GO:0004340 glucokinase activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0004340 glucokinase activity is defined as catalysis of the reaction ATP + D-glucose = ADP + D-glucose-6-phosphate, making it the first committed step of glucose phosphorylation in cells.
• Glucokinase (GCK) is a hexokinase-family enzyme with a high Km for glucose, positioning it as a glucose sensor in pancreatic beta cells and hepatocytes.
• Mutations in GCK cause a spectrum of glycemic disorders including maturity-onset diabetes of the young (MODY2), permanent neonatal diabetes, and hyperinsulinemic hypoglycemia.
• Glucokinase activators (GKA) such as dorzagliatin have been developed as antidiabetic therapies, and their structure-activity relationships are well characterized.
• Beyond canonical glucose phosphorylation, glucokinase can translocate to the nucleus and act as a protein kinase, phosphorylating TAZ to promote tumour growth.
• ADP-dependent glucokinase (ADPGK) supports metabolic fitness in prostate cancer, illustrating context-dependent roles of glucokinase activity in malignancy.
Description
Glucokinase activity (GO:0004340) is a molecular function that catalyzes the phosphorylation of D-glucose to D-glucose-6-phosphate using ATP as the phosphate donor. This reaction is the first committed step in glycolysis and glycogen synthesis, and it is essential for maintaining glucose homeostasis in organisms ranging from bacteria to humans. Unlike other hexokinases, glucokinase has a low affinity for glucose and is not inhibited by its product, glucose-6-phosphate, which allows it to respond to fluctuations in blood glucose concentration. The enzyme is predominantly expressed in pancreatic beta cells and hepatocytes, where it functions as a glucose sensor that couples glucose availability to insulin secretion and glucose metabolism, respectively. Because of this central role, glucokinase activity is a major focus in diabetes research, and both loss-of-function and gain-of-function mutations have been linked to human disease. In recent years, additional roles for glucokinase have emerged, including nuclear translocation and protein kinase activity that can influence tumour growth and metabolic reprogramming. Understanding the molecular mechanism, regulation, and disease relevance of glucokinase activity is therefore critical for researchers in metabolism, endocrinology, and oncology.
glucokinase activity At A Glance
| GO ID | GO:0004340 |
|---|---|
| GO term | glucokinase activity |
| Ontology | molecular_function |
| Synonym | ATP:D-glucose 6-phosphotransferase activity; glucokinase (phosphorylating); glucose kinase activity |
| Definition | Catalysis of the reaction: ATP + D-glucose = ADP + D-glucose-6-phosphate. |
| Major function | Phosphorylation of glucose as the first step of glycolysis and glucose sensing. |
| Representative enzyme | Glucokinase (GCK), a hexokinase IV family member. |
| Tissue distribution | Pancreatic beta cells, hepatocytes, and some neuroendocrine cells. |
| Kinetic property | High Km for glucose (low affinity) and no product inhibition by glucose-6-phosphate. |
What Is GO:0004340?
According to the Gene Ontology, GO:0004340 glucokinase activity is defined as the catalysis of the reaction ATP + D-glucose = ADP + D-glucose-6-phosphate. In other words, it is the enzyme activity that transfers a phosphate group from ATP to the C6 hydroxyl of D-glucose, producing ADP and D-glucose-6-phosphate. This activity is synonymous with ATP:D-glucose 6-phosphotransferase activity, glucokinase (phosphorylating), and glucose kinase activity. It is a molecular_function term that describes the catalytic capability of a protein, typically a hexokinase-family enzyme, and is distinct from the broader hexokinase activity (GO:0004396) because glucokinase exhibits a lower affinity for glucose and is not feedback-inhibited by glucose-6-phosphate.
Why Is glucokinase activity Important in Cell Biology?
Glucokinase activity is a cornerstone of glucose homeostasis because it determines the rate of glucose entry into glycolysis and glycogen synthesis in key metabolic tissues. In pancreatic beta cells, it acts as the glucose sensor that triggers insulin secretion, while in hepatocytes it regulates glucose uptake and storage. Dysregulation of this activity is directly linked to monogenic diabetes and hyperinsulinism, and pharmacological activation or inhibition is a validated therapeutic strategy. Moreover, emerging evidence shows that glucokinase can function beyond canonical glucose phosphorylation, including nuclear roles in tumour promotion, making it a versatile target for metabolic and cancer research.
