GO:1904893 negative regulation of receptor signaling pathway via STAT: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1904893 describes any process that stops, prevents, or reduces the frequency, rate, or extent of receptor signaling via STAT.
• Negative regulation of STAT signaling is essential for terminating cytokine and interferon responses, preventing excessive inflammation and autoimmunity.
• Key negative regulators include SOCS proteins, PTPN2, PJA2, and viral proteins that target the type I interferon receptor.
• Dysregulation of this process is linked to autoimmunity, cancer, and viral immune evasion.
• CRISPR knockout, point mutation, and knock-in models enable precise dissection of negative regulators in this pathway.
• Understanding GO:1904893 provides a framework for therapeutic targeting of JAK/STAT-driven diseases.
Description
Receptor signaling via the JAK/STAT pathway is a central mechanism by which cytokines, interferons, and growth factors transmit signals from the cell surface to the nucleus. This cascade is tightly controlled by negative regulatory processes that prevent excessive or prolonged signaling. GO:1904893, negative regulation of receptor signaling pathway via STAT, encompasses all molecular events that stop, prevent, or reduce the frequency, rate, or extent of receptor signaling via STAT. These regulatory mechanisms are critical for maintaining immune homeostasis and preventing pathological conditions such as autoimmunity and cancer. Researchers study this term to identify novel therapeutic targets and to understand how pathogens subvert host immunity.
negative regulation of receptor signaling pathway via STAT At A Glance
| GO ID | GO:1904893 |
|---|---|
| GO term | negative regulation of receptor signaling pathway via STAT |
| Ontology | biological_process |
| Synonym | negative regulation of STAT cascade; inhibition of STAT signalling pathway; down-regulation of kinase-STAT cascade |
| Major function | Termination or attenuation of JAK/STAT signaling downstream of cytokine and interferon receptors |
| Key regulators | SOCS1-7, PTPN2, PJA2, PIAS, viral proteins (e.g., ASFV p22) |
| Associated diseases | Autoimmunity, cancer, viral immune evasion |
| Research methods | CRISPR KO/point mutation/knock-in, RNA-seq, proteomics, flow cytometry |
What Is GO:1904893?
GO:1904893 is a biological process term defined as any process that stops, prevents, or reduces the frequency, rate, or extent of receptor signaling via STAT. This includes mechanisms such as dephosphorylation of JAK or STAT proteins, degradation of cytokine receptors, induction of suppressor of cytokine signaling (SOCS) proteins, and viral inhibition of interferon signaling.
Why Is negative regulation of receptor signaling pathway via STAT Important in Cell Biology?
Negative regulation of receptor signaling via STAT is essential for preventing uncontrolled inflammation and autoimmunity, and its dysregulation contributes to cancer and infectious diseases. Understanding this process provides insights into therapeutic strategies for modulating JAK/STAT signaling in disease.
• Prevents excessive cytokine and interferon responses that can damage tissues.
• Maintains immune homeostasis by terminating STAT activation.
• Dysregulation is linked to autoimmune diseases such as inflammatory bowel disease and type 1 diabetes.
• Viruses often target this process to evade host immunity.
• Cancer cells may exploit negative regulators to escape immune surveillance.
• Provides targets for anti-inflammatory and anti-cancer therapies.
• Key for understanding cytokine signaling in development and differentiation.
• Enables precise CRISPR-based dissection of regulatory networks.
What Happens During negative regulation of receptor signaling pathway via STAT?
Initiation of negative feedback by SOCS proteins
In simple terms: SOCS proteins are induced by STAT signaling and then act to shut it down.
Upon cytokine or interferon stimulation, STAT proteins are activated and induce the expression of SOCS family proteins, which bind to JAK kinases or cytokine receptors to inhibit further signaling. SOCS2, for example, regulates neurotrophin receptor signaling by suppressing STAT activation.
Dephosphorylation by phosphatases
In simple terms: Phosphatases remove phosphate groups from JAK or STAT proteins, turning off the signal.
