GO:0007267 cell-cell signaling: Mechanisms, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0007267 cell-cell signaling is defined as any process that mediates the transfer of information from one cell to another, including ligand release, transport, presentation, and signal transduction in the receiving cell.
• Cell-cell signaling encompasses soluble ligands, cell adhesion molecules, gap junctions, and mechanotransduction, making it central to development, immunity, and tissue homeostasis.
• Single-cell transcriptomics and computational tools such as CellChat enable systematic inference of cell-cell communication networks across tissues and disease states.
• Dysregulated cell-cell signaling underlies cancer progression, cardiovascular disease, and developmental disorders, with Notch signaling serving as a paradigm.
• Bacterial systems reveal that cell-cell signaling can drive altruistic feeding and phenotypic heterogeneity, expanding the evolutionary scope of this GO term.
• CRISPR-based knockout, knock-in, and overexpression models are essential for causally testing signaling genes identified by transcriptomic and proteomic screens.
Description
Cell-cell signaling (GO:0007267) is a fundamental biological process that mediates the transfer of information from one cell to another, encompassing ligand release, transport, presentation, and signal transduction in the receiving cell. This process is essential for coordinating multicellular behavior, from embryonic development to immune responses and tissue repair. The QuickGO definition explicitly includes signaling via soluble ligands, cell adhesion molecules, and gap junctions, reflecting the diverse molecular mechanisms that cells use to communicate. Understanding cell-cell signaling is critical for researchers because its dysregulation is implicated in cancer, cardiovascular disease, and developmental disorders. Recent advances in single-cell transcriptomics and computational inference have transformed our ability to map communication networks across thousands of cells simultaneously. As a result, cell-cell signaling has become a central focus for both basic biology and translational medicine.
cell-cell signaling At A Glance
| GO ID | GO:0007267 |
|---|---|
| GO term | cell-cell signaling |
| Ontology | biological_process |
| Synonym | cell-cell signalling |
| Major function | Transfer of information from one cell to another via ligands, adhesion molecules, or gap junctions |
| Included processes | Ligand release, transport, presentation, and signal transduction in the receiving cell |
| Example modalities | Soluble ligands, cell adhesion molecules, gap junctions, mechanotransduction |
| Relevance | Development, immunity, tissue homeostasis, cancer, cardiovascular disease |
What Is GO:0007267?
GO:0007267 cell-cell signaling is defined by QuickGO as any process that mediates the transfer of information from one cell to another. This includes signal transduction in the receiving cell and, where applicable, release of a ligand and any processes that actively facilitate its transport and presentation to the receiving cell. Examples include signaling via soluble ligands, via cell adhesion molecules, and via gap junctions. In practice, this term covers a wide range of intercellular communication modalities, from secreted growth factors and cytokines to direct membrane contact and mechanotransduction.
Why Is cell-cell signaling Important in Cell Biology?
Cell-cell signaling is essential for coordinating the behavior of individual cells within multicellular organisms, enabling processes such as embryonic patterning, immune surveillance, and tissue regeneration. Dysregulation of this process contributes to a broad spectrum of human diseases, including cancer, where tumor-stroma communication drives progression and therapy resistance. In cardiovascular tissue engineering, mechano-regulated cell-cell signaling determines how cells respond to mechanical forces and maintain tissue function. Bacterial systems further illustrate that cell-cell signaling can actively enhance phenotypic heterogeneity and altruistic feeding during differentiation. Therefore, understanding the molecular players and regulatory logic of cell-cell signaling is a prerequisite for developing targeted therapeutic interventions.
• Cell-cell signaling coordinates embryonic development and tissue patterning through pathways such as Notch.
• It is a hallmark of cancer progression, where tumor cells communicate with stromal and immune cells.
• Mechano-regulated cell-cell signaling is critical for cardiovascular tissue engineering and homeostasis.
• Single-cell transcriptomics has made cell-cell signaling a tractable computational problem via tools like CellChat.
• Bacterial cell-cell signaling drives phenotypic heterogeneity and altruistic feeding during differentiation.
• Dysregulated signaling underlies developmental disorders, neurodegeneration, and immune pathologies.
• Engineering cell-cell signaling enables synthetic biology applications and therapeutic design.
