Details for: PTHLH

Gene ID: 5744

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: PTHLH

Ensembl ID: ENSG00000087494

Description: parathyroid hormone like hormone

Cell Significance Landscape

Associated with

Significant Cells

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

  • glial cell CL0000125
    CSI 5.53
    rCSI 21.04%
    PRS 94.05
  • bronchus fibroblast of lung CL2000093
    CSI 4.49
    rCSI 3.65%
    PRS 97.53
  • neural progenitor cell CL0011020
    CSI 4.07
    rCSI 17.89%
    PRS 90.92
  • epithelial cell CL0000066
    CSI 3.87
    rCSI 5.94%
    PRS 90.23
  • luminal epithelial cell of mammary gland CL0002326
    CSI 3.61
    rCSI 6.57%
    PRS 98.55
  • VIP GABAergic cortical interneuron CL4023016
    CSI 3.5
    rCSI 4.19%
    PRS 92.27
  • basal cell CL0000646
    CSI 3.27
    rCSI 4.37%
    PRS 96
  • respiratory basal cell CL0002633
    CSI 2.92
    rCSI 3.03%
    PRS 97.87
  • alveolar adventitial fibroblast CL4028006
    CSI 2.86
    rCSI 4.52%
    PRS 98.07
  • chondrocyte CL0000138
    CSI 2.81
    rCSI 4.47%
    PRS 95.44
  • respiratory hillock cell CL4030023
    CSI 2.7
    rCSI 4.82%
    PRS 98.32
  • stem cell CL0000034
    CSI 2.41
    rCSI 2.32%
    PRS 96.3
  • GABAergic neuron CL0000617
    CSI 2.1
    rCSI 7.02%
    PRS 89.95
  • melanocyte of skin CL1000458
    CSI 1.48
    rCSI 2.01%
    PRS 79.24
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 1.28
    rCSI 3.99%
    PRS 93.6
  • hair follicular keratinocyte CL2000092
    CSI 0.41
    rCSI 7.2%
    PRS 96.77

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

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • 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 [PTHLH](/details-gene/5744) encodes the parathyroid hormone-like hormone, a secreted protein critically involved in skeletal development, calcium homeostasis, and cell signaling. Initially identified as the causative agent in humoral hypercalcemia of malignancy ([168470](https://omim.org/entry/168470)) ([Link](https://doi.org/10.1126/science.3616618), [Link](https://doi.org/10.1073/pnas.85.2.597)), its physiological roles are pleiotropic. **Overall**, expression data reveals its significance not only in expected cell types like `chondrocyte`s ([CL:0000138]) but also highlights a prominent role in a diverse array of other cells, including `glial cell`s ([CL:0000125]), `bronchus fibroblast of lung` ([CL:2000093]), and various `epithelial cell` ([CL:0000066]) populations. This broad expression pattern underscores its function as a versatile signaling molecule in tissue development, maintenance, and pathological processes. ## Cellular Roles and Expression Landscape The expression profile of [PTHLH](/details-gene/5744) indicates its widespread importance across multiple cellular lineages, extending beyond its classical role in bone and mineral metabolism. **Overall**, the gene shows the highest significance in non-classical cell types, suggesting diverse paracrine or autocrine functions. It is a top marker in `glial cell`s ([CL:0000125]) (CSI: 5.53) and `neural progenitor cell`s ([CL:0011020]) (CSI: 4.07), pointing towards a potential role in nervous system development or homeostasis. Its strong signal in structural cells, such as `bronchus fibroblast of lung` ([CL:2000093]) (CSI: 4.49) and `alveolar adventitial fibroblast` ([CL:4028006]) (CSI: 2.86), is consistent with its involvement in tissue architecture and repair. A key functional axis for [PTHLH](/details-gene/5744) is in epithelial biology. It is highly significant in various epithelial populations, including general `epithelial cell`s ([CL:0000066]) (CSI: 3.87), `luminal epithelial cell of mammary gland` ([CL:0002326]) (CSI: 3.61), `basal cell`s ([CL:0000646]) (CSI: 3.27), and `respiratory basal cell`s ([CL:0002633]) (CSI: 2.92). This suggests a critical function in regulating epithelial proliferation and differentiation in organs like the lung and mammary gland. Finally, its established role in skeletal development is confirmed by its significant expression in `chondrocyte`s ([CL:0000138]) (CSI: 2.81). ## Pathways and Molecular Function [PTHLH](/details-gene/5744) functions primarily as a secreted hormone ([GO:0005179]) that initiates intracellular signaling cascades by binding to G protein-coupled receptors ([GO:0051428]). Its activity is central to several developmental and metabolic processes. The gene's role in skeletal biology is well-supported by its annotation in processes such as `skeletal system development` ([GO:0001501](https://www.ebi.ac.uk/QuickGO/term/GO:0001501)), `bone mineralization` ([GO:0030282](https://www.ebi.ac.uk/QuickGO/term/GO:0030282)), `osteoblast development` ([GO:0002076](https://www.ebi.ac.uk/QuickGO/term/GO:0002076)), and the dual `regulation of chondrocyte differentiation` ([GO:0032330](https://www.ebi.ac.uk/QuickGO/term/GO:0032330)). These functions are consistent with its expression in `chondrocyte`s ([CL:0000138]) and are mediated through signaling pathways that modulate cell proliferation, including both `positive regulation of cell population proliferation` ([GO:0008284](https://www.ebi.ac.uk/QuickGO/term/GO:0008284)) and `negative regulation of cell population proliferation` ([GO:0008285](https://www.ebi.ac.uk/QuickGO/term/GO:0008285)), highlighting its context-dependent effects. Mechanistically, [PTHLH](/details-gene/5744) acts through the `adenylate cyclase-activating g protein-coupled receptor signaling pathway` ([GO:0007189](https://www.ebi.ac.uk/QuickGO/term/GO:0007189)), a process detailed in Reactome pathways like `