AGK (gene)

The human gene AGK encodes the enzyme mitochondrial acylglycerol kinase.[5][6][7][8]

AGK
Identifiers
Aliases	AGK, CATC5, CTRCT38, MTDPS10, MULK, acylglycerol kinase
External IDs	OMIM: 610345 MGI: 1917173 HomoloGene: 41239 GeneCards: AGK
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q34 Start 141,551,278 bp[1] End 141,655,244 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6|6 B1 Start 40,325,172 bp[2] End 40,396,762 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • transferase activity • ceramide kinase activity • nucleotide binding • lipid kinase activity • diacylglycerol kinase activity • ATP binding • acylglycerol kinase activity • kinase activity • NAD+ kinase activity Cellular component • mitochondrial outer membrane • intracellular membrane-bounded organelle • mitochondrion • membrane • cytosol • integral component of mitochondrial inner membrane • TIM22 mitochondrial import inner membrane insertion complex • mitochondrial inner membrane • mitochondrial intermembrane space Biological process • glycerolipid metabolic process • ceramide biosynthetic process • lipid phosphorylation • phosphorylation • metabolism • glycerophospholipid biosynthetic process • protein import into mitochondrial inner membrane Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	55750	69923
Ensembl	ENSG00000006530 ENSG00000262327	ENSMUSG00000029916
UniProt	Q53H12	Q9ESW4
RefSeq (mRNA)	NM_018238 NM_001364948	NM_023538
RefSeq (protein)	NP_060708	NP_076027
Location (UCSC)	Chr 7: 141.55 – 141.66 Mb	Chr 6: 40.33 – 40.4 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

The protein encoded by this gene is a mitochondrial membrane protein involved in lipid and glycerolipid metabolism. It catalyzes the formation of phosphatidic and lysophosphatidic acids. Defects in this gene have been associated with mitochondrial DNA depletion syndrome 10.

Diseases associated with AGK include cataracts and cardiomyopathy. An important paralog of this gene is CERKL.

Structure

The AGK gene is located on the 7th chromosome, with its specific location being 7q34. The gene contains 18 exons.[8] AGK encodes a 47.1 kDa protein that is composed of 422 amino acids; 32 peptides have been observed through mass spectrometry data.[9][10]

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. [11]

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.[12] 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.[13]

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.[14] 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.[15] In prostate cancer, AGK expression amplifies EGF signaling pathways, thus playing a significant role in the development of prostate cancer.[16] It’s also correlated tumor-nodule-metastasis (TNM) classification breast cancer, and an overall shorter overall survival.[17]

Interactions

In the progression of diabetic retinopathy, the ATX-AGK-LPA signaling axis plays a significant role.[18]

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.[16] Acylglycerol kinase also augments JAK2/STAT3 signaling in esophageal squamous cells.[15]

References

1. ENSG00000262327 GRCh38: Ensembl release 89: ENSG00000006530, ENSG00000262327 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000029916 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Waggoner DW, Johnson LB, Mann PC, Morris V, Guastella J, Bajjalieh SM (Sep 2004). "MuLK, a eukaryotic multi-substrate lipid kinase". The Journal of Biological Chemistry. 279 (37): 38228–35. doi:10.1074/jbc.M405932200. PMID 15252046.
6. Bektas M, Payne SG, Liu H, Goparaju S, Milstien S, Spiegel S (Jun 2005). "A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells". The Journal of Cell Biology. 169 (5): 801–11. doi:10.1083/jcb.200407123. PMC 2171605. PMID 15939762.
7. Spiegel S, Milstien S (Jan 2007). "Functions of the multifaceted family of sphingosine kinases and some close relatives". The Journal of Biological Chemistry. 282 (4): 2125–9. doi:10.1074/jbc.R600028200. PMID 17135245.
8. "Entrez Gene: AGK acylglycerol kinase".
9. ]Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
10. "Acylglycerol kinase, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
11. Mayr JA, Haack TB, Graf E, Zimmermann FA, Wieland T, Haberberger B, Superti-Furga A, Kirschner J, Steinmann B, Baumgartner MR, Moroni I, Lamantea E, Zeviani M, Rodenburg RJ, Smeitink J, Strom TM, Meitinger T, Sperl W, Prokisch H (Feb 2012). "Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome". American Journal of Human Genetics. 90 (2): 314–20. doi:10.1016/j.ajhg.2011.12.005. PMC 3276657. PMID 22284826.
12. Aldahmesh MA, Khan AO, Mohamed JY, Alghamdi MH, Alkuraya FS (Jun 2012). "Identification of a truncation mutation of acylglycerol kinase (AGK) gene in a novel autosomal recessive cataract locus". Human Mutation. 33 (6): 960–2. doi:10.1002/humu.22071. PMID 22415731. S2CID 10579886.
13. Siriwardena K, Mackay N, Levandovskiy V, Blaser S, Raiman J, Kantor PF, Ackerley C, Robinson BH, Schulze A, Cameron JM (Jan 2013). "Mitochondrial citrate synthase crystals: novel finding in Sengers syndrome caused by acylglycerol kinase (AGK) mutations". Molecular Genetics and Metabolism. 108 (1): 40–50. doi:10.1016/j.ymgme.2012.11.282. PMID 23266196.
14. Nouh MA, Wu XX, Okazoe H, Tsunemori H, Haba R, Abou-Zeid AM, Saleem MD, Inui M, Sugimoto M, Aoki J, Kakehi Y (Sep 2009). "Expression of autotaxin and acylglycerol kinase in prostate cancer: association with cancer development and progression". Cancer Science. 100 (9): 1631–8. doi:10.1111/j.1349-7006.2009.01234.x. PMID 19549252. S2CID 27776078.
15. Chen X, Ying Z, Lin X, Lin H, Wu J, Li M, Song L (Jun 2013). "Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells". The Journal of Clinical Investigation. 123 (6): 2576–89. doi:10.1172/JCI68143. PMC 3668815. PMID 23676499.
16. Bektas M, Payne SG, Liu H, Goparaju S, Milstien S, Spiegel S (Jun 2005). "A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells". The Journal of Cell Biology. 169 (5): 801–11. doi:10.1083/jcb.200407123. PMC 2171605. PMID 15939762.
17. Wang X, Lin C, Zhao X, Liu A, Zhu J, Li X, Song L (8 May 2014). "Acylglycerol kinase promotes cell proliferation and tumorigenicity in breast cancer via suppression of the FOXO1 transcription factor". Molecular Cancer. 13: 106. doi:10.1186/1476-4598-13-106. PMC 4028287. PMID 24886245.
18. Abu El-Asrar AM, Mohammad G, Nawaz MI, Siddiquei MM, Kangave D, Opdenakker G (Jun 2013). "Expression of lysophosphatidic acid, autotaxin and acylglycerol kinase as biomarkers in diabetic retinopathy". Acta Diabetologica. 50 (3): 363–71. doi:10.1007/s00592-012-0422-1. PMID 22864860. S2CID 22594417.

External links

• Human AGK genome location and AGK gene details page in the UCSC Genome Browser.

Further reading

• Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Van Overloop H, Gijsbers S, Van Veldhoven PP (Feb 2006). "Further characterization of mammalian ceramide kinase: substrate delivery and (stereo)specificity, tissue distribution, and subcellular localization studies". Journal of Lipid Research. 47 (2): 268–83. doi:10.1194/jlr.M500321-JLR200. PMID 16269826.