• Glucokinase activity is the rate-limiting step for glucose utilization in hepatocytes and pancreatic beta cells.
• Mutations in GCK cause MODY2, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia.
• Glucokinase activators such as dorzagliatin are approved or in development for type 2 diabetes.
• The enzyme's high Km allows it to sense glucose concentrations within the physiological range.
• Nuclear-translocated glucokinase can phosphorylate TAZ, promoting tumour growth in cancer models.
• ADP-dependent glucokinase (ADPGK) supports metabolic fitness in prostate cancer progression.
• Glucokinase activity is regulated by glucokinase regulatory protein (GKRP) in the liver.
• ChREBP, a transcription factor, is activated by reductive stress and mediates GCKR-associated metabolic traits.
• Small-molecule glucokinase activators have been optimized through structure-activity relationship studies.
• Glucokinase activity is a biomarker and therapeutic target in both diabetes and cancer research.
What Happens During glucokinase activity?
Substrate binding and glucose phosphorylation
In simple terms: Glucokinase grabs a glucose molecule and attaches a phosphate group to it, using ATP as the phosphate donor.
The catalytic cycle begins with the binding of D-glucose and Mg2+-ATP to the glucokinase active site. Glucokinase catalyzes the transfer of the gamma-phosphate from ATP to the C6 hydroxyl group of D-glucose, yielding ADP and D-glucose-6-phosphate. This reaction is the first committed step in glycolysis and is essential for glucose sensing in pancreatic beta cells and hepatocytes. The enzyme exhibits a high Km for glucose, meaning it only becomes fully active at higher glucose concentrations, which is critical for its role as a glucose sensor.
Conformational change and kinetic cooperativity
In simple terms: The enzyme changes shape when it binds glucose, which allows it to respond to glucose levels in a switch-like manner.
Glucokinase displays positive cooperativity with glucose, a property that arises from a conformational transition between a super-open and a closed state upon glucose binding. This kinetic behavior is not observed in other hexokinases and is central to its function as a glucose sensor. The enzyme's activity is not inhibited by physiological concentrations of glucose-6-phosphate, allowing continuous flux when glucose is abundant. These unique kinetic properties make glucokinase a critical regulator of glucose-stimulated insulin secretion in beta cells.
Nuclear translocation and non-canonical protein kinase activity
In simple terms: Glucokinase can move into the cell nucleus and act as a different type of enzyme that modifies other proteins.
Recent studies have shown that glucokinase can translocate to the nucleus, where it functions as a protein kinase to phosphorylate TAZ (WWTR1), a transcriptional co-activator involved in cell proliferation and tumour growth. This nuclear role is distinct from its canonical glucose-phosphorylating activity and highlights the multifunctional nature of the enzyme. The phosphorylation of TAZ by nuclear glucokinase promotes tumour growth in cancer models, suggesting that glucokinase activity can contribute to oncogenesis beyond metabolic reprogramming.
Regulation by glucokinase regulatory protein (GKRP)
In simple terms: In the liver, a partner protein called GKRP can hold glucokinase back or release it depending on glucose levels.
In hepatocytes, glucokinase is regulated by the glucokinase regulatory protein (GKRP), which binds to glucokinase in the nucleus and inhibits its activity under low-glucose conditions. When glucose levels rise, glucokinase is released from GKRP and translocates to the cytoplasm to phosphorylate glucose. This regulatory mechanism is critical for maintaining hepatic glucose homeostasis, and genetic variants in GCKR (encoding GKRP) are associated with altered metabolic traits. ChREBP, a transcription factor activated by reductive stress, mediates some of the metabolic effects linked to GCKR variants.
ADP-dependent glucokinase in cancer metabolism
In simple terms: Some cancer cells use a different version of glucokinase that uses ADP instead of ATP to phosphorylate glucose.
