GO:1904567 response to wortmannin: PI3K Signaling Response, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1904567 (response to wortmannin) describes any cellular or organismal process that changes in state or activity following exposure to wortmannin, a fungal steroidal metabolite and classic covalent inhibitor of phosphoinositide 3-kinases (PI3Ks).
• Wortmannin-sensitive responses include inhibition of PI3K-dependent signaling, suppression of platelet activation and pleckstrin phosphorylation, and modulation of DNA damage repair and checkpoint pathways.
• The term is a biological_process and is used to annotate experimental observations where wortmannin is the stimulus, not a molecular function or cellular component.
• Key genes and proteins studied in this context include PIK3CA/PIK3CB/PIK3CD, ATM, ATR, PRKDC (DNA-PK), AKT1, SRC, CAV1, ERBB1 (EGFR), and TERT.
• Wortmannin is widely used as a pharmacological tool to dissect PI3K/AKT/mTOR, DNA damage response, autophagy, and platelet signaling pathways.
• CRISPR knockout, point-mutation, knock-in, and overexpression cell models enable causal testing of candidate genes in wortmannin-response pathways.
Description
GO:1904567, response to wortmannin, is a Gene Ontology biological_process term defined as any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a wortmannin stimulus. Wortmannin is a cell-permeable fungal metabolite that acts as a potent, irreversible inhibitor of phosphoinositide 3-kinases (PI3Ks) and related phosphatidylinositol 3-kinase-related kinases (PIKKs), making it a widely used pharmacological probe for dissecting PI3K-dependent signaling. The term captures the downstream cellular consequences of wortmannin exposure, including altered enzyme activity, secretion, gene expression, and DNA repair responses.
response to wortmannin At A Glance
| GO ID | GO:1904567 |
|---|---|
| GO term | response to wortmannin |
| Ontology | biological_process |
| Synonym | response to wartmannin |
| Definition | Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a wortmannin stimulus. |
| Major function | Captures cellular and organismal responses to wortmannin, a PI3K/PIKK inhibitor, including changes in signaling, secretion, enzyme activity, and gene expression. |
| Example annotated processes | Suppression of platelet responses and pleckstrin phosphorylation; modulation of DNA double-strand break repair; release of secreted beta-amyloid precursor protein from platelets. |
| Common experimental use | Wortmannin is used as a pharmacological inhibitor to probe PI3K/AKT/mTOR, DNA damage response, autophagy, and platelet signaling pathways. |
| Related kinases | PIK3CA, PIK3CB, PIK3CD, PIK3CG, ATM, ATR, PRKDC (DNA-PK), MTOR. |
What Is GO:1904567?
In practical terms, GO:1904567 describes the collection of cellular and organismal responses triggered when a cell encounters wortmannin. The QuickGO definition states: Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a wortmannin stimulus. This is a response-to-chemical term, so it is used to annotate experimental findings where wortmannin is the external stimulus and the measured output is a biological process change, such as inhibition of platelet responses, altered DNA double-strand break repair, or changes in secreted protein release.
Why Is response to wortmannin Important in Cell Biology?
Understanding response to wortmannin is important because wortmannin remains a standard tool for interrogating PI3K and PIKK signaling in cancer, immunology, neuroscience, and platelet biology. The term provides a controlled vocabulary for annotating experiments in which wortmannin is used to perturb signaling, allowing researchers to compare results across studies and to link pharmacological inhibition to specific biological outcomes such as DNA repair, autophagy, secretion, and cell survival.
• Provides a standardized GO annotation for experiments using wortmannin as a PI3K/PIKK inhibitor.
• Links wortmannin exposure to DNA double-strand break repair and telomerase activation responses.
• Captures wortmannin-sensitive platelet activation and pleckstrin phosphorylation.
• Relevant to DNA damage checkpoint signaling through ATM and Med1/TRAP220 phosphorylation.
• Used in autophagy research to modulate PI3K-dependent autophagic flux.
• Relevant to amyloid precursor protein secretion in platelets.
• Relevant to neutrophil superoxide generation and inflammatory signaling.
• Supports drug-target validation when combined with CRISPR knockout of PI3K genes.
• Helps interpret off-target or class effects of PI3K inhibitors in preclinical models.
• Enables cross-study comparison of wortmannin-sensitive pathways in cancer and immune cells.
