Human PHOSPHO1 exhibits phosphatidylcholine- and phosphatidylethanolamine-phospholipase C activities and interacts with diacylglycerol kinase δ

Houston, B., Seawright, E., Jefferies, D., Hoogland, E., Lester, D., Whitehead, C. and Farquharson, C. (1999). Identification and cloning of a novel phosphatase expressed at high levels in differentiating growth plate chondrocytes. Biochim Biophys Acta 1448, 500-6.

Houston, B., Paton, I.R., Burt, D.W. and Farquharson, C. (2002). Chromosomal localization of the chicken and mammalian orthologues of the orphan phosphatase PHOSPHO1 gene. Animal Genetics 33, 451-454.

Roberts, S.J., Stewart, A.J., Sadler, P.J. and Farquharson, C. (2004). Human PHOSPHO1 exhibits high specific phosphoethanolamine and phosphocholine phosphatase activities. Biochem J 382, 59-65.

Houston, B., Stewart, A.J. and Farquharson, C. (2004). PHOSPHO1-A novel phosphatase specifically expressed at sites of mineralisation in bone and cartilage. Bone 34, 629-37.

Roberts, S., Narisawa, S., Harmey, D., Millán, J.L. and Farquharson, C. (2007). Functional Involvement of PHOSPHO1 in Matrix Vesicle–Mediated Skeletal Mineralization. Journal of Bone and Mineral Research 22, 617-627.

Stewart, A.J., Roberts, S.J., Seawright, E., Davey, M.G., Fleming, R.H. and Farquharson, C. (2006). The presence of PHOSPHO1 in matrix vesicles and its developmental expression prior to skeletal mineralization. Bone 39, 1000-1007.

Lacal, J.C., Zimmerman, T. and Campos, J.M. (2021). Choline Kinase: An Unexpected Journey for a Precision Medicine Strategy in Human Diseases. Pharmaceutics 13

Abra, R.M. and Quinn, P.J. (1975). A novel pathway for phosphatidylcholine catabolism in rat brain homogenates. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 380, 436-441.

Pavoine, C. and Pecker, F. (2009). Sphingomyelinases: their regulation and roles in cardiovascular pathophysiology. Cardiovascular Research 82, 175-183.

Cocco, L., Follo, M.Y., Manzoli, L. and Suh, P.-G. (2015). Phosphoinositide-specific phospholipase C in health and disease. Journal of Lipid Research 56, 1853-1860.

Li, H., Zhang, L., Yin, D., Zhang, Y. and Miao, J. (2010). Targeting phosphatidylcholine-specific phospholipase C for atherogenesis therapy. Trends Cardiovasc Med 20, 172-6.

Gibellini, F. and Smith, T.K. (2010). The Kennedy pathway--De novo synthesis of phosphatidylethanolamine and phosphatidylcholine. IUBMB Life 62, 414-28.

Iorio, E. et al. (2010). Activation of Phosphatidylcholine Cycle Enzymes in Human Epithelial Ovarian Cancer Cells. Cancer Research 70, 2126-2135.

Roitman, A. and Gatt, S. (1963). Isolation of phospholipase-C from rat brain. Israel J. Chem 1, 190.

Druzhinina, K.V. and Kritsman, M.G. (1952). Lecithinase C in animal tissue. Biokhimiia 17, 77-81.

Szumiło, M. and Rahden-Staroń, I. (2008). [Biological role of phosphatidylcholine-specific phospholipase C in mammalian cells]. Postepy Hig Med Dosw (Online) 62, 593-8.

Dowdall, M.J., Barker, L.A. and Whittaker, V.P. (1972). Choline metabolism in the cerebral cortex of guinea pigs. Phosphorylcholine and lipid choline. Biochem J 130, 1081-94.

Hostetler, K.Y. and Hall, L.B. (1980). Phospholipase C activity of rat tissues. Biochem Biophys Res Commun 96, 388-93.

Matsuzawa, Y. and Hostetler, K.Y. (1980). Properties of phospholipase C isolated from rat liver lysosomes. Journal of Biological Chemistry 255, 646-652.

Clark, M.A., Shorr, R.G. and Bomalaski, J.S. (1986). Antibodies prepared to Bacillus cereus phospholipase C crossreact with a phosphatidylcholine preferring phospholipase C in mammalian cells. Biochem Biophys Res Commun 140, 114-9.