• CRISPR screens can identify causal signaling genes within complex communication networks.
What Happens During cell-cell signaling?
Ligand release and presentation
In simple terms: The sending cell makes and releases a signal molecule that can reach another cell.
The first stage of cell-cell signaling involves the production and release of a ligand from the signaling cell. This can occur through secretion of soluble factors, presentation of membrane-bound ligands, or direct transfer of small molecules through gap junctions. The QuickGO definition explicitly includes release of a ligand and any processes that actively facilitate its transport and presentation to the receiving cell. In the colorectal cancer microenvironment, for example, tumor cells release a variety of ligands that act on stromal and immune cells. Engineering approaches have been developed to control ligand release and presentation for synthetic signaling circuits.
Ligand transport and reception
In simple terms: The signal molecule travels to the receiving cell and binds to a receptor.
Once released, ligands must be transported to and recognized by the receiving cell. This may involve diffusion through the extracellular space, presentation on the cell surface, or direct cell-cell contact. Receptors on the receiving cell bind the ligand with specificity, initiating a signaling cascade. In cardiovascular tissue engineering, mechanical forces can modulate the transport and presentation of ligands, thereby influencing receptor activation. Computational tools such as CellChat infer ligand-receptor interactions from single-cell transcriptomic data to map these communication events.
Signal transduction in the receiving cell
In simple terms: Binding of the signal triggers a chain reaction inside the receiving cell.
The QuickGO definition explicitly includes signal transduction in the receiving cell as part of cell-cell signaling. Upon ligand binding, receptors activate intracellular pathways such as phosphorylation cascades, second messenger production, and transcriptional programs. Notch signaling is a classic example where receptor-ligand interaction leads to proteolytic cleavage and nuclear translocation of the Notch intracellular domain to regulate gene expression. In cancer, aberrant signal transduction in receiving cells can drive proliferation and survival. Single-cell atlases have revealed extensive heterogeneity in signal transduction responses across cell types.
Gap junction and adhesion-mediated signaling
In simple terms: Cells can also talk directly through physical connections.
Beyond soluble ligands, cell-cell signaling includes communication via gap junctions and cell adhesion molecules. Gap junctions allow direct cytoplasmic exchange of ions and small molecules between adjacent cells, enabling rapid electrical and metabolic coupling. Adhesion molecules such as cadherins mediate mechanical and biochemical signaling upon cell contact. These modalities are particularly important in tissues where rapid coordination is required, such as cardiac muscle and developing embryos. The QuickGO definition explicitly lists gap junctions and cell adhesion molecules as examples of cell-cell signaling.
Mechanotransduction and feedback
In simple terms: Physical forces can also act as signals between cells.
Mechano-regulated cell-cell signaling represents an emerging dimension of GO:0007267, where mechanical forces are converted into biochemical signals that influence neighboring cells. This is critical in cardiovascular tissue engineering, where cells sense and respond to stretch, shear stress, and matrix stiffness. Feedback loops between signaling and mechanical cues ensure tissue homeostasis and adaptation. Computational models and single-cell analyses are increasingly used to dissect these mechano-signaling networks.
Bacterial cell-cell signaling and heterogeneity
In simple terms: Even bacteria use cell-cell signals to coordinate behavior.
Cell-cell signaling is not limited to multicellular eukaryotes; bacteria also employ intercellular signals to coordinate differentiation and altruistic feeding. In Bacillus subtilis, signaling during sporulation actively enhances phenotypic heterogeneity, allowing subpopulations to survive changing environments. This finding expands the evolutionary scope of GO:0007267 and highlights conserved principles of intercellular communication. Such bacterial systems provide tractable models for studying the logic of cell-cell signaling.