What Happens During response to wortmannin?
Wortmannin exposure and PI3K inhibition
In simple terms: Wortmannin enters the cell and blocks PI3K enzymes, which are lipid kinases that normally generate PIP3 to drive survival and growth signals.
Wortmannin is a steroidal fungal metabolite that covalently modifies the catalytic subunit of phosphoinositide 3-kinases (PI3Ks), leading to irreversible inhibition of PI3K activity. Because PI3K activity is required for many downstream responses, wortmannin exposure rapidly changes the state of cells, including suppression of pleckstrin phosphorylation in platelets and inhibition of neutrophil superoxide generation. These early biochemical changes define the initial phase of the response to wortmannin.
Downstream signaling and secretion changes
In simple terms: When PI3K is blocked, cells change what they secrete and how they respond to other stimuli.
Wortmannin alters secretion and enzyme production in multiple cell types. In human platelets stimulated with thrombin, wortmannin affects the release of secreted beta-amyloid precursor protein, indicating that PI3K-dependent pathways contribute to regulated secretion. In neutrophils, wortmannin suppresses superoxide generation in response to tumor necrosis factor-alpha and antibodies against CD18 and CD11a, showing that the response to wortmannin includes inhibition of inflammatory effector functions.
DNA damage response and repair modulation
In simple terms: Wortmannin also inhibits kinases related to PI3K that control DNA repair, so cells respond differently to DNA damage.
Wortmannin inhibits PIKK family members such as ATM, ATR, and DNA-PK, which are central to DNA damage signaling and repair. Activation of telomerase by ionizing radiation is differentially affected by wortmannin compared with other inhibitors, indicating that wortmannin-sensitive pathways modulate telomerase and DNA double-strand break repair. ATM is activated in response to N-methyl-N'-nitro-N-nitrosoguanidine-induced DNA alkylation, and wortmannin can blunt such checkpoint responses. Checkpoint-dependent phosphorylation of Med1/TRAP220 in response to DNA damage is also part of this regulatory network.
Autophagy and metabolic responses
In simple terms: Wortmannin can change autophagy, the cell's recycling system, because PI3K signaling controls autophagic flux.
Quantitative and temporal measurement of dynamic autophagy rates has been used to study how PI3K inhibitors such as wortmannin affect autophagic flux. Because autophagy is sensitive to PI3K class III activity, wortmannin exposure can alter autophagosome formation and degradation rates, making response to wortmannin relevant to studies of cellular stress, nutrient sensing, and protein homeostasis.
Cell-type-specific outcomes
In simple terms: Different cells respond to wortmannin in different ways depending on which PI3K isoforms and receptors they express.
In human squamous and epidermoid carcinoma cells, caveolin-1 phosphorylation depends on ErbB1 expression and Src activation, and wortmannin can modulate these signaling events. In platelets, wortmannin suppresses responses to multiple stimuli due to inhibition of pleckstrin phosphorylation. These examples show that the response to wortmannin is context-dependent and shaped by the expressed repertoire of PI3K isoforms, receptor tyrosine kinases, and downstream effectors.