Li, B., Li, H., Wang, Z., Wang, Y., Gao, A., Cui, Y., Liu, Y. and Chen, G. (2015). Evidence for the role of phosphatidylcholine-specific phospholipase in experimental subarachnoid hemorrhage in rats. Exp Neurol 272, 145-51.

Spadaro, F. et al. (2008). Phosphatidylcholine-specific phospholipase C activation in epithelial ovarian cancer cells. Cancer Res 68, 6541-9.

Wu, X., Lu, H., Zhou, L., Huang, Y. and Chen, H. (1997). Changes of phosphatidylcholine-specific phospholipase C in hepatocarcinogenesis and in the proliferation and differentiation of rat liver cancer cells. Cell Biol Int 21, 375-81.

Paris, L. et al. (2010). Inhibition of phosphatidylcholine-specific phospholipase C downregulates HER2 overexpression on plasma membrane of breast cancer cells. Breast Cancer Res 12, R27.

Mateos, M.V., Salvador, G.A. and Giusto, N.M. (2010). Selective localization of phosphatidylcholine-derived signaling in detergent-resistant membranes from synaptic endings. Biochimica et Biophysica Acta (BBA) - Biomembranes 1798, 624-636.

Murakami, C., Mizuno, S., Kado, S. and Sakane, F. (2017). Development of a liquid chromatography-mass spectrometry based enzyme activity assay for phosphatidylcholine-specific phospholipase C. Anal Biochem 526, 43-49.

Mateos, M.V., Uranga, R.M., Salvador, G.A. and Giusto, N.M. (2006). Coexistence of phosphatidylcholine-specific phospholipase C and phospholipase D activities in rat cerebral cortex synaptosomes. Lipids 41, 273-80.

Ramoni, C., Spadaro, F., Menegon, M. and Podo, F. (2001). Cellular localization and functional role of phosphatidylcholine-specific phospholipase C in NK cells. J Immunol 167, 2642-50.

Podo, F. et al. (2016). Activation of Phosphatidylcholine-Specific Phospholipase C in Breast and Ovarian Cancer: Impact on MRS-Detected Choline Metabolic Profile and Perspectives for Targeted Therapy. Front Oncol 6, 171.

Amtmann, E. and Sauer, G. (1987). Selective killing of tumor cells by xanthates. Cancer Lett 35, 237-44.

Kiss, Z. and Tomono, M. (1995). Compound D609 inhibits phorbol ester-stimulated phospholipase D activity and phospholipase C-mediated phosphatidylethanolamine hydrolysis. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 1259, 105-108.

Müller-Decker, K. (1989). Interruption of TPA-induced signals by an antiviral and antitumoral xanthate compound: Inhibition of a phospholipase C-type reaction. Biochemical and Biophysical Research Communications 162, 198-205.

Adibhatla, R.M., Hatcher, J.F. and Gusain, A. (2012). Tricyclodecan-9-yl-xanthogenate (D609) mechanism of actions: a mini-review of literature. Neurochem Res 37, 671-9.

Bhat, A.H., Dar, K.B., Khan, A., Alshahrani, S., Alshehri, S.M., Ghoneim, M.M., Alam, P. and Shakeel, F. (2022). Tricyclodecan-9-yl-Xanthogenate (D609): Mechanism of Action and Pharmacological Applications. Int J Mol Sci 23

Ramoni, C., Spadaro, F., Barletta, B., Dupuis, M.L. and Podo, F. (2004). Phosphatidylcholine-specific phospholipase C in mitogen-stimulated fibroblasts. Exp Cell Res 299, 370-82.

Sakai, H., Kado, S., Taketomi, A. and Sakane, F. (2014). Diacylglycerol kinase δ phosphorylates phosphatidylcholine-specific phospholipase C-dependent, palmitic acid-containing diacylglycerol species in response to high glucose levels. J Biol Chem 289, 26607-17.

Carman, G.M. and Han, G.S. (2009). Phosphatidic acid phosphatase, a key enzyme in the regulation of lipid synthesis. J Biol Chem 284, 2593-7.

Carman, G.M. and Han, G.S. (2019). Fat-regulating phosphatidic acid phosphatase: a review of its roles and regulation in lipid homeostasis. J Lipid Res 60, 2-6.

