AGK (gene)

Structure

The AGK gene is located on the 7th chromosome, with its specific location being 7q34. The gene contains 18 exons. AGK encodes a 47.1 kDa protein that is composed of 422 amino acids; 32 peptides have been observed through mass spectrometry data.

Function

Acylglycerol kinase synthesizes phosphatidic and lysophosphatidic acids. The enzyme uses ATP to put a phosphate group on acyl glycerol and diacylglycerol. It catalyzes the following reactions:

ATP + acylglycerol = ADP + acyl-sn-glycerol 3-phosphate. ATP + 1,2-diacyl-sn-glycerol = ADP + 1,2-diacyl-sn-glycerol 3-phosphate.

The enzyme is involved in the more general pathway of fatty acid metabolism. AGK also has an implicated role in the assembly of the adenine nucleotide translocator in the inner mitochondrial membrane.

Clinical significance

Mutations in the AGK gene were the first to be implicated in isolated cataract development, although it is unclear whether these mutations cause a change in lipid composition of the lenses, or if signaling results in the defect. This gene has also been associated with Sengers syndrome. Two different phenotypes have been observed. One form of the disorder presented as vascular strokes, lactic acidosis, cardiomyopathy and cataracts, abnormal muscle cell histopathology and mitochondrial function. In those patients, there was also a markedly high rate of citrate synthase. The second phenotype presented with similar clinical symptoms, but no strokes. As phosphatidic acid is also involved in the synthesis of phospholipids, its loss will result in changes to the lipid composition of the inner mitochondrial membrane. These effects manifest as cataract formation in the eye, respiratory chain dysfunction and cardiac hypertrophy in heart tissue.

AGK expression has also been correlated with certain cancer phenotypes. AGK expression, in coordination with AGX, was not detected in non-neoplastic epithelia, while both were weakly expressed in the majority of high-grade intra-epithelial neoplasia (HG-PIN). Expressions of both enzymes were significantly correlated with primary Gleason grade of cancer foci and capsular invasion. Overexpression of AGK sustains constitutive JAK2/STAT3 activation, consequently promoting the cancer stem cell population and augmenting the tumorigenicity of esophageal squamous cell carcinoma (ESCC) cells both in vivo and in vitro. Furthermore, AGK levels significantly increases STAT3 phosphorylation, poorer disease-free survival, and shorter overall survival in primary ESCC. More importantly, AGK expression was significantly correlated with JAK2/STAT3 hyperactivation in ESCC, as well as in lung and breast cancer. In prostate cancer, AGK expression amplifies EGF signaling pathways, thus playing a significant role in the development of prostate cancer. It's also correlated tumor-nodule-metastasis (TNM) classification breast cancer, and an overall shorter overall survival.

Interactions

In the progression of diabetic retinopathy, the ATX-AGK-LPA signaling axis plays a significant role.

In the proliferation of prostate cancer, AGK interacts with and regulates PC-3 prostate cancer cells markedly increased formation and secretion of LPA. This increase also affects the EGF receptor and sustained activation of extracellular signal related kinase (ERK) 1/2, culminating in enhanced cell proliferation. Acylglycerol kinase also augments JAK2/STAT3 signaling in esophageal squamous cells.

References

References

1. (Sep 2004). "MuLK, a eukaryotic multi-substrate lipid kinase". The Journal of Biological Chemistry.
2. (Jun 2005). "A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells". The Journal of Cell Biology.
3. (Jan 2007). "Functions of the multifaceted family of sphingosine kinases and some close relatives". The Journal of Biological Chemistry.
4. "Entrez Gene: AGK acylglycerol kinase".
5. (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research.
6. (September 2019). "Acylglycerol kinase, mitochondrial }}{{Dead link". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
7. (Feb 2012). "Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome". American Journal of Human Genetics.
8. (Jun 2012). "Identification of a truncation mutation of acylglycerol kinase (AGK) gene in a novel autosomal recessive cataract locus". Human Mutation.
9. (Jan 2013). "Mitochondrial citrate synthase crystals: novel finding in Sengers syndrome caused by acylglycerol kinase (AGK) mutations". Molecular Genetics and Metabolism.
10. (Sep 2009). "Expression of autotaxin and acylglycerol kinase in prostate cancer: association with cancer development and progression". Cancer Science.
11. (Jun 2013). "Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells". The Journal of Clinical Investigation.
12. (Jun 2005). "A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells". The Journal of Cell Biology.
13. (8 May 2014). "Acylglycerol kinase promotes cell proliferation and tumorigenicity in breast cancer via suppression of the FOXO1 transcription factor". Molecular Cancer.
14. (Jun 2013). "Expression of lysophosphatidic acid, autotaxin and acylglycerol kinase as biomarkers in diabetic retinopathy". Acta Diabetologica.