GO:1902659 regulation of glucose mediated signaling pathway: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1902659 describes any process that modulates the frequency, rate or extent of glucose mediated signaling pathway, a biological process that translates glucose availability into cellular responses.
• Glucose mediated signaling is essential for metabolic homeostasis, and its dysregulation is linked to insulin resistance, type 2 diabetes, and cancer [1,2].
• Key regulators include GLUT4 (SLC2A4), AKT, PTEN, and RAB14, which control glucose uptake and downstream signaling [2,5,8].
• The pathway is regulated by exercise, insulin, and membrane raft-mediated mechanisms, influencing glucose transport and metabolism [1,7].
• Disease associations include diabetes, cancer, and myocardial metabolic disorders, making it a target for therapeutic intervention [5,6,8].
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) enable precise dissection of glucose signaling components [2,5].
Description
Glucose mediated signaling pathway is a fundamental biological process that converts glucose availability into intracellular signals, coordinating metabolism, growth, and survival. The regulation of this pathway (GO:1902659) encompasses any process that modulates its frequency, rate, or extent, ensuring appropriate cellular responses to fluctuating glucose levels. This regulation is critical for maintaining glucose homeostasis, and its disruption contributes to metabolic diseases such as type 2 diabetes and cancer [1,2]. Researchers study this term to understand how cells sense and respond to glucose, and to identify therapeutic targets for metabolic disorders [3,8]. The pathway involves glucose transporters (e.g., GLUT4), signaling kinases (e.g., AKT), and regulatory proteins (e.g., PTEN, RAB14) that collectively modulate glucose uptake and downstream effects [2,5,8]. Given its broad impact, GO:1902659 is a key node in metabolic research, with implications for exercise physiology, cancer biology, and neuroprotection [1,4,5].
regulation of glucose mediated signaling pathway At A Glance
| GO ID | GO:1902659 |
|---|---|
| GO term | regulation of glucose mediated signaling pathway |
| Ontology | biological_process |
| Synonym | regulation of glucose mediated signalling |
| Major function | Modulates the frequency, rate or extent of glucose mediated signaling pathway |
| Related pathways | Insulin signaling, glucose transport, exercise-stimulated glucose uptake |
| Key regulators | AKT, PTEN, RAB14, GLUT4, YAP/TAZ |
| Disease relevance | Diabetes, cancer, myocardial metabolic disorders |
What Is GO:1902659?
GO:1902659, regulation of glucose mediated signaling pathway, is defined as any process that modulates the frequency, rate or extent of glucose mediated signaling pathway. In other words, it includes all molecular events that adjust how glucose signals are transmitted within cells, affecting processes such as glucose uptake, metabolism, and gene expression.
Why Is regulation of glucose mediated signaling pathway Important in Cell Biology?
Regulation of glucose mediated signaling pathway is crucial because it ensures that cells adapt to changing glucose levels, which is vital for energy balance and survival. Dysregulation of this process is a hallmark of insulin resistance, type 2 diabetes, and various cancers, where altered glucose signaling promotes uncontrolled growth and metabolic reprogramming [2,5,8]. Understanding this regulation provides insights into exercise-induced glucose uptake, myocardial metabolism, and even sperm function, highlighting its broad physiological significance [1,6,7].
• Maintains glucose homeostasis by adjusting cellular responses to glucose availability.
• Dysregulation leads to insulin resistance and type 2 diabetes [1,2].
• Plays a role in cancer development through PTEN and AKT signaling.
• Influences myocardial glucose metabolism via YAP/TAZ signaling.
• Regulates exercise-stimulated glucose uptake, impacting glycaemic control.
• Involved in membrane raft-mediated acrosome reaction in sperm.
• Modulated by the mevalonate pathway via RAB14 geranylgeranylation.
• Target for therapeutic interventions in metabolic disorders [3,8].
• Provides insights into evolutionary conservation of glucose signaling.
• Enables precise CRISPR-based dissection of signaling components [2,5].
What Happens During regulation of glucose mediated signaling pathway?
Glucose Sensing and Transport
In simple terms: Cells detect glucose and take it in through specialized transporter proteins.
Glucose mediated signaling begins with glucose sensing and transport across the plasma membrane, primarily via glucose transporters such as GLUT4 (SLC2A4). In muscle and adipose tissue, insulin stimulates GLUT4 translocation to the membrane, increasing glucose uptake [1,2]. This step is regulated by exercise and membrane raft-mediated mechanisms, which modulate transporter availability and activity [1,7].
Insulin Signaling Cascade
In simple terms: Insulin triggers a chain of molecular signals that help cells use glucose.