Key Genes Involved in GO:1904567 response to wortmannin
The following genes and proteins are experimentally linked to wortmannin-sensitive pathways and are commonly studied in the context of GO:1904567.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PIK3CA | Catalytic subunit of PI3K alpha; primary wortmannin target | Wortmannin inhibition of PI3K alpha blocks AKT signaling; key in cancer |
| PIK3CB | Catalytic subunit of PI3K beta | Wortmannin-sensitive PI3K beta signaling in platelets and immune cells |
| PIK3CD | Catalytic subunit of PI3K delta | Wortmannin inhibits PI3K delta in leukocytes; relevant to inflammation |
| PIK3CG | Catalytic subunit of PI3K gamma | Wortmannin-sensitive neutrophil and platelet responses |
| ATM | PIKK kinase activated by DNA damage | Wortmannin inhibits ATM-dependent checkpoint signaling |
| ATR | PIKK kinase in replication stress response | Wortmannin can inhibit ATR-related repair pathways |
| PRKDC | DNA-PK catalytic subunit; PIKK family | Wortmannin inhibits DNA-PK, affecting double-strand break repair |
| MTOR | PI3K-related kinase controlling growth and autophagy | Wortmannin indirectly modulates mTORC1 signaling and autophagy |
| AKT1 | Serine/threonine kinase downstream of PI3K | Wortmannin blocks AKT activation; central to survival signaling |
| SRC | Non-receptor tyrosine kinase | Wortmannin-sensitive Src-dependent caveolin-1 phosphorylation |
| CAV1 | Caveolar scaffolding protein | Phosphorylation depends on ErbB1 and Src and is modulated by wortmannin |
| EGFR (ERBB1) | Receptor tyrosine kinase | ErbB1 expression determines caveolin-1 phosphorylation response |
| TERT | Telomerase reverse transcriptase | Telomerase activation after radiation is differentially affected by wortmannin |
| PLEK | Pleckstrin; PKC substrate in platelets | Wortmannin suppresses pleckstrin phosphorylation |
| APP | Amyloid precursor protein | Wortmannin affects secreted APP release from platelets |
| MED1 (TRAP220) | Mediator subunit phosphorylated after DNA damage | Checkpoint-dependent phosphorylation modulated by wortmannin-sensitive kinases |
| ITGB2 (CD18) | Integrin beta-2 subunit | Wortmannin-sensitive neutrophil superoxide generation via CD18 |
| ITGAL (CD11a) | Integrin alpha-L subunit | Wortmannin-sensitive neutrophil responses via CD11a |
How Is response to wortmannin Regulated?
The response to wortmannin is regulated by the availability and activity of its primary targets, the PI3K enzymes and PIKK family kinases. Because wortmannin acts as an irreversible covalent inhibitor, the duration and magnitude of the response depend on target protein turnover and on the cell's capacity to synthesize new PI3K or PIKK molecules. Downstream regulation involves AKT1, mTOR, and checkpoint kinases such as ATM and ATR, which integrate PI3K-dependent signals with DNA damage and metabolic cues. In platelets and neutrophils, the response is further modulated by receptor tyrosine kinases, integrins, and Src-family kinases that operate upstream or parallel to PI3K.
response to wortmannin and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| PIK3CA | PI3K-driven cancers | PIK3CA knockout or point-mutation cancer cell lines treated with wortmannin |
| ATM | DNA damage response and genomic instability | ATM knockout cells with wortmannin and radiation treatment |
| PRKDC | DNA repair deficiency | PRKDC knockout cells to test wortmannin sensitivity |
| PLEK | Platelet activation disorders | PLEK knockout platelet-like cells with wortmannin |
| ITGB2 | Leukocyte adhesion deficiency and inflammation | ITGB2 knockout neutrophils or HL-60-derived cells with wortmannin |
Cancer and PI3K pathway dependencies
Wortmannin is widely used to study PI3K-dependent cancer cell survival because it inhibits PIK3CA, PIK3CB, PIK3CD, and PIK3CG, thereby blocking AKT1 activation and downstream growth signals. Cancer cells with activating mutations in PI3K pathway genes often show altered sensitivity to wortmannin, making the response to wortmannin a useful readout for pathway dependency and drug-target validation.
DNA damage response and genomic instability
Because wortmannin inhibits ATM, ATR, and DNA-PK, it modulates DNA double-strand break repair and checkpoint signaling. This links response to wortmannin to genomic instability, telomerase regulation, and cellular sensitivity to radiation or alkylating agents such as N-methyl-N'-nitro-N-nitrosoguanidine.
Platelet and inflammatory disorders
Wortmannin suppresses platelet responses to stimuli by inhibiting pleckstrin phosphorylation and affects secreted beta-amyloid precursor protein release. In neutrophils, wortmannin inhibits superoxide generation triggered by TNF-alpha and integrin engagement, connecting the response to wortmannin with inflammatory and thrombotic biology.
