Details for: PLPP6

Gene ID: 403313

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: PLPP6

Ensembl ID: ENSG00000205808

Description: phospholipid phosphatase 6

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • colon goblet cell CL0009039
    CSI 1.83
    rCSI 4.35%
    PRS 99.67
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.35
    rCSI 3.27%
    PRS 98.39

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
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    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Phospholipid phosphatase 6 ([PLPP6](/details-gene/403313)) is a protein-coding gene located on chromosome 9p24.1. It encodes an integral membrane enzyme with broad lipid phosphatase activity, primarily localized to the endoplasmic reticulum and plasma membrane. The enzyme plays a crucial role in several metabolic pathways, including [cholesterol biosynthesis](/details-pathway/R-HSA-191273) by acting as a presqualene diphosphate phosphatase [Link](https://doi.org/10.1074/jbc.m512970200), and the metabolism of phospholipids like phosphatidate [Link](https://doi.org/10.1016/j.bbalip.2008.09.001). **Overall**, expression data indicates that [PLPP6](/details-gene/403313) is a gene of particularly high significance in secretory cells of the digestive tract, such as the [colon goblet cell](/details-cell/CL0009039), and in specific neuronal populations, including the [L2/3-6 intratelencephalic projecting glutamatergic neuron](/details-cell/CL4023040), suggesting diverse roles in both metabolic homeostasis and specialized cellular functions. ## Cellular Roles and Expression Landscape The expression profile of [PLPP6](/details-gene/403313) highlights its importance in distinct and functionally diverse cell types. The highest significance score (**Overall** context) is observed in the [colon goblet cell](/details-cell/CL0009039) (CSI: 1.83), a specialized epithelial cell responsible for synthesizing and secreting mucus. This strong association suggests that the lipid phosphatase activity of [PLPP6](/details-gene/403313) may be integral to the complex processes of vesicle formation, membrane trafficking, or lipid signaling required for mucin production and exocytosis in the gut. A significant, albeit lower, score is also found in the [L2/3-6 intratelencephalic projecting glutamatergic neuron](/details-cell/CL4023040) (CSI: 1.35). This indicates a potentially important role for [PLPP6](/details-gene/403313) in the central nervous system. Given its function in isoprenoid and cholesterol metabolism, its activity in these neurons could be linked to the maintenance of myelin sheaths, synaptic membrane integrity, or the synthesis of lipid-derived signaling molecules essential for neuronal health and communication. The prominent expression in these two disparate cell types suggests that [PLPP6](/details-gene/403313) performs fundamental roles in lipid metabolism that are adapted for specialized cellular demands. ## Pathways and Molecular Function Functionally, [PLPP6](/details-gene/403313) is annotated as a hydrolase with broad substrate specificity, primarily exerting [lipid phosphatase activity](/details-go/GO:0042577). Its molecular functions are central to lipid and sterol metabolism. It participates in the dephosphorylation of multiple key lipid intermediates, including phosphatidate ([GO:0008195](https://www.ebi.ac.uk/QuickGO/term/GO:0008195)), sphingosine-1-phosphate ([GO:0042392](https://www.ebi.ac.uk/QuickGO/term/GO:0042392)), and lysophosphatidic acid ([GO:0052642](https://www.ebi.ac.uk/QuickGO/term/GO:0052642)). A critical role for [PLPP6](/details-gene/403313) is in the [cholesterol biosynthetic process](/details-go/GO:0006695), as detailed in the Reactome pathway [Cholesterol biosynthesis](/details-pathway/R-HSA-191273). The enzyme has been identified as a presqualene diphosphate (PSDP) phosphatase, catalyzing a key step in the non-canonical "Squalene Synthase-like" pathway of cholesterol synthesis [Link](https://doi.org/10.1074/jbc.m512970200). It also acts on other isoprenoid diphosphates, such as farnesyl diphosphate ([GO:0045339](https://www.ebi.ac.uk/QuickGO/term/GO:0045339)) and geranylgeranyl diphosphate ([GO:1902247](https://www.ebi.ac.uk/QuickGO/term/GO:1902247)), linking it broadly to [isoprenoid metabolic processes](/details-go/GO:0006720) and protein prenylation ([GO:0018342](https://www.ebi.ac.uk/QuickGO/term/GO:0018342)). Beyond its metabolic functions, [PLPP6](/details-gene/403313) is also implicated in the [innate immune response](/details-go/GO:0045087). Specifically, it is involved in the [positive regulation of neutrophil activation](/details-go/GO:1902565). Research has shown that its activity can be regulated by anti-inflammatory lipids like 15-Epi-lipoxin A4, which inhibits neutrophil superoxide generation by modulating [PLPP6](/details-gene/403313) function [Link](https://doi.org/10.1096/fj.12-223982). ## Research Directions The distinct expression pattern and multifaceted functions of [PLPP6](/details-gene/403313) suggest several avenues for future research. The data points toward specialized roles in both mucosal biology and neurobiology that warrant further investigation. **Testable Hypotheses:** 1. In [colon goblet cells](/details-cell/CL0009039), the high expression of [PLPP6](/details-gene/403313) is essential for maintaining endoplasmic reticulum membrane homeostasis during the high-volume synthesis and packaging of mucin proteins into granules, where its phosphatidate phosphatase activity regulates membrane lipid composition. 2. The expression of [PLPP6](/details-gene/403313) in [glutamatergic neurons](/details-cell/CL4023040) is critical for local isoprenoid and cholesterol metabolism, which supports the structural integrity of dendritic spines and synaptic vesicles, thereby influencing synaptic plasticity. 3. Given its role in regulating neutrophil activation, [PLPP6](/details-gene/403313) activity within the colonic mucosa acts as a homeostatic brake on inflammation, and its dysregulation could be a contributing factor to inflammatory bowel disease (IBD). **Proposed Experimental Approach:** To test the first hypothesis regarding its role in [colon goblet cells](/details-cell/CL0009039), a powerful approach would be to use a CRISPR-Cas9-mediated knockout of [PLPP6](/details-gene/403313) in human colon organoids. Following successful knockout, the organoids could be analyzed for defects in goblet cell function. Key readouts would include: (i) quantification of MUC2 expression and localization using immunofluorescence, (ii) assessment of mucus granule morphology and number via transmission electron microscopy, and (iii) measurement of secreted mucins in the culture supernatant by ELISA. Furthermore, lipidomic analysis of the organoids could directly assess whether loss of [PLPP6](/details-gene/403313) leads to an accumulation of its substrates, such as phosphatidic acid, and alters the overall lipid landscape of the endoplasmic reticulum. **Therapeutic Potential:** The function of [PLPP6](/details-gene/403313) presents a nuanced therapeutic landscape. Its demonstrated role in down-regulating neutrophil activation [Link](https://doi.org/10.1096/fj.12-223982) suggests it could be a target for inflammatory diseases. Developing small molecule activators of [PLPP6](/details-gene/403313) could represent a novel anti-inflammatory strategy, particularly for gut-related inflammation like IBD, where its expression is naturally high in the target tissue. Conversely, because cholesterol biosynthesis pathways are often upregulated in cancers, inhibition of [PLPP6](/details-gene/403313) might be explored as a potential strategy to disrupt cancer cell metabolism, although this would require careful consideration of on-target effects in healthy tissues like the nervous system and gut.