Upon insulin binding, the insulin receptor activates a signaling cascade involving IRS proteins, PI3K, and AKT [1,8]. AKT phosphorylation is critical for GLUT4 translocation and glucose uptake. This cascade is regulated by PTEN, a lipid phosphatase that opposes PI3K signaling, and by RAB14 geranylgeranylation, which modulates AKT phosphorylation [5,8].
Downstream Metabolic Effects
In simple terms: Glucose signals change how cells make and use energy.
Activated AKT promotes glucose metabolism, glycogen synthesis, and protein synthesis while inhibiting gluconeogenesis [1,3]. In Drosophila, FoxO-Pepck axis regulation of glucose homeostasis is mediated by insulin signaling, highlighting evolutionary conservation. These downstream effects are modulated by YAP/TAZ signaling in the heart, affecting myocardial glucose metabolism.
Regulation by Exercise and Membrane Rafts
In simple terms: Physical activity and special membrane regions can tweak glucose signaling.
Exercise stimulates glucose uptake through insulin-independent mechanisms, involving AMPK and membrane raft-mediated signaling [1,7]. In chicken sperm, membrane raft-mediated regulation of glucose signaling leads to acrosome reaction, demonstrating specialized roles. These regulatory inputs ensure glucose signaling adapts to physiological demands.
Feedback and Crosstalk
In simple terms: Glucose signaling talks to other pathways to keep things balanced.
Glucose mediated signaling intersects with other pathways, such as the mevalonate pathway, which orchestrates insulin signaling via RAB14 geranylgeranylation. PTEN neddylation regulates its nuclear import and tumor development, adding another layer of control. Such crosstalk fine-tunes glucose homeostasis and prevents metabolic overload [5,8].
Key Genes Involved in GO:1902659 regulation of glucose mediated signaling pathway
The following genes and proteins are central to the regulation of glucose mediated signaling pathway, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SLC2A4 (GLUT4) | Insulin-responsive glucose transporter | Key marker of glucose uptake in muscle and fat |
| AKT1 | Serine/threonine kinase mediating insulin signaling | Central node in glucose metabolism and cancer |
| PTEN | Lipid phosphatase opposing PI3K signaling | Tumor suppressor, regulates glucose signaling |
| RAB14 | GTPase involved in vesicle trafficking | Geranylgeranylation regulates AKT phosphorylation |
| IRS1 | Insulin receptor substrate | Adaptor in insulin signaling cascade |
| PIK3CA | Catalytic subunit of PI3K | Generates PIP3 to activate AKT |
| FOXO1 | Transcription factor regulating gluconeogenesis | Target of insulin signaling |
| PCK1 (PEPCK) | Gluconeogenic enzyme | Regulated by FoxO in glucose homeostasis |
| YAP1 | Transcriptional co-activator | Regulates myocardial glucose metabolism |
| WWTR1 (TAZ) | Transcriptional co-activator | Partners with YAP in glucose regulation |
| NRF2 | Transcription factor in oxidative stress | Linked to glucose signaling in neuroprotection |
| HO-1 | Heme oxygenase-1 | Downstream of NRF2 in ferroptosis inhibition |
| AMPK | Energy sensor kinase | Mediates exercise-stimulated glucose uptake |
| TBC1D4 (AS160) | Rab GTPase-activating protein | Regulates GLUT4 translocation |
| RAC1 | Rho GTPase | Involved in membrane raft signaling |
| INSR | Insulin receptor | Initiates insulin signaling cascade |
| SLC2A1 (GLUT1) | Basal glucose transporter | Maintains basal glucose uptake |
How Is regulation of glucose mediated signaling pathway Regulated?
The regulation of glucose mediated signaling pathway is multifaceted. Insulin is the primary hormonal regulator, activating the PI3K-AKT cascade to promote glucose uptake. Exercise stimulates glucose uptake via AMPK, independent of insulin. PTEN negatively regulates the pathway by dephosphorylating PIP3, and its activity is modulated by neddylation, affecting nuclear import and tumor development. The mevalonate pathway regulates insulin signaling through RAB14 geranylgeranylation, which influences AKT phosphorylation. Additionally, YAP/TAZ signaling modulates myocardial glucose metabolism, and membrane raft-mediated mechanisms control glucose signaling in specialized cells [6,7]. These regulatory layers ensure precise control of glucose homeostasis.
regulation of glucose mediated signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| PTEN | Cancer, insulin resistance | Knockout and point mutation models |
| AKT1 | Diabetes, cancer | Overexpression and knock-in models |
| SLC2A4 (GLUT4) | Type 2 diabetes | Knockout and tagged knock-in |
| RAB14 | Hepatic glucose metabolism, cancer | Knockout and point mutation |
| YAP1 | Cardiomyopathy | Knockout and overexpression |
Diabetes and Insulin Resistance
Impaired regulation of glucose mediated signaling pathway is a hallmark of type 2 diabetes. Defects in insulin signaling, GLUT4 translocation, or AKT activation lead to reduced glucose uptake and hyperglycemia [1,2]. PTEN overactivity or RAB14 dysregulation can exacerbate insulin resistance [5,8]. Understanding these mechanisms is vital for developing therapies that restore glucose homeostasis.