Key Genes Involved in GO:0007267 cell-cell signaling
The following genes and proteins are central players in cell-cell signaling pathways, including ligands, receptors, adhesion molecules, and junction components.
| Gene | Major Role | Research Relevance |
|---|---|---|
| NOTCH1 | Notch receptor mediating juxtacrine signaling | Development, tissue homeostasis, cancer |
| DLL1 | Notch ligand presented on signaling cell | Embryonic patterning, stem cell maintenance |
| JAG1 | Notch ligand involved in cell fate decisions | Alagille syndrome, cancer |
| CDH1 | E-cadherin mediating adhesion and signaling | Epithelial integrity, cancer invasion |
| CTNNB1 | Beta-catenin transducing adhesion and Wnt signals | Colorectal cancer, development |
| GJA1 | Connexin 43 forming gap junctions | Cardiac conduction, tissue coupling |
| CXCL12 | Chemokine ligand for CXCR4 | Immune cell recruitment, cancer metastasis |
| CXCR4 | Chemokine receptor mediating migration | Cancer, immune responses |
| TGFB1 | Secreted ligand regulating growth and differentiation | Fibrosis, cancer, immune suppression |
| TGFBR1 | TGF-beta receptor serine/threonine kinase | Cancer, cardiovascular disease |
| VEGFA | Angiogenic ligand acting on endothelial cells | Angiogenesis, tumor growth |
| KDR | VEGFR2 receptor for VEGF | Endothelial signaling, cardiovascular biology |
| IL6 | Cytokine mediating inflammatory signaling | Inflammation, cancer microenvironment |
| IL6R | Interleukin-6 receptor | Inflammation, immune signaling |
| FN1 | Fibronectin mediating adhesion and mechanotransduction | Cardiovascular tissue engineering |
| ITGB1 | Integrin beta-1 transducing mechanical signals | Mechanobiology, cancer |
| YAP1 | Mechanosensitive transcriptional regulator | Cardiovascular, cancer |
How Is cell-cell signaling Regulated?
Cell-cell signaling is regulated at multiple levels, including ligand availability, receptor expression, and intracellular feedback loops. In cardiovascular tissue engineering, mechanical forces modulate signaling through integrins and mechanosensitive transcription factors such as YAP1. Notch signaling is regulated by proteolytic cleavage and endocytosis of ligands and receptors, ensuring precise spatial and temporal control. In cancer, the tumor microenvironment regulates signaling through soluble factors and cell adhesion, often creating feedback loops that sustain proliferation. Computational inference from single-cell data has revealed that signaling networks are highly context-dependent and dynamically regulated. Bacterial cell-cell signaling during sporulation is regulated by nutrient availability and population density, leading to phenotypic heterogeneity.
cell-cell signaling and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| NOTCH1 | Alagille syndrome, T-cell acute lymphoblastic leukemia | Knockout and point-mutation cell models |
| CDH1 | Hereditary diffuse gastric cancer | Knockout of CDH1 in gastric organoids |
| GJA1 | Oculodentodigital dysplasia, cardiac arrhythmia | Knock-in of patient mutations in cardiomyocytes |
| CXCR4 | WHIM syndrome, cancer metastasis | Overexpression and knockout in immune cells |
| TGFBR1 | Marfan syndrome, cancer | Point-mutation knock-in in fibroblasts |
Cell-cell signaling in cancer
Dysregulated cell-cell signaling is a hallmark of cancer, where tumor cells communicate with stromal, endothelial, and immune cells to promote growth, angiogenesis, and immune evasion. The colorectal cancer microenvironment exemplifies how ligand-receptor interactions drive tumor progression and therapy resistance. Computational tools such as CellChat have been used to infer these communication networks from single-cell transcriptomics, identifying key signaling axes as potential therapeutic targets.
Notch signaling in developmental disorders and disease
Notch signaling is a paradigm of cell-cell signaling, and its dysregulation causes developmental disorders such as Alagille syndrome and contributes to cancer. Mutations in NOTCH1, DLL1, and JAG1 disrupt cell fate decisions during development and tissue homeostasis. Understanding Notch signaling has led to targeted therapies for diseases driven by aberrant Notch activity.
Mechano-regulated signaling in cardiovascular disease
Mechano-regulated cell-cell signaling is critical for cardiovascular tissue engineering and disease. Altered mechanical forces in the heart and vasculature can disrupt signaling through integrins and gap junctions, contributing to hypertrophy, fibrosis, and heart failure. Experimental models that recapitulate mechanical cues are essential for studying these processes.
Bacterial cell-cell signaling and heterogeneity
In bacteria, cell-cell signaling during differentiation actively enhances phenotypic heterogeneity, which can influence survival and pathogenesis. Altruistic feeding and signaling in Bacillus subtilis provide a model for understanding how intercellular communication shapes population-level behaviors. These findings have implications for antibiotic tolerance and microbial ecology.