Protein tyrosine phosphatases such as PTPN2 dephosphorylate JAK and STAT proteins, thereby terminating receptor signaling via STAT. Deletion of Ptpn2 in B cells leads to hyperactivation of JAK/STAT signaling and autoimmunity.
Receptor degradation and trafficking
In simple terms: Receptors can be degraded or removed from the cell surface to stop signaling.
Negative regulators can promote ubiquitination and degradation of cytokine receptors. For instance, the African swine fever virus protein p22 promotes TAX1BP1-mediated degradation of the type I interferon receptor, inhibiting JAK-STAT signaling. PJA2 also negatively regulates type I interferon signaling by targeting proximal signaling components.
Inhibition by viral and cellular inhibitors
In simple terms: Some proteins block STAT signaling directly, often as a viral strategy.
Viral proteins such as ASFV p22 inhibit JAK-STAT signaling by degrading the interferon receptor. Cellular inhibitors like PIAS proteins block STAT DNA binding and transcriptional activity. The short coreceptor Eye Transformer/Latran negatively regulates JAK/STAT pathway in Drosophila.
Key Genes Involved in GO:1904893 negative regulation of receptor signaling pathway via STAT
The following genes and proteins are key players in negative regulation of receptor signaling via STAT, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SOCS1 | Inhibits JAK kinase activity | Negative feedback regulator of cytokine signaling |
| SOCS2 | Regulates neurotrophin receptor signaling | New player in Trk signaling regulation |
| SOCS3 | Inhibits JAK/STAT in inflammation | Key regulator of cytokine responses |
| PTPN2 | Dephosphorylates JAK and STAT | Autoimmunity via TLR and JAK/STAT signaling |
| PJA2 | E3 ubiquitin ligase targeting interferon signaling | Negative regulator of type I IFN cascade |
| PIAS1 | Inhibits STAT DNA binding | Modulates STAT transcriptional activity |
| PIAS3 | Inhibits STAT3 activity | Regulates STAT3-driven transcription |
| TAX1BP1 | Adaptor for receptor degradation | Mediates ASFV p22-induced IFNAR degradation |
| ASFV p22 | Viral inhibitor of JAK-STAT | Promotes IFNAR degradation |
| Eye Transformer/Latran | Short coreceptor inhibiting JAK/STAT | Drosophila negative regulation |
| CIS | Inhibits STAT5 binding to receptor | Negative regulator of cytokine signaling |
| SHP-1 | Phosphatase inhibiting JAK | Terminates cytokine signaling |
| SHP-2 | Phosphatase modulating STAT | Regulates JAK/STAT balance |
| USP18 | Inhibits type I IFN signaling | Negative regulator of interferon response |
| TRIM24 | Regulates STAT3 activity | Modulates STAT3-driven transcription |
| Insulin receptor | Cross-talk with JAK/STAT | Immuno-oncological implications |
| JAK2 | Kinase activated by cytokines | Target of negative regulation |
How Is negative regulation of receptor signaling pathway via STAT Regulated?
Negative regulation of receptor signaling via STAT is itself regulated at multiple levels. SOCS proteins are transcriptionally induced by STAT activation, forming a negative feedback loop. Phosphatases such as PTPN2 are constitutively expressed and rapidly dephosphorylate JAK/STAT components. Viral proteins can hijack this process by promoting receptor degradation. Additionally, insulin signaling can cross-talk with JAK/STAT pathways, influencing immuno-oncological outcomes.
negative regulation of receptor signaling pathway via STAT and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| PTPN2 | Autoimmunity | B cell-specific knockout mouse |
| SOCS2 | Neurodegeneration | SOCS2 knockout or overexpression in neurons |
| ASFV p22 | Viral immune evasion | Infection of porcine macrophages with ASFV |
| PJA2 | Interferonopathies | PJA2 knockout cells treated with IFN |
| Insulin receptor | Cancer immunology | Insulin receptor knockout cancer cells |
Autoimmunity
Loss of negative regulators such as PTPN2 leads to hyperactivation of JAK/STAT signaling and autoimmunity, as shown in B cell-specific Ptpn2 knockout mice. This highlights the importance of GO:1904893 in preventing autoimmune responses.