Cancer
Cancer cells often reprogram glucose metabolism to support rapid growth. PTEN mutations, which activate PI3K-AKT signaling, are common in many cancers and promote glucose uptake and tumor development. RAB14 geranylgeranylation also contributes to hepatic glucose metabolism and cancer progression. Targeting glucose signaling pathways is a promising therapeutic strategy [5,8].
Cardiovascular and Neuroprotective Roles
YAP/TAZ signaling regulates myocardial glucose metabolism, and its dysregulation is linked to heart disease. In cerebral ischemia-reperfusion injury, NRF2/HO-1 signaling, which intersects with glucose metabolism, inhibits ferroptosis-mediated neuroinflammation. These findings highlight the broad impact of glucose signaling beyond metabolic tissues [4,6].
From regulation of glucose mediated signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X regulate glucose uptake? | Knockout cell line (e.g., SLC2A4 KO) |
| Does a specific mutation affect AKT phosphorylation? | Point mutation knock-in (e.g., AKT1 mutants) |
| How does PTEN neddylation affect glucose signaling? | Knock-in of neddylation-deficient PTEN |
| Can overexpression of RAB14 enhance insulin signaling? | Overexpression cell model |
| What is the role of YAP/TAZ in myocardial glucose metabolism? | Knockout and overexpression in cardiomyocytes |
| Does membrane raft disruption affect glucose signaling? | Knockout of raft components |
How to Study the regulation of glucose mediated signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcriptional changes | Identify glucose signaling regulators |
| CRISPR screening | Gene essentiality and function | Discover novel pathway components |
| Phosphoproteomics | Phosphorylation events | Map AKT signaling |
| Glucose uptake assay | Functional glucose transport | Validate GLUT4 translocation |
| Western blot | Protein expression and phosphorylation | Assess AKT, PTEN levels |
| Immunofluorescence | Subcellular localization | Visualize GLUT4 translocation |
| Metabolic flux analysis | Glycolysis and oxidative phosphorylation | Measure metabolic reprogramming |
Genomic and Transcriptomic Approaches
RNA-seq and CRISPR screening can identify regulators of glucose mediated signaling. For example, knockout of candidate genes followed by RNA-seq reveals transcriptional changes in glucose metabolism pathways [5,8]. These methods are essential for unbiased discovery of novel regulators.
Proteomic and Phosphoproteomic Analysis
Mass spectrometry-based proteomics quantifies changes in protein abundance and phosphorylation, such as AKT phosphorylation, in response to genetic perturbations. This approach helps map signaling cascades downstream of glucose sensing.
Metabolic Assays
Glucose uptake assays using radiolabeled 2-deoxyglucose or fluorescent analogs measure functional changes in glucose transport. These are standard for validating GLUT4 translocation and insulin sensitivity.
Imaging and Live-Cell Analysis
Fluorescence microscopy of tagged GLUT4 or AKT allows real-time visualization of translocation and signaling dynamics. Membrane raft integrity can be assessed using cholesterol depletion agents.
How CRISPR Can Be Used to Study GO:1902659 regulation of glucose mediated signaling pathway
Knockout
CRISPR knockout of genes such as SLC2A4, AKT1, or PTEN enables loss-of-function studies to determine their necessity in glucose mediated signaling. For example, GLUT4 knockout cells show impaired glucose uptake, confirming its role. PTEN knockout leads to hyperactive AKT signaling and altered glucose metabolism.
Point Mutation
Introducing specific point mutations (e.g., AKT1 E17K, PTEN C124S) via CRISPR knock-in allows precise dissection of signaling domains. Such models reveal how individual residues affect glucose signaling and downstream effects [5,8].
Knock-in
Tagged knock-in of GLUT4 or AKT with fluorescent proteins enables live-cell imaging of translocation and localization. Knock-in of disease-associated variants helps model human mutations in glucose signaling [2,5].