From response to wortmannin-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is PIK3CA required for wortmannin-induced AKT inhibition? | PIK3CA knockout cell line |
| Does a specific PI3K point mutation alter wortmannin sensitivity? | PIK3CA point-mutation knock-in cell line |
| Can a tagged PI3K allele report wortmannin binding and turnover? | Tagged knock-in of PIK3CA |
| Does ATM loss change the response to wortmannin after DNA damage? | ATM knockout with radiation or alkylating agent |
| Does overexpression of SRC enhance wortmannin-sensitive caveolin-1 phosphorylation? | SRC overexpression cell line |
| Can CRISPR library screening identify modifiers of wortmannin response? | Genome-wide CRISPR knockout library screening |
How to Study the response to wortmannin Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Western blot for phospho-AKT | PI3K-dependent AKT activation | Testing wortmannin inhibition of survival signaling |
| Pleckstrin phosphorylation assay | PKC substrate phosphorylation in platelets | Measuring wortmannin suppression of platelet responses |
| Superoxide generation assay | Neutrophil oxidative burst | Testing wortmannin sensitivity of inflammatory signaling |
| Telomerase activity assay | Telomerase activation after radiation | Evaluating wortmannin effects on DNA repair and telomerase |
| Checkpoint phosphorylation immunoblot | ATM/ATR-dependent phosphorylation | Studying DNA damage response with wortmannin |
| Autophagy flux assay | Dynamic autophagy rates | Quantifying wortmannin effects on autophagic flux |
| Secreted APP ELISA | Release of beta-amyloid precursor protein | Measuring wortmannin effects on platelet secretion |
| Caveolin-1 phosphorylation immunoblot | Src/ErbB1-dependent phosphorylation | Testing wortmannin modulation of adhesion signaling |
Pharmacological and biochemical assays
Wortmannin response is commonly measured by treating cells with wortmannin and assaying PI3K-dependent readouts such as AKT phosphorylation, pleckstrin phosphorylation, or superoxide generation. These assays establish the baseline response and are often combined with receptor stimulation to test pathway specificity.
DNA damage and checkpoint assays
Because wortmannin inhibits ATM, ATR, and DNA-PK, researchers use DNA damage inducers such as ionizing radiation or N-methyl-N'-nitro-N-nitrosoguanidine and then measure checkpoint phosphorylation, telomerase activation, or repair foci in the presence or absence of wortmannin.
Autophagy flux measurement
Quantitative and temporal measurement of dynamic autophagy rates allows researchers to determine how wortmannin alters autophagosome formation and degradation. These methods are useful for distinguishing changes in autophagic flux from changes in autophagosome number.
Secretion and platelet function assays
Wortmannin effects on secretion can be measured by detecting released proteins such as beta-amyloid precursor protein from thrombin-stimulated platelets. Platelet aggregation and pleckstrin phosphorylation assays provide additional functional readouts of the response to wortmannin.
How CRISPR Can Be Used to Study GO:1904567 response to wortmannin
Knockout
CRISPR knockout of PI3K genes (PIK3CA, PIK3CB, PIK3CD, PIK3CG) or PIKK genes (ATM, ATR, PRKDC) can be used to determine which targets mediate the response to wortmannin. Comparing knockout cells with wild-type cells treated with wortmannin helps distinguish on-target from off-target effects.
Point Mutation
Point-mutation knock-in of residues in PI3K catalytic domains can test whether specific amino acids are required for wortmannin sensitivity. Such models are useful for dissecting covalent inhibition mechanisms and for validating drug-target interactions.
Knock-in
Tagged knock-in of PI3K or PIKK genes allows tracking of protein localization, turnover, and interaction partners after wortmannin treatment. This approach supports mechanistic studies of how cells respond to wortmannin at the protein level.
Overexpression
Overexpression of candidate genes such as SRC, CAV1, or EGFR (ERBB1) can enhance or modify wortmannin-sensitive signaling outputs, helping to map the pathways that shape the response to wortmannin.
How EDITGENE Supports response to wortmannin Research
Researchers studying response to wortmannin-related genes often need to determine whether a candidate gene is causally involved in the cellular response to wortmannin or simply correlated with it. CRISPR-based cell models provide a rigorous way to test causality by removing, mutating, tagging, or overexpressing the gene of interest and measuring the resulting change in wortmannin sensitivity.
Contact EDITGENE today to design your custom CRISPR model for response to wortmannin research.
Frequently Asked Questions About response to wortmannin
What is GO:1904567 response to wortmannin?
GO:1904567 is a Gene Ontology biological_process term defined as any process that results in a change in state or activity of a cell or an organism as a result of a wortmannin stimulus.
What is wortmannin and how does it work?
Wortmannin is a fungal steroidal metabolite that covalently inhibits phosphoinositide 3-kinases (PI3Ks) and related PIKK kinases such as ATM, ATR, and DNA-PK.