From cell-cell signaling-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is a candidate ligand required for intercellular signaling? | CRISPR knockout of the ligand gene |
| Does a specific receptor mutation alter signal transduction? | Point-mutation knock-in of the receptor |
| Can a signaling gene be tagged for live imaging? | Knock-in of fluorescent tag |
| Does overexpression of a ligand drive tumor growth? | Overexpression cell model |
| Which genes mediate mechanotransduction? | Knockout of integrin or YAP1 in mechano-stimulated cells |
| How does Notch signaling affect cell fate? | Knockout and knock-in of NOTCH1 in stem cells |
How to Study the cell-cell signaling Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Single-cell RNA-seq + CellChat | Ligand-receptor co-expression and communication networks | Mapping cell-cell signaling in tissues |
| Phosphoproteomics | Kinase activity and signaling pathway activation | Identifying downstream signal transduction events |
| Live-cell imaging | Real-time ligand-receptor dynamics and second messengers | Validating signaling interactions |
| CRISPR knockout screens | Gene requirement for cell-cell signaling | Discovering causal signaling regulators |
| Gap junction dye transfer | Direct intercellular communication | Assessing gap junction function |
| Notch reporter assays | Notch pathway activation | Studying Notch signaling in development and disease |
| Bacterial differentiation assays | Phenotypic heterogeneity and altruistic feeding | Modeling bacterial cell-cell signaling |
Single-cell transcriptomics and cell-cell communication inference
Single-cell RNA sequencing combined with computational tools such as CellChat allows researchers to infer cell-cell communication networks by analyzing ligand-receptor co-expression across cell types. This approach has been applied to diverse tissues and diseases, revealing signaling axes that are not apparent from bulk analysis. Mining single-cell atlases for cell-cell signaling is now a standard method in the field.
Proteomics and phosphoproteomics
Mass spectrometry-based proteomics can quantify ligand secretion, receptor abundance, and post-translational modifications that mediate signal transduction. Phosphoproteomics is particularly useful for mapping kinase cascades activated downstream of cell-cell signaling. These methods complement transcriptomic inference by providing direct evidence of protein-level signaling events.
Imaging and biosensors
Live-cell imaging with fluorescent biosensors enables real-time visualization of cell-cell signaling dynamics, including ligand diffusion, receptor activation, and second messenger production. Gap junction communication can be assessed using dye transfer or genetically encoded indicators. These techniques are essential for validating computational predictions.
Functional genomics and CRISPR screens
CRISPR-based knockout and activation screens can systematically identify genes required for cell-cell signaling in a given context. Pooled screens coupled with single-cell readouts allow unbiased discovery of signaling regulators. Such functional validation is critical for translating inferred networks into causal mechanisms.
How CRISPR Can Be Used to Study GO:0007267 cell-cell signaling
Knockout
CRISPR knockout of genes encoding ligands, receptors, or adhesion molecules is a powerful approach to test their necessity in cell-cell signaling. For example, knocking out NOTCH1 or its ligands can abolish Notch-dependent cell fate decisions. In cancer models, knockout of chemokine receptors such as CXCR4 can reduce metastasis in vivo. EDITGENE provides validated knockout cell models for signaling genes to support causal studies.
Point Mutation
Point-mutation knock-in allows researchers to model disease-associated missense mutations in signaling genes, such as those found in NOTCH1 or TGFBR1. These models are essential for understanding how specific amino acid changes alter receptor activity or ligand binding. CRISPR-based base editing or homology-directed repair can introduce precise mutations in cell lines or primary cells.
Knock-in
Knock-in of fluorescent tags or reporter cassettes enables live imaging of signaling proteins and their dynamics. For example, tagging a receptor with GFP allows tracking of its trafficking and activation in response to ligands. Knock-in of patient-specific mutations can also create isogenic disease models for drug testing.
Overexpression
Overexpression of ligands or receptors can drive constitutive signaling and model gain-of-function states observed in cancer. CRISPR activation (CRISPRa) or cDNA overexpression can be used to elevate gene expression. These models are useful for studying how excess signaling contributes to disease phenotypes.