ADP-dependent glucokinase (ADPGK) is an enzyme that catalyzes the phosphorylation of glucose using ADP as the phosphate donor, and it has been implicated in metabolic fitness of prostate cancer cells. Unlike canonical glucokinase, ADPGK operates under anaerobic or hypoxic conditions and supports glycolytic flux in cancer cells. Knockdown of ADPGK impairs prostate cancer progression, indicating that this alternative glucokinase activity is important for tumour metabolism. This finding expands the functional landscape of glucokinase activity beyond the classical ATP-dependent reaction.
Key Genes Involved in GO:0004340 glucokinase activity
The following genes and proteins are directly or indirectly involved in glucokinase activity, its regulation, and its downstream metabolic effects.
| Gene | Major Role | Research Relevance |
|---|---|---|
| GCK | Encodes glucokinase, the enzyme that catalyzes glucose phosphorylation | Mutations cause MODY2, neonatal diabetes, and hyperinsulinism |
| GCKR | Encodes glucokinase regulatory protein (GKRP), which inhibits glucokinase in the liver | Variants associated with metabolic traits and ChREBP activation |
| ADPGK | Encodes ADP-dependent glucokinase, an alternative glucose-phosphorylating enzyme | Supports metabolic fitness in prostate cancer |
| TAZ (WWTR1) | Transcriptional co-activator phosphorylated by nuclear glucokinase | Promotes tumour growth downstream of glucokinase |
| ChREBP (MLXIPL) | Transcription factor activated by reductive stress, mediates GCKR-associated traits | Links glucokinase regulatory pathway to lipogenesis |
| HNF1A | Transcription factor regulating GCK expression in beta cells | Mutations cause MODY3, overlapping with GCK-MODY |
| HNF4A | Transcription factor regulating GCK expression in hepatocytes | Mutations cause MODY1 |
| INS | Insulin gene, downstream of glucokinase-mediated glucose sensing | Glucokinase activity controls insulin secretion |
| SLC2A2 (GLUT2) | Glucose transporter that facilitates glucose uptake for glucokinase | Required for beta-cell glucose sensing |
| PFKL | Phosphofructokinase, downstream glycolytic enzyme | Glucokinase activity feeds into glycolysis |
| G6PC | Glucose-6-phosphatase, opposes glucokinase in gluconeogenesis | Regulates hepatic glucose output |
| PYGL | Glycogen phosphorylase, mobilizes glycogen | Glucokinase activity promotes glycogen synthesis |
| GYS2 | Glycogen synthase, stores glucose as glycogen | Glucokinase activity provides glucose-6-phosphate for glycogen |
| INSR | Insulin receptor, upstream of glucokinase regulation | Insulin signaling modulates GCK expression |
| FOXO1 | Transcription factor regulating gluconeogenic genes | Opposes glucokinase action in liver |
| SIRT1 | Deacetylase that modulates hepatic glucose metabolism | May regulate glucokinase expression |
| AMPK | Energy sensor kinase that regulates glucose metabolism | Modulates glucokinase activity indirectly |
How Is glucokinase activity Regulated?
Glucokinase activity is regulated at multiple levels. In hepatocytes, the glucokinase regulatory protein (GKRP) binds and inhibits glucokinase in the nucleus under low-glucose conditions, and glucose releases this inhibition by promoting translocation to the cytoplasm. Transcriptionally, GCK expression is controlled by tissue-specific factors such as HNF1A and HNF4A in beta cells and hepatocytes, and mutations in these factors cause MODY subtypes. Hormonal signals, including insulin, can induce GCK expression, while glucagon and cAMP signaling suppress it. Additionally, post-translational modifications and protein-protein interactions, such as phosphorylation by AMPK, may influence glucokinase stability and activity. In cancer cells, ADP-dependent glucokinase (ADPGK) is regulated by hypoxia and metabolic stress, supporting glycolytic adaptation.