Waggoner, D.W., Xu, J., Singh, I., Jasinska, R., Zhang, Q.X. and Brindley, D.N. (1999). Structural organization of mammalian lipid phosphate phosphatases: implications for signal transduction. Biochim Biophys Acta 1439, 299-316.

Tang, X. and Brindley, D.N. (2020). Lipid Phosphate Phosphatases and Cancer. Biomolecules 10

Stukey, J. and Carman, G.M. (1997). Identification of a novel phosphatase sequence motif. Protein Sci 6, 469-72.

Sakane, F., Murakami, C. and Sakai, H. (2025). Upstream and downstream pathways of diacylglycerol kinase : Novel phosphatidylinositol turnover-independent signal transduction pathways. Advances in Biological Regulation 95, 101054.

Suzuki, R., Murakami, C., Dilimulati, K., Atsuta-Tsunoda, K., Kawai, T. and Sakane, F. (2023). Human sphingomyelin synthase 1 generates diacylglycerol in the presence and absence of ceramide via multiple enzymatic activities. FEBS Lett 597, 2672-2686.

Murakami, C. and Sakane, F. (2021). Sphingomyelin synthase-related protein generates diacylglycerol via the hydrolysis of glycerophospholipids in the absence of ceramide. J Biol Chem, 100454.

Murakami, C., Dilimulati, K., Atsuta-Tsunoda, K., Kawai, T., Inomata, S., Hijikata, Y., Sakai, H. and Sakane, F. (2024). Multiple activities of sphingomyelin synthase 2 generate saturated fatty acid- and/or monounsaturated fatty acid-containing diacylglycerol. Journal of Biological Chemistry

Murakami, C., Hoshino, F., Sakai, H., Hayashi, Y., Yamashita, A. and Sakane, F. (2020). Diacylglycerol kinase delta and sphingomyelin synthase-related protein functionally interact via their sterile alpha motif domains. J Biol Chem 295, 2932-2947.

Han, G.S., Wu, W.I. and Carman, G.M. (2006). The Saccharomyces cerevisiae Lipin homolog is a Mg2+-dependent phosphatidate phosphatase enzyme. J Biol Chem 281, 9210-8.

Koonin, E.V. and Tatusov, R.L. (1994). Computer Analysis of Bacterial Haloacid Dehalogenases Defines a Large Superfamily of Hydrolases with Diverse Specificity: Application of an Iterative Approach to Database Search. Journal of Molecular Biology 244, 125-132.

Stewart, A.J., Schmid, R., Blindauer, C.A., Paisey, S.J. and Farquharson, C. (2003). Comparative modelling of human PHOSPHO1 reveals a new group of phosphatases within the haloacid dehalogenase superfamily. Protein Eng 16, 889-95.

Furuta, M., Murakami, C., Numagami, Y., Suzuki, R. and Sakane, F. (2023). Diacylglycerol kinase zeta interacts with sphingomyelin synthase 1 and sphingomyelin synthase-related protein via different regions. FEBS Open Bio 13, 1333-1345.

Bligh, E.G. and Dyer, W.J. (1959). A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37, 911-7.

Ray, S. and Hewitt, K. (2023). Sticky, Adaptable, and Many-sided: SAM protein versatility in normal and pathological hematopoietic states. Bioessays 45, e2300022.

Roberts, S.J., Stewart, A.J., Schmid, R., Blindauer, C.A., Bond, S.R., Sadler, P.J. and Farquharson, C. (2005). Probing the substrate specificities of human PHOSPHO1 and PHOSPHO2. Biochim Biophys Acta 1752, 73-82.

Kawasaki, T., Kobayashi, T., Ueyama, T., Shirai, Y. and Saito, N. (2008). Regulation of clathrin-dependent endocytosis by diacylglycerol kinase delta: importance of kinase activity and binding to AP2alpha. Biochem J 409, 471-9.

Imai, S., Yasuda, S., Kai, M., Kanoh, H. and Sakane, F. (2009). Diacylglycerol kinase delta associates with receptor for activated C kinase 1, RACK1. Biochim Biophys Acta 1791, 246-53.

Tercé, F., Brun, H. and Vance, D.E. (1994). Requirement of phosphatidylcholine for normal progression through the cell cycle in C3H/10T1/2 fibroblasts. Journal of Lipid Research 35, 2130-2142.