How EDITGENE Supports cell-cell signaling Research
Researchers studying cell-cell signaling-related genes often need to determine whether a candidate gene is causally involved in intercellular communication or simply correlated with it. CRISPR-based genome editing provides the gold standard for establishing causality by enabling precise knockout, point mutation, knock-in, and overexpression of signaling genes in relevant cell models. EDITGENE offers a comprehensive suite of services to support these studies, from custom cell line generation to library screening and bioinformatics analysis.
Contact EDITGENE today to design your custom CRISPR model for cell-cell signaling research.
Frequently Asked Questions About cell-cell signaling
What is cell-cell signaling (GO:0007267)?
Cell-cell signaling is any process that mediates the transfer of information from one cell to another, including ligand release, transport, presentation, and signal transduction in the receiving cell.
What genes are involved in cell-cell signaling?
Key genes include NOTCH1, DLL1, JAG1, CDH1, CTNNB1, GJA1, CXCL12, CXCR4, TGFB1, and VEGFA, among many others.
What are examples of cell-cell signaling?
Examples include signaling via soluble ligands such as cytokines and growth factors, via cell adhesion molecules like cadherins, and via gap junctions.
How is cell-cell signaling studied?
It is studied using single-cell transcriptomics with tools like CellChat, proteomics, live-cell imaging, and CRISPR screens.
Why is cell-cell signaling important in cancer?
Dysregulated cell-cell signaling in the tumor microenvironment drives proliferation, angiogenesis, and immune evasion.
What is the role of Notch signaling in cell-cell signaling?
Notch signaling is a juxtacrine cell-cell signaling pathway critical for development, tissue homeostasis, and disease.
Can CRISPR be used to study cell-cell signaling?
Yes, CRISPR knockout, knock-in, and overexpression models are widely used to test the causal role of signaling genes.
What is mechano-regulated cell-cell signaling?
It is a form of cell-cell signaling where mechanical forces are converted into biochemical signals, important in cardiovascular tissue engineering.
Do bacteria use cell-cell signaling?
Yes, bacteria use cell-cell signaling during differentiation, which can enhance phenotypic heterogeneity and altruistic feeding.
What tools infer cell-cell communication from single-cell data?
CellChat and similar computational tools infer cell-cell communication by analyzing ligand-receptor co-expression in single-cell transcriptomics data.
Conclusion
GO:0007267 cell-cell signaling is a broad and fundamental biological process that encompasses diverse mechanisms of intercellular communication, from soluble ligands and adhesion molecules to gap junctions and mechanotransduction. Its dysregulation is central to cancer, cardiovascular disease, and developmental disorders, making it a key area of biomedical research. Advances in single-cell transcriptomics and CRISPR genome editing have transformed our ability to map and functionally test signaling networks. Continued integration of computational inference with causal experimental models will be essential for translating cell-cell signaling insights into therapeutic strategies.
References
- 1. Jin S et al.. 2021. Inference and analysis of cell-cell communication using CellChat.. Nat Commun 12(1):1088 PMID: 33597522
- 2. AlMusawi S et al.. 2021. Understanding cell-cell communication and signaling in the colorectal cancer microenvironment.. Clin Transl Med 11(2):e308 PMID: 33635003
- 3. Blagovic K et al.. 2013. Engineering cell-cell signaling.. Curr Opin Biotechnol 24(5):940-947 PMID: 23856592
- 4. Deng M et al.. 2022. Mining cell-cell signaling in single-cell transcriptomics atlases.. Curr Opin Cell Biol 76:102101 PMID: 35609365
- 5. Su J et al.. 2024. Cell-cell communication: new insights and clinical implications.. Signal Transduct Target Ther 9(1):196 PMID: 39107318
- 6. Karakaya C et al.. 2022. Mechano-regulated cell-cell signaling in the context of cardiovascular tissue engineering.. Biomech Model Mechanobiol 21(1):5-54 PMID: 34613528
- 7. Siebel C et al.. 2017. Notch Signaling in Development, Tissue Homeostasis, and Disease.. Physiol Rev 97(4):1235-1294 PMID: 28794168
- 8. Updegrove TB et al.. 2024. Altruistic feeding and cell-cell signaling during bacterial differentiation actively enhance phenotypic heterogeneity.. Sci Adv 10(42):eadq0791 PMID: 39423260