glucokinase activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| GCK | MODY2, permanent neonatal diabetes, hyperinsulinemic hypoglycemia | Knock-in mouse models with patient mutations; beta-cell-specific KO |
| GCKR | Metabolic traits, hypertriglyceridemia | Liver-specific KO or point-mutation knock-in |
| ADPGK | Prostate cancer progression | Xenograft models with ADPGK knockdown or KO |
| TAZ (WWTR1) | Tumour growth downstream of glucokinase | Phospho-mutant knock-in of TAZ at glucokinase target sites |
| ChREBP (MLXIPL) | Reductive stress, lipogenesis | Overexpression or KO in hepatocytes |
Glucokinase activity in monogenic diabetes and hyperinsulinism
Mutations in GCK cause a spectrum of glycemic disorders. Loss-of-function mutations lead to maturity-onset diabetes of the young type 2 (MODY2) and permanent neonatal diabetes, while gain-of-function mutations cause hyperinsulinemic hypoglycemia. These mutations alter the enzyme's kinetic properties, such as its affinity for glucose or its cooperativity, leading to impaired glucose sensing in beta cells and hepatocytes. The clinical severity depends on the specific mutation, and genetic testing is essential for diagnosis and management.
Glucokinase activators as antidiabetic therapy
Small-molecule glucokinase activators (GKAs) have been developed to enhance glucokinase activity in patients with type 2 diabetes. Dorzagliatin is a first-in-class GKA approved for clinical use, and its mechanism involves allosteric activation of glucokinase, leading to increased glucose phosphorylation and improved glycemic control. Structure-activity relationship studies of azaindole-based GKAs have provided insights into the pharmacophore and optimized drug candidates. However, excessive glucokinase activation can cause hypoglycemia, highlighting the need for careful dosing.
Glucokinase activity in cancer metabolism
Beyond diabetes, glucokinase activity contributes to cancer progression. Nuclear-translocated glucokinase phosphorylates TAZ, promoting tumour growth in various cancer models. In prostate cancer, ADP-dependent glucokinase (ADPGK) supports metabolic fitness and knockdown of ADPGK impairs tumour progression. These findings suggest that targeting glucokinase activity or its downstream effectors could be a therapeutic strategy in oncology.
GCKR variants and metabolic traits
Genetic variants in GCKR, encoding the glucokinase regulatory protein, are associated with altered metabolic traits such as triglyceride levels and fasting glucose. ChREBP, a transcription factor activated by reductive stress, mediates some of these effects, linking glucokinase regulation to lipogenesis and metabolic syndrome. Understanding the GCKR-GCK-ChREBP axis may provide new targets for metabolic disorders.
From glucokinase activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of GCK impair glucose sensing? | GCK knockout in pancreatic beta cells or hepatocytes |
| Do patient-specific GCK mutations alter enzyme kinetics? | Point-mutation knock-in of GCK variants (e.g., MODY2 mutations) |
| Can glucokinase activators rescue diabetes phenotypes? | Knock-in mouse models treated with GKAs |
| What is the role of nuclear glucokinase in cancer? | Tagged knock-in of GCK with nuclear localization signal; overexpression |
| How does ADPGK support prostate cancer metabolism? | ADPGK knockout or knockdown in prostate cancer cell lines |
| Does GKRP regulate glucokinase in vivo? | Liver-specific GCKR knockout or overexpression |
How to Study the glucokinase activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Coupled enzymatic assay | Glucokinase activity via NADPH production | Kinetic characterization of wild-type and mutant GCK |
| CRISPR knockout | Loss of glucokinase function | Studying glucose sensing in beta cells |
| Point-mutation knock-in | Effect of specific GCK mutations | Modeling MODY2 and hyperinsulinism |
| Tagged knock-in | Subcellular localization and interactions | Tracking nuclear translocation of glucokinase |
| RNA-seq | Transcriptional changes | Identifying ChREBP target genes |
| Proteomics | Protein interactions and modifications | Discovering glucokinase substrates like TAZ |
| Metabolic flux analysis | Glycolytic flux | Assessing ADPGK role in cancer metabolism |
| Small-molecule screening | Glucokinase activator potency | Drug discovery for type 2 diabetes |
Enzymatic assays for glucokinase activity
Glucokinase activity can be measured using coupled enzymatic assays that monitor the production of glucose-6-phosphate or ADP. These assays typically use glucose-6-phosphate dehydrogenase to generate NADPH, which is quantified spectrophotometrically or fluorometrically. Kinetic parameters such as Km and Vmax are determined by varying glucose concentrations. Such assays are essential for characterizing mutant enzymes and evaluating glucokinase activators.