What genes are involved in response to wortmannin?
Key genes include PIK3CA, PIK3CB, PIK3CD, PIK3CG, ATM, ATR, PRKDC, MTOR, AKT1, SRC, CAV1, EGFR, TERT, PLEK, APP, MED1, ITGB2, and ITGAL.
How is response to wortmannin measured experimentally?
Common methods include phospho-AKT western blot, pleckstrin phosphorylation assays, superoxide generation assays, telomerase activity assays, checkpoint phosphorylation immunoblots, autophagy flux assays, and secreted APP ELISA.
Why is wortmannin used in cancer research?
Wortmannin is used to block PI3K/AKT survival signaling in cancer cells, helping researchers test pathway dependency and validate PI3K as a drug target.
Does wortmannin affect DNA repair?
Yes, wortmannin inhibits ATM, ATR, and DNA-PK, thereby modulating DNA double-strand break repair and checkpoint signaling after DNA damage.
Can CRISPR knockout help study response to wortmannin?
Yes, CRISPR knockout of PI3K or PIKK genes allows researchers to test which targets mediate the cellular response to wortmannin.
What cell types are used to study response to wortmannin?
Platelets, neutrophils, squamous and epidermoid carcinoma cells, and other PI3K-dependent cell lines are commonly used.
Is wortmannin the same as LY294002?
No, wortmannin and LY294002 are distinct PI3K inhibitors, though both have been used to study DNA double-strand break repair and PI3K signaling.
What GO aspect is GO:1904567?
GO:1904567 belongs to the biological_process aspect of the Gene Ontology.
Conclusion
GO:1904567 response to wortmannin provides a standardized way to annotate and interpret experiments using wortmannin as a PI3K/PIKK inhibitor. The term connects wortmannin exposure to diverse biological outcomes, including suppression of platelet responses, modulation of DNA repair and checkpoint signaling, changes in autophagy, and altered secretion. Researchers can use CRISPR knockout, point-mutation, knock-in, and overexpression models to test which genes causally shape the response to wortmannin and to translate these findings into cancer, inflammatory, and DNA repair biology.
References
- 1. Neuhof D et al.. 2007. Activation of telomerase by ionizing radiation: differential response to the inhibition of DNA double-strand break repair by abrogation of poly (ADP-ribosyl)ation, by LY294002, or by Wortmannin.. Int J Radiat Oncol Biol Phys 69(3):887-94 PMID: 17889269
- 2. Kim YN et al.. 2002. Caveolin-1 phosphorylation in human squamous and epidermoid carcinoma cells: dependence on ErbB1 expression and Src activation.. Exp Cell Res 280(1):134-47 PMID: 12372346
- 3. Yatomi Y et al.. 1992. Suppression by wortmannin of platelet responses to stimuli due to inhibition of pleckstrin phosphorylation.. Biochem J 285 ( Pt 3)(Pt 3):745-51 PMID: 1497612
- 4. Adamson AW et al.. 2002. ATM is activated in response to N-methyl-N'-nitro-N-nitrosoguanidine-induced DNA alkylation.. J Biol Chem 277(41):38222-9 PMID: 12151394
- 5. Beesabathuni NS et al.. 2023. Quantitative and temporal measurement of dynamic autophagy rates.. Autophagy 19(4):1164-1183 PMID: 36026492
- 6. Hedin HL et al.. 2001. Effects of staurosporine, U-73122, wortmannin, 4-hydroxynonenal and sodium azide upon the release of secreted beta-amyloid precursor protein from human platelets in response to thrombin stimulation.. Mol Cell Biochem 219(1-2):145-52 PMID: 11354246
- 7. Kim HJ et al.. 2017. Checkpoint-dependent phosphorylation of Med1/TRAP220 in response to DNA damage.. Acta Biochim Biophys Sin (Shanghai) 49(6):496-502 PMID: 28430840
- 8. Laudanna C et al.. 1993. Effect of inhibitors of distinct signalling pathways on neutrophil Q2- generation in response to tumor necrosis factor-alpha, and antibodies against CD18 and CD11a: evidence for a common and unique pattern of sensitivity to wortmannin and protein tyrosine kinase inhibitors.. Biochem Biophys Res Commun 190(3):935-40 PMID: 8094958
