7k2v

Structural highlights

Disease

FYV1_HUMAN Fleck corneal dystrophy. The disease is caused by variants affecting the gene represented in this entry.

Function

FYV1_HUMAN Dual specificity kinase implicated in myriad essential cellular processes such as maintenance of endomembrane homeostasis, and endocytic-vacuolar pathway, lysosomal trafficking, nuclear transport, stress- or hormone-induced signaling and cell cycle progression (PubMed:23086417). The PI(3,5)P2 regulatory complex regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). Sole enzyme to catalyze the phosphorylation of phosphatidylinositol 3-phosphate on the fifth hydroxyl of the myo-inositol ring, to form (PtdIns(3,5)P2) (PubMed:17556371). Also catalyzes the phosphorylation of phosphatidylinositol on the fifth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 5-phosphate (PtdIns(5)P) (PubMed:22621786). Has serine-protein kinase activity and is able to autophosphorylate and transphosphorylate. Autophosphorylation inhibits its own phosphatidylinositol 3-phosphate 5-kinase activity, stimulates FIG4 lipid phosphatase activity and down-regulates lipid product formation (PubMed:33098764). Involved in key endosome operations such as fission and fusion in the course of endosomal cargo transport (PubMed:22621786). Required for the maturation of early into late endosomes, phagosomes and lysosomes (PubMed:30612035). Regulates vacuole maturation and nutrient recovery following engulfment of macromolecules, initiates the redistribution of accumulated lysosomal contents back into the endosome network (PubMed:27623384). Critical regulator of the morphology, degradative activity, and protein turnover of the endolysosomal system in macrophages and platelets (By similarity). In neutrophils, critical to perform chemotaxis, generate ROS, and undertake phagosome fusion with lysosomes (PubMed:28779020). Plays a key role in the processing and presentation of antigens by major histocompatibility complex class II (MHC class II) mediated by CTSS (PubMed:30612035). Regulates melanosome biogenesis by controlling the delivery of proteins from the endosomal compartment to the melanosome (PubMed:29584722). Essential for systemic glucose homeostasis, mediates insulin-induced signals for endosome/actin remodeling in the course of GLUT4 translocation/glucose uptake activation (By similarity). Supports microtubule-based endosome-to-trans-Golgi network cargo transport, through association with SPAG9 and RABEPK (By similarity). Mediates EGFR trafficking to the nucleus (PubMed:17909029).[UniProtKB:Q9Z1T6]^{[1] [2] [3] [4] [5] [6] [7] [8] [9]} (Microbial infection) Required for cell entry of coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus EMC (HCoV-EMC) by endocytosis.^[10]

References

1. ↑ Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, Shisheva A. Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex. J Biol Chem. 2007 Aug 17;282(33):23878-91. PMID:17556371 doi:10.1074/jbc.M611678200
2. ↑ Kim J, Jahng WJ, Di Vizio D, Lee JS, Jhaveri R, Rubin MA, Shisheva A, Freeman MR. The phosphoinositide kinase PIKfyve mediates epidermal growth factor receptor trafficking to the nucleus. Cancer Res. 2007 Oct 1;67(19):9229-37. PMID:17909029 doi:10.1158/0008-5472.CAN-07-1333
3. ↑ Sbrissa D, Ikonomov OC, Filios C, Delvecchio K, Shisheva A. Functional dissociation between PIKfyve-synthesized PtdIns5P and PtdIns(3,5)P2 by means of the PIKfyve inhibitor YM201636. Am J Physiol Cell Physiol. 2012 Aug 15;303(4):C436-46. PMID:22621786 doi:10.1152/ajpcell.00105.2012
4. ↑ Krishna S, Palm W, Lee Y, Yang W, Bandyopadhyay U, Xu H, Florey O, Thompson CB, Overholtzer M. PIKfyve Regulates Vacuole Maturation and Nutrient Recovery following Engulfment. Dev Cell. 2016 Sep 12;38(5):536-47. PMID:27623384 doi:10.1016/j.devcel.2016.08.001
5. ↑ Dayam RM, Sun CX, Choy CH, Mancuso G, Glogauer M, Botelho RJ. The Lipid Kinase PIKfyve Coordinates the Neutrophil Immune Response through the Activation of the Rac GTPase. J Immunol. 2017 Sep 15;199(6):2096-2105. PMID:28779020 doi:10.4049/jimmunol.1601466
6. ↑ Liggins MC, Flesher JL, Jahid S, Vasudeva P, Eby V, Takasuga S, Sasaki J, Sasaki T, Boissy RE, Ganesan AK. PIKfyve regulates melanosome biogenesis. PLoS Genet. 2018 Mar 27;14(3):e1007290. PMID:29584722 doi:10.1371/journal.pgen.1007290
7. ↑ Baranov MV, Bianchi F, Schirmacher A, van Aart MAC, Maassen S, Muntjewerff EM, Dingjan I, Ter Beest M, Verdoes M, Keyser SGL, Bertozzi CR, Diederichsen U, van den Bogaart G. The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation. iScience. 2019 Jan 25;11:160-177. PMID:30612035 doi:10.1016/j.isci.2018.12.015
8. ↑ Lees JA, Li P, Kumar N, Weisman LS, Reinisch KM. Insights into Lysosomal PI(3,5)P2 Homeostasis from a Structural-Biochemical Analysis of the PIKfyve Lipid Kinase Complex. Mol Cell. 2020 Oct 15. pii: S1097-2765(20)30686-9. doi:, 10.1016/j.molcel.2020.10.003. PMID:33098764 doi:http://dx.doi.org/10.1016/j.molcel.2020.10.003
9. ↑ Shisheva A. PIKfyve and its Lipid products in health and in sickness. Curr Top Microbiol Immunol. 2012;362:127-62. PMID:23086417 doi:10.1007/978-94-007-5025-8_7
10. ↑ Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, Guo L, Guo R, Chen T, Hu J, Xiang Z, Mu Z, Chen X, Chen J, Hu K, Jin Q, Wang J, Qian Z. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun. 2020 Mar 27;11(1):1620. PMID:32221306 doi:10.1038/s41467-020-15562-9