Genular Protein ID: 30241655

Symbol: PLPP6_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q8IY26 B3KY05 Q5JVJ6 Q8NCK9

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 40 ChiTaRS 1 DEPOD 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 4 Ensembl 1 GO 21 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 2 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 1 RefSeq 1 Rhea 18 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15164053

Title: DNA sequence and analysis of human chromosome 9.

PubMed ID: 15164053

DOI: 10.1038/nature02465

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 16464866

Title: Identification and functional characterization of a presqualene diphosphate phosphatase.

PubMed ID: 16464866

DOI: 10.1074/jbc.m512970200

PubMed ID: 18930839

Title: Novel function of the human presqualene diphosphate phosphatase as a type II phosphatidate phosphatase in phosphatidylcholine and triacylglyceride biosynthesis pathways.

PubMed ID: 18930839

DOI: 10.1016/j.bbalip.2008.09.001

PubMed ID: 19220020

Title: Activation of polyisoprenyl diphosphate phosphatase 1 remodels cellular presqualene diphosphate.

PubMed ID: 19220020

DOI: 10.1021/bi8020636

PubMed ID: 20110354

Title: Functional characterization of the atypical integral membrane lipid phosphatase PDP1/PPAPDC2 identifies a pathway for interconversion of isoprenols and isoprenoid phosphates in mammalian cells.

PubMed ID: 20110354

DOI: 10.1074/jbc.m109.083931

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 23568778

Title: 15-Epi-lipoxin A4 inhibits human neutrophil superoxide anion generation by regulating polyisoprenyl diphosphate phosphatase 1.

PubMed ID: 23568778

DOI: 10.1096/fj.12-223982

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

Sequence Information:

  • Length: 295
  • Mass: 32194
  • Checksum: 92024580CE727AED
  • Sequence:
    • MPSPRRSMEG RPLGVSASSS SSSPGSPAHG GGGGGSRFEF QSLLSSRATA VDPTCARLRA 
SESPVHRRGS FPLAAAGPSQ SPAPPLPEED RMDLNPSFLG IALRSLLAID LWLSKKLGVC 
AGESSSWGSV RPLMKLLEIS GHGIPWLLGT LYCLCRSDSW AGREVLMNLL FALLLDLLLV 
ALIKGLVRRR RPAHNQMDMF VTLSVDKYSF PSGHATRAAL MSRFILNHLV LAIPLRVLVV 
LWAFVLGLSR VMLGRHNVTD VAFGFFLGYM QYSIVDYCWL SPHNAPVLFL LWSQR