Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Gene Ontology annotation based on curation of immunofluorescence data
Combined Automated Annotation using Multiple IEA Methods
PA is dephosphorylated to DAG by LPIN
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Reactome models LPIN1, LPIN2, and LPIN3 at the ER membrane as catalysts of phosphatidate dephosphorylation to diacylglycerol.
"At the endoplasmic reticulum (ER) membrane, phosphatidate phosphatase 1-3 (LPIN) dephosphorylates phosphatidic acid (PA) to form diacylglycerol (DAG) (Grimsey et al. 2008, Donkor et al. 2007)."
Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns.
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Recombinant lipin-3 has direct phosphatidate phosphatase type-1 activity.
"Consistent with this possibility, recombinant lipin-2 and lipin-3 possess PAP1 activity."
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Lipin family PAP1 activities were magnesium-dependent and phosphatidate-specific under the tested conditions.
"Each of the three lipin family members showed Mg2+-dependent activity that was specific for phosphatidate under the conditions employed."
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The three mammalian lipins have distinct tissue-expression patterns.
"The different lipins showed distinct tissue expression patterns."
The phosphatidic acid-binding, polybasic domain is responsible for the differences in the phosphoregulation of lipins 1 and 3.
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In vitro phosphorylation did not alter lipin-3 catalytic activity or association with phosphatidate.
"In the present study, we show that phosphorylation does not affect the catalytic activity of lipin 3 or its ability to associate with PA in vitro"
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Lipin-1 and lipin-3 polybasic-domain swaps showed that their different polybasic domains determine their different phosphoregulation.
"We show that the different PBDs of lipins 1 and 3 are responsible for the presence of phosphoregulation on the former but not the latter enzyme."
Lipin-1 and lipin-3 together determine adiposity in vivo.
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Mouse single- and double-knockout experiments support a cooperative role for Lpin3 and Lpin1 in adipogenesis and adiposity.
"Using lipin single- and double-knockout models we identified a cooperative relationship between lipin-3 and lipin-1 that influences adipogenesis in vitro and adiposity in vivo."
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Mouse tissue assays support joint lipin-1/lipin-3 contributions to PAP activity in adipose tissue and several other organs.
"Our findings establish that lipin-1 and lipin-3 cooperate in vivo to determine adipose tissue PAP activity and adiposity, and may have implications in understanding the protection of lipin-1-deficient humans from overt lipodystrophy."
Lipin 2/3 phosphatidic acid phosphatases maintain phospholipid homeostasis to regulate chylomicron synthesis.
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Mouse small intestine expresses lipin 2 and lipin 3 rather than lipin 1.
"One exception is the small intestine, which is unique in expressing exclusively lipin 2 and lipin 3."
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Combined lipin-2/lipin-3 deficiency perturbs phosphatidate, mTORC1 activity, membrane phospholipids, and chylomicron synthesis.
"Lipin 2/3 deficiency caused phosphatidic acid accumulation and mammalian target of rapamycin complex 1 (mTORC1) activation, which were associated with enhanced protein levels of a key phospholipid biosynthetic enzyme (CTP:phosphocholine cytidylyltransferase α) and altered membrane phospholipid composition."
Redundant roles of the phosphatidate phosphatase family in triacylglycerol synthesis in human adipocytes.
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Depletion of each LPIN family member altered early adipogenic and lipid-biosynthetic gene expression in a human pre-adipocyte model.
"Depletion of every lipin family member in a human Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell line, alters expression levels of adipogenic transcription factors and lipid biosynthesis genes in early stages of differentiation."
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Even combined lipin knockdown caused only mild effects on mature adipocyte triacylglycerol accumulation, indicating substantial pathway compensation.
"Even combinatorial knockdown of lipins shows mild effects on triacylglycerol accumulation in mature adipocytes."
Lipin proteins form homo- and hetero-oligomers.
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Lipin-1 formed hetero-oligomers with lipin-2 and lipin-3 in the experimental systems used.
"In the present study, using various approaches, we revealed that lipin 1 formed stable homo-oligomers with itself and hetero-oligomers with lipin 2/3."
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Oligomerization can influence lipin-1 localization while individual lipin-1 monomers retain independent PAP catalysis.
"We also show that lipin 1 subcellular localization can be influenced through oligomerization, and the individual lipin 1 monomers in the oligomer function independently in catalysing dephosphorylation of PA."
A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2.
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Direct transcriptional-coactivation assays in this family study were performed for lipin-2, with comparison to lipin-1, not lipin-3.
"We also determined that lipin-2 has transcriptional coactivator activity for peroxisome proliferator-activated receptor-response elements similar to lipin-1 and that this activity is not affected by mutating the conserved serine."
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The conserved serine was required for mouse lipin-1/lipin-2 PAP activity but not microsomal membrane association.
"Here we demonstrate that mutation of the equivalent serine in mouse lipin-1 and lipin-2 to leucine or aspartate abolishes PAP activity but does not impair lipin association with microsomal membranes, the major site of glycerolipid synthesis."
Glucocorticoids and cyclic AMP selectively increase hepatic lipin-1 expression, and insulin acts antagonistically.
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In rat and mouse hepatocytes, dexamethasone/cAMP increased lipin-1 but not lipin-2 or lipin-3 mRNA.
"Lipin-2 and lipin-3 mRNA were not increased by dex/cAMP, indicating that increased PAP1 activity is attributable specifically to enhanced lipin-1 expression."
Temporal and spatial regulation of the phosphatidate phosphatases lipin 1 and 2.
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This Reactome-cited study directly compared lipin-1 and lipin-2 localization and regulation in HeLa M cells, not lipin-3.
"The two lipins display distinct intracellular localization in HeLa M cells, with a pool of lipin 2 exhibiting a tight membrane association."
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Lipin-2 depletion increased lipin-1 abundance and cellular PAP1 activity, demonstrating compensatory regulation between those paralogs.
"Small interfering RNA-mediated silencing of lipin 1 leads to a dramatic decrease of the cellular PAP1 activity in HeLa M cells, whereas silencing of lipin 2 leads to an increase of lipin 1 levels and PAP1 activity."