Genetic and CRISPR-based models
CRISPR-Cas9 genome editing enables the generation of knockout, point-mutation, and knock-in models to study glucokinase function. Knockout of GCK in cell lines or animal models abolishes glucose phosphorylation, while point mutations can mimic patient variants. Knock-in of tagged glucokinase allows tracking of subcellular localization and protein interactions. These models are critical for dissecting the role of glucokinase in diabetes and cancer.
Transcriptomic and proteomic profiling
RNA sequencing and proteomics can reveal changes in gene expression and protein abundance associated with altered glucokinase activity. For example, ChREBP target genes are induced by reductive stress in a GCKR-dependent manner. Proteomic analysis of glucokinase interactors can identify novel regulatory partners, such as GKRP and TAZ.
Metabolic flux analysis
Metabolic flux analysis using stable isotopes (e.g., 13C-glucose) can quantify glycolytic and oxidative fluxes downstream of glucokinase. This approach has been used to show that ADPGK supports metabolic fitness in prostate cancer cells. Flux analysis is valuable for understanding how glucokinase activity affects central carbon metabolism.
How CRISPR Can Be Used to Study GO:0004340 glucokinase activity
Knockout
CRISPR-Cas9 knockout of GCK or ADPGK eliminates glucokinase activity, allowing researchers to study the consequences of loss of function in cell lines and animal models. For example, GCK knockout in pancreatic beta cells abolishes glucose-stimulated insulin secretion, while ADPGK knockout impairs prostate cancer cell proliferation. Knockout models are essential for validating the role of glucokinase in metabolic pathways and disease.
Point Mutation
Point-mutation knock-in using CRISPR can recreate patient-specific GCK mutations, such as those causing MODY2 or hyperinsulinism. These models allow precise dissection of how single amino acid changes alter enzyme kinetics, glucose sensing, and disease phenotypes. Point mutations can also be introduced into the catalytic site to study mechanism.
Knock-in
Knock-in of tagged glucokinase (e.g., GFP or HA) enables visualization of its subcellular localization and interaction partners. For instance, tagged glucokinase revealed nuclear translocation and phosphorylation of TAZ. Knock-in of reporter genes under the GCK promoter can monitor expression dynamics in response to glucose.
Overexpression
Overexpression of wild-type or mutant glucokinase in cell lines can enhance glucose phosphorylation and downstream metabolic flux. Overexpression models are useful for studying gain-of-function effects, such as those seen in hyperinsulinism, and for testing glucokinase activators. However, overexpression may cause non-physiological effects, so results should be interpreted cautiously.
How EDITGENE Supports glucokinase activity Research
Researchers studying glucokinase activity-related genes often need to determine whether a candidate gene is causally involved in glucose metabolism, diabetes, or cancer. EDITGENE provides a comprehensive suite of CRISPR-based services to generate precisely engineered cell models, enabling functional validation of glucokinase pathway components.
Contact EDITGENE today to design your custom CRISPR model for glucokinase activity research.
Related Products
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| HK3 Knockout HEK293 Cell Line | EDJ-KQ916 | Human | 3101 | Details Get a Quote |
| HK1 Knockout HEK293 Cell Line | EDJ-KQ1506 | Human | 3098 | Details Get a Quote |
| HK2 Knockout HEK293 Cell Line | EDJ-KQ1507 | Human | 3099 | Details Get a Quote |
| HKDC1 Knockout HEK293 Cell Line | EDJ-KQ1508 | Human | 80201 | Details Get a Quote |
| GCK Knockout HEK293 Cell Line | EDJ-KQ3139 | Human | 2645 | Details Get a Quote |
| HK1 Knockout A-549 Cell Line | EDJ-KQ21124 | Human | 3098 | Details Get a Quote |
| HK1 Knockout HCT 116 Cell Line | EDJ-KQ21125 | Human | 3098 | Details Get a Quote |
| HK1 Knockout HeLa Cell Line | EDJ-KQ21126 | Human | 3098 | Details Get a Quote |
| HK2 Knockout HCT 116 Cell Line | EDJ-KQ21127 | Human | 3099 | Details Get a Quote |
| HK2 Knockout HeLa Cell Line | EDJ-KQ21128 | Human | 3099 | Details Get a Quote |
| HKDC1 Knockout A-549 Cell Line | EDJ-KQ21129 | Human | 80201 | Details Get a Quote |
| HKDC1 Knockout HCT 116 Cell Line | EDJ-KQ19785 | Human | 80201 | Details Get a Quote |
| GCK Knockout HeLa Cell Line | EDJ-KQ53317 | Human | 2645 | Details Get a Quote |
| HK3 Knockout HeLa Cell Line | EDJ-KQ53517 | Human | 3101 | Details Get a Quote |
| HKDC1 Knockout HeLa Cell Line | EDJ-KQ57309 | Human | 80201 | Details Get a Quote |
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Frequently Asked Questions About glucokinase activity
What is glucokinase activity?