Milo, R. (2013). What is the total number of protein molecules per cell volume? A call to rethink some published values. Bioessays 35, 1050-5.

Choy, P.C., Paddon, H.B. and Vance, D.E. (1980). An increase in cytoplasmic CTP accelerates the reaction catalyzed by CTP:phosphocholine cytidylyltransferase in poliovirus-infected HeLa cells. Journal of Biological Chemistry 255, 1070-1073.

Millington, W.R. and Wurtman, R.J. (1982). Choline administration elevates brain phosphorylcholine concentrations. J Neurochem 38, 1748-52.

Tokmakjian, S., Haines, D.S.M. and Possmayer, F. (1981). Pulmonary phosphatidylcholine biosynthesis: Alterations in the pool sizes of choline and choline derivatives in rabbit fetal lung during development. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 663, 557-568.

Guerra, G., Segrado, F., Pasanisi, P., Bruno, E., Lopez, S., Raspagliesi, F., Bianchi, M. and Venturelli, E. (2023). Circulating choline and phosphocholine measurement by a hydrophilic interaction liquid chromatography–tandem mass spectrometry. Heliyon 9, e21921.

Whitehead, F.W., Trip, E. and Vance, D.E. (1981). Semliki Forest virus does not inhibit phosphatidylcholine biosynthesis in BHK-21 cells. Can J Biochem 59, 38-47.

Hafez, M.M. and Costlow, M.E. (1989). Phosphatidylethanolamine turnover is an early event in the response of NB2 lymphoma cells to prolactin. Experimental Cell Research 184, 37-43.

Wolf, R.A. and Gross, R.W. (1985). Identification of neutral active phospholipase C which hydrolyzes choline glycerophospholipids and plasmalogen selective phospholipase A2 in canine myocardium. Journal of Biological Chemistry 260, 7295-7303.

Chiang, Y.P., Li, Z., Chen, Y., Cao, Y. and Jiang, X.C. (2021). Sphingomyelin synthases 1 and 2 exhibit phosphatidylcholine phospholipase C activity. J Biol Chem 297, 101398.

Chiang, Y.P., Li, Z., Chen, Y., Cao, Y. and Jiang, X.C. (2021). Sphingomyelin synthase related protein is a mammalian phosphatidylethanolamine phospholipase C. Biochim Biophys Acta Mol Cell Biol Lipids 1866, 159017.

Hu, K. et al. (2024). Cryo-EM structure of human sphingomyelin synthase and its mechanistic implications for sphingomyelin synthesis. Nat Struct Mol Biol

Stefan, C., Jansen, S. and Bollen, M. (2005). NPP-type ectophosphodiesterases: unity in diversity. Trends in Biochemical Sciences 30, 542-550.

Dillon, S., Staines, K.A., Millan, J.L. and Farquharson, C. (2019). How To Build a Bone: PHOSPHO1, Biomineralization, and Beyond. JBMR Plus 3, e10202.

Uhlén, M. et al. (2015). Tissue-based map of the human proteome. Science 347, 1260419.

Sakane, F., Imai, S., Kai, M., Wada, I. and Kanoh, H. (1996). Molecular cloning of a novel diacylglycerol kinase isozyme with a pleckstrin homology domain and a C-terminal tail similar to those of the EPH family of protein-tyrosine kinases. J Biol Chem 271, 8394-401.

Thul, P.J. et al. (2017). A subcellular map of the human proteome. Science 356

Sakane, F., Imai, S., Yamada, K., Murakami, T., Tsushima, S. and Kanoh, H. (2002). Alternative splicing of the human diacylglycerol kinase 8 gene generates two isoforms differing in their expression patterns and in regulatory functions. Journal of Biological Chemistry 277, 43519-43526.

Takeuchi, M., Sakiyama, S., Usuki, T., Sakai, H. and Sakane, F. (2012). Diacylglycerol kinase delta1 transiently translocates to the plasma membrane in response to high glucose. Biochim Biophys Acta 1823, 2210-6.

Imai, S., Sakane, F. and Kanoh, H. (2002). Phorbol ester-regulated oligomerization of diacylglycerol kinase delta linked to its phosphorylation and translocation. J Biol Chem 277, 35323-32.

Huesa, C. et al. (2011). PHOSPHO1 is essential for mechanically competent mineralization and the avoidance of spontaneous fractures. Bone 48, 1066-74.