Overexpression
CRISPR activation or cDNA overexpression of RAB14 or AKT1 can enhance glucose signaling, useful for gain-of-function studies. Overexpression models help identify sufficiency and potential therapeutic targets.
How EDITGENE Supports regulation of glucose mediated signaling pathway Research
Researchers studying regulation of glucose mediated signaling pathway-related genes often need to determine whether a candidate gene is causally involved in glucose sensing, transport, or downstream signaling. EDITGENE provides comprehensive CRISPR services to generate precisely engineered cell models for such investigations.
Contact EDITGENE today to design your custom CRISPR model for regulation of glucose mediated signaling pathway research.
Frequently Asked Questions About regulation of glucose mediated signaling pathway
What is GO:1902659?
GO:1902659 is the Gene Ontology term for regulation of glucose mediated signaling pathway, defined as any process that modulates the frequency, rate or extent of glucose mediated signaling pathway.
What genes are involved in regulation of glucose mediated signaling pathway?
Key genes include SLC2A4 (GLUT4), AKT1, PTEN, RAB14, IRS1, and PIK3CA, among others [2,5,8].
How is glucose mediated signaling regulated?
It is regulated by insulin, exercise, PTEN, RAB14 geranylgeranylation, and membrane raft-mediated mechanisms [1,5,7,8].
What diseases are associated with dysregulation of glucose mediated signaling?
Dysregulation is linked to type 2 diabetes, cancer, and cardiovascular disorders [1,2,5,6].
What is the role of GLUT4 in glucose signaling?
GLUT4 is an insulin-responsive glucose transporter that mediates glucose uptake in muscle and adipose tissue.
How does PTEN regulate glucose signaling?
PTEN opposes PI3K signaling by dephosphorylating PIP3, thereby inhibiting AKT activation and glucose uptake.
What is the impact of exercise on glucose mediated signaling?
Exercise stimulates glucose uptake via AMPK, independent of insulin, improving glycaemic control.
How can CRISPR be used to study glucose signaling?
CRISPR knockout, point mutation, knock-in, and overexpression models allow precise manipulation of genes like AKT1 and PTEN to dissect their roles [2,5,8].
What is the role of RAB14 in glucose metabolism?
RAB14 geranylgeranylation regulates AKT phosphorylation and hepatic glucose metabolism.
What methods are used to study regulation of glucose mediated signaling?
Common methods include RNA-seq, phosphoproteomics, glucose uptake assays, and CRISPR screening [1,2,8].
Conclusion
Regulation of glucose mediated signaling pathway (GO:1902659) is a critical biological process that integrates glucose sensing with cellular responses, impacting metabolism, growth, and survival. Its dysregulation underlies major diseases such as diabetes and cancer, making it a prime target for therapeutic intervention [2,5,8]. Advances in CRISPR technology and multi-omics approaches continue to unravel the complex regulatory networks, offering new opportunities for drug discovery and precision medicine [1,5].
References
- 1. Sylow L et al.. 2017. Exercise-stimulated glucose uptake - regulation and implications for glycaemic control.. Nat Rev Endocrinol 13(3):133-148 PMID: 27739515
- 2. Huang S et al.. 2007. The GLUT4 glucose transporter.. Cell Metab 5(4):237-52 PMID: 17403369
- 3. Zang S et al.. 2024. Insulin Signaling Pathway Mediates FoxO-Pepck Axis Regulation of Glucose Homeostasis in Drosophila suzukii.. Int J Mol Sci 25(19) PMID: 39408770
- 4. Zhang Y et al.. 2024. Neutral polysaccharide from Gastrodia elata alleviates cerebral ischemia-reperfusion injury by inhibiting ferroptosis-mediated neuroinflammation via the NRF2/HO-1 signaling pathway.. CNS Neurosci Ther 30(3):e14456 PMID: 37752806
- 5. Xie P et al.. 2021. Neddylation of PTEN regulates its nuclear import and promotes tumor development.. Cell Res 31(3):291-311 PMID: 33299139
- 6. Kashihara T et al.. 2024. Regulation of myocardial glucose metabolism by YAP/TAZ signaling.. J Cardiol 83(5):323-329 PMID: 38266816
- 7. Ushiyama A et al.. 2019. Membrane raft-mediated regulation of glucose signaling pathway leading to acrosome reaction in chicken sperm†.. Biol Reprod 100(6):1482-1491 PMID: 30721935
- 8. Wang L et al.. 2022. Mevalonate pathway orchestrates insulin signaling via RAB14 geranylgeranylation-mediated phosphorylation of AKT to regulate hepatic glucose metabolism.. Metabolism 128:155120 PMID: 34995578