Glucokinase activity (GO:0004340) is the catalysis of the reaction ATP + D-glucose = ADP + D-glucose-6-phosphate, the first step of glucose metabolism.
What genes are involved in glucokinase activity?
The primary gene is GCK, which encodes glucokinase. Other related genes include GCKR (regulatory protein), ADPGK (ADP-dependent glucokinase), and TAZ (a downstream target).
What diseases are associated with glucokinase mutations?
Mutations in GCK cause maturity-onset diabetes of the young (MODY2), permanent neonatal diabetes, and hyperinsulinemic hypoglycemia.
How is glucokinase activity regulated?
It is regulated by the glucokinase regulatory protein (GKRP) in the liver, by transcription factors like HNF1A and HNF4A, and by hormonal signals such as insulin.
What are glucokinase activators?
Glucokinase activators are small molecules that allosterically increase glucokinase activity, used for treating type 2 diabetes. Dorzagliatin is a first-in-class approved GKA.
Can glucokinase be targeted in cancer?
Yes, nuclear glucokinase phosphorylates TAZ to promote tumour growth, and ADP-dependent glucokinase supports prostate cancer metabolism, making it a potential cancer target.
What is the difference between glucokinase and hexokinase?
Glucokinase (hexokinase IV) has a high Km for glucose and is not inhibited by glucose-6-phosphate, unlike other hexokinases, making it a glucose sensor.
How can I study glucokinase activity in the lab?
You can use enzymatic assays, CRISPR knockout or knock-in models, RNA-seq, proteomics, and metabolic flux analysis.
What cell models are available for glucokinase research?
EDITGENE provides knockout, point-mutation, knock-in, and overexpression cell models for GCK and related genes, as well as CRISPR library screening services.
Is glucokinase activity important for insulin secretion?
Yes, in pancreatic beta cells, glucokinase acts as the glucose sensor that couples glucose metabolism to insulin secretion.
Conclusion
Glucokinase activity (GO:0004340) is a fundamental molecular function that governs glucose phosphorylation and serves as a critical glucose sensor in metabolic tissues. Its dysregulation is directly linked to monogenic diabetes and hyperinsulinism, and it has emerging roles in cancer metabolism. The development of glucokinase activators highlights its therapeutic potential. Researchers can leverage CRISPR-based models and advanced omics to further dissect its mechanism and regulation, accelerating discoveries in diabetes and oncology.
References
- 1. Ashcroft FM et al.. 2023. Glucokinase activity in diabetes: too much of a good thing?. Trends Endocrinol Metab 34(2):119-130 PMID: 36586779
- 3. Osbak KK et al.. 2009. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia.. Hum Mutat 30(11):1512-26 PMID: 19790256
- 4. Zhao G et al.. 2025. Nucleus-translocated glucokinase functions as a protein kinase to phosphorylate TAZ and promote tumour growth.. Nat Commun 16(1):7156 PMID: 40759645
- 5. Singh C et al.. 2024. ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits.. Cell Metab 36(1):144-158.e7 PMID: 38101397
- 6. Xu H et al.. 2023. ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression.. Mil Med Res 10(1):64 PMID: 38082365
- 7. Syed YY. 2022. Dorzagliatin: First Approval.. Drugs 82(18):1745-1750 PMID: 36449148
- 8. Paczal A et al.. 2016. Structure-Activity Relationship of Azaindole-Based Glucokinase Activators.. J Med Chem 59(2):687-706 PMID: 26685731