Cancer
Dysregulation of negative regulation of STAT signaling can contribute to cancer. For example, insulin signaling cross-talk with JAK/STAT has immuno-oncological implications, and SOCS proteins are often silenced in tumors.
Viral immune evasion
Viruses such as African swine fever virus encode proteins like p22 that inhibit JAK-STAT signaling by degrading the type I interferon receptor, thereby evading host immunity. This demonstrates how pathogens target GO:1904893.
From negative regulation of receptor signaling pathway via STAT-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X negatively regulate STAT signaling? | CRISPR knockout in HEK293 or HeLa cells |
| Does a point mutation in SOCS1 affect JAK binding? | CRISPR point mutation knock-in |
| How does PTPN2 dephosphorylate JAK2? | Knock-in of tagged PTPN2 |
| Can overexpression of SOCS3 suppress STAT3? | Overexpression cell line |
| What is the role of PJA2 in IFN signaling? | PJA2 knockout and proteomics |
| How does ASFV p22 degrade IFNAR? | Knockout of TAX1BP1 in porcine cells |
How to Study the negative regulation of receptor signaling pathway via STAT Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Loss-of-function of candidate negative regulators | Identify genes that inhibit STAT signaling |
| CRISPR point mutation | Effect of specific amino acid changes | Dissect SOCS-JAK interaction domains |
| Knock-in tagging | Localization and interactions of regulators | Study PTPN2 dynamics |
| Overexpression | Gain-of-function of negative regulators | Suppress STAT signaling |
| Proteomics | Protein interactions and degradation | Identify PJA2 targets |
| RNA-seq | Transcriptional changes | Measure STAT target gene expression |
| Flow cytometry | Phospho-STAT levels | Quantify signaling inhibition |
| Bioinformatics | Pathway enrichment and network analysis | Interpret CRISPR screen data |
CRISPR knockout screening
Genome-wide CRISPR knockout screens can identify negative regulators of STAT signaling. For example, deletion of Ptpn2 in B cells revealed its role in autoimmunity. Combinational silencing of JAK/STAT components has also been achieved.
Proteomics and interactomics
Proximal protein landscapes of the type I interferon signaling cascade revealed negative regulation by PJA2 using proteomic approaches. Such methods identify novel regulators and their interaction networks.
Transcriptomics and RNA-seq
RNA-seq can measure changes in STAT target genes upon knockout or overexpression of negative regulators. This helps quantify the impact on receptor signaling via STAT.
Flow cytometry and phospho-STAT analysis
Flow cytometry with phospho-specific antibodies allows single-cell measurement of STAT activation and its negative regulation.
How CRISPR Can Be Used to Study GO:1904893 negative regulation of receptor signaling pathway via STAT
Knockout
CRISPR knockout of negative regulators such as PTPN2 or SOCS proteins leads to enhanced STAT signaling, providing causal evidence for their role in GO:1904893.
Point Mutation
Point mutations can be introduced into key residues of SOCS or phosphatases to test their functional domains, as demonstrated in combinational silencing studies.
Knock-in
Knock-in of tagged versions of negative regulators (e.g., GFP-PTPN2) allows real-time tracking of their localization and interactions during STAT signaling.
Overexpression
Overexpression of SOCS or PJA2 can suppress STAT signaling, validating their negative regulatory function and providing tools for pathway modulation.
How EDITGENE Supports negative regulation of receptor signaling pathway via STAT Research
Researchers studying negative regulation of receptor signaling pathway via STAT-related genes often need to determine whether a candidate gene is causally involved in terminating or attenuating STAT signaling. This requires precise genetic models that can knockout, mutate, tag, or overexpress the gene of interest in relevant cell types.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of receptor signaling pathway via STAT research.
