.. Can J Physiol Pharmacol 74(7):787-800 PMID: 8946065
- 4. Sumathipala R et al.. 2006. The "linker" region (amino acids 38-47) of the disintegrin elegantin is a novel inhibitory domain of integrin alpha5beta1-dependent cell adhesion on fibronectin: evidence for the negative regulation of fibronectin synergy site biological activity.. J Biol Chem 281(49):37686-96 PMID: 16982624
- 5. Corti A et al.. 2011. Isoaspartate-dependent molecular switches for integrin-ligand recognition.. J Cell Sci 124(Pt 4):515-22 PMID: 21282473
- 6. Grossi M et al.. 2005. Negative control of keratinocyte differentiation by Rho/CRIK signaling coupled with up-regulation of KyoT1/2 (FHL1) expression.. Proc Natl Acad Sci U S A 102(32):11313-8 PMID: 16061799
- 7. Thomas GJ et al.. 1997. Integrins and oral cancer.. Oral Oncol 33(6):381-8 PMID: 9509120
- 8. Lee YG et al.. 2010. Cell-permeable ceramides act as novel regulators of U937 cell-cell adhesion mediated by CD29, CD98, and CD147.. Immunobiology 215(4):294-303 PMID: 19576658