Chibalin, A.V. et al. (2008). Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance. Cell 132, 375-86.

Sato, T. et al. (2021). Diacylglycerol kinase δ functions as a proliferation suppressor in pancreatic β-cells. The FASEB Journal 35, e21420.

Usuki, T., Takato, T., Lu, Q., Sakai, H., Bando, K., Kiyonari, H. and Sakane, F. (2016). Behavioral and pharmacological phenotypes of brain-specific diacylglycerol kinase delta-knockout mice. Brain Res 1648, 193-201.

Lu, Q., Murakami, C., Murakami, Y., Hoshino, F., Asami, M., Usuki, T., Sakai, H. and Sakane, F. (2020). 1-Stearoyl-2-docosahexaenoyl-phosphatidic acid interacts with and activates Praja-1, the E3 ubiquitin ligase acting on the serotonin transporter in the brain. FEBS Lett

Wu, Y., Xin, J., Li, X., Yang, T., Liu, Y., Zhao, Y., Xie, W. and Jiang, M. (2024). Repurposing lansoprazole to alleviate metabolic syndrome via PHOSPHO1 inhibition. Acta Pharm Sin B 14, 1711-1725.

Jiang, M., Chavarria, T.E., Yuan, B., Lodish, H.F. and Huang, N.J. (2020). Phosphocholine accumulation and PHOSPHO1 depletion promote adipose tissue thermogenesis. Proc Natl Acad Sci U S A 117, 15055-15065.

Liu, Y., Wu, Y. and Jiang, M. (2022). The emerging roles of PHOSPHO1 and its regulated phospholipid homeostasis in metabolic disorders. Front Physiol 13, 935195.

Song, Y. et al. (2024). Phosphocholine-induced energy source shift alleviates mitochondrial dysfunction in lung cells caused by geospecific PM(2.5) components. Proc Natl Acad Sci U S A 121, e2317574121.

Schindelin, J. et al. (2012). Fiji: an open-source platform for biological-image analysis. Nature Methods 9, 676-682.

Roberts, S.J., Owen, H.C. and Farquharson, C. (2008). Identification of a novel splice variant of the haloacid dehalogenase: PHOSPHO1. Biochem Biophys Res Commun 371, 872-6.

Gerhard, D.S. et al. (2004). The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res 14, 2121-7.

Sheikhnejad, R.G. and Srivastava, P.N. (1986). Isolation and properties of a phosphatidylcholine-specific phospholipase C from bull seminal plasma. Journal of Biological Chemistry 261, 7544-7549.

Paris, L. et al. (2017). Phosphatidylcholine-specific phospholipase C inhibition reduces HER2-overexpression, cell proliferation and in vivo tumor growth in a highly tumorigenic ovarian cancer model. Oncotarget 8, 55022-55038.

Strosznajder, J. (1997). Regulation of Phosphatidylethanolamine Degradation by Enzyme(s) of Subcellular Fractions from Cerebral Cortex. Neurochemical Research 22, 1199-1204.

Vacaru, A.M. et al. (2009). Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER. J Cell Biol 185, 1013-27.

Kol, M. et al. (2017). Switching head group selectivity in mammalian sphingolipid biosynthesis by active-site-engineering of sphingomyelin synthases. J Lipid Res 58, 962-973.

Taniguchi, M. and Okazaki, T. (2021). Role of ceramide/sphingomyelin (SM) balance regulated through "SM cycle" in cancer. Cell Signal 87, 110119.

Taniguchi, M. and Okazaki, T. (2014). The role of sphingomyelin and sphingomyelin synthases in cell death, proliferation and migration-from cell and animal models to human disorders. Biochim Biophys Acta 1841, 692-703.

Yeang, C., Varshney, S., Wang, R., Zhang, Y., Ye, D. and Jiang, X.C. (2008). The domain responsible for sphingomyelin synthase (SMS) activity. Biochim Biophys Acta 1781, 610-7.

Tafesse, F.G., Huitema, K., Hermansson, M., van der Poel, S., van den Dikkenberg, J., Uphoff, A., Somerharju, P. and Holthuis, J.C. (2007). Both sphingomyelin synthases SMS1 and SMS2 are required for sphingomyelin homeostasis and growth in human HeLa cells. J Biol Chem 282, 17537-47.