Frequently Asked Questions About negative regulation of receptor signaling pathway via STAT
What is GO:1904893?
GO:1904893 is a Gene Ontology term for any process that stops, prevents, or reduces the frequency, rate, or extent of receptor signaling via STAT.
What genes are involved in negative regulation of STAT signaling?
Key genes include SOCS1, SOCS2, SOCS3, PTPN2, PJA2, PIAS1, PIAS3, and viral proteins like ASFV p22.
How does PTPN2 regulate JAK/STAT signaling?
PTPN2 dephosphorylates JAK and STAT proteins, terminating signaling; its deletion in B cells causes autoimmunity.
What is the role of SOCS proteins in STAT negative regulation?
SOCS proteins are induced by STAT activation and inhibit JAK kinase activity or receptor binding, forming a negative feedback loop.
How do viruses inhibit JAK-STAT signaling?
Viruses such as African swine fever virus encode proteins like p22 that promote degradation of the type I interferon receptor, inhibiting JAK-STAT signaling.
What diseases are linked to defective negative regulation of STAT signaling?
Autoimmunity, cancer, and viral immune evasion are linked to dysregulation of this process.
What research methods are used to study GO:1904893?
CRISPR knockout, point mutation, knock-in, overexpression, proteomics, RNA-seq, and flow cytometry are commonly used.
How can CRISPR screens identify negative regulators of STAT signaling?
Genome-wide CRISPR knockout screens can reveal genes whose loss enhances STAT activation, as shown for Ptpn2.
What is the significance of PJA2 in interferon signaling?
PJA2 negatively regulates type I interferon signaling by targeting proximal components of the cascade.
Can overexpression of SOCS proteins suppress STAT signaling?
Yes, overexpression of SOCS proteins can suppress STAT activation, validating their negative regulatory role.
Conclusion
GO:1904893, negative regulation of receptor signaling pathway via STAT, is a critical biological process that maintains immune homeostasis and prevents disease. Key regulators such as SOCS proteins, PTPN2, and PJA2 terminate STAT signaling through diverse mechanisms. Dysregulation of this process contributes to autoimmunity, cancer, and viral immune evasion. Advanced CRISPR models and omics approaches are essential for dissecting these pathways and developing targeted therapies.
References
- 1. Schiefer S et al.. 2024. Proximal protein landscapes of the type I interferon signaling cascade reveal negative regulation by PJA2.. Nat Commun 15(1):4484 PMID: 38802340
- 2. Alexander BN et al.. 2025. Deletion of Ptpn2 in B cells promotes autoimmunity via TLR and JAK/STAT signaling.. JCI Insight 10(24) PMID: 41424386
- 3. Liongue C et al.. 2016. Evolution of Cytokine Receptor Signaling.. J Immunol 197(1):11-8 PMID: 27317733
- 4. van Niekerk G et al.. 2021. The immuno-oncological implications of insulin.. Life Sci 264:118716 PMID: 33159956
- 5. Ren H et al.. 2025. The African swine fever virus p22 inhibits the JAK-STAT signaling pathway by promoting the TAX1BP1-mediated degradation of the type I interferon receptor.. PLoS Pathog 21(7):e1013319 PMID: 40668839
- 6. Fisher KH et al.. 2016. Mechanisms of JAK/STAT pathway negative regulation by the short coreceptor Eye Transformer/Latran.. Mol Biol Cell 27(3):434-41 PMID: 26658615
- 7. Bousoik E et al.. 2022. Combinational silencing of components involved in JAK/STAT signaling pathway.. Eur J Pharm Sci 175:106233 PMID: 35680032
- 8. Uren RT et al.. 2014. Regulation of neurotrophin receptor (Trk) signaling: suppressor of cytokine signaling 2 (SOCS2) is a new player.. Front Mol Neurosci 7:39 PMID: 24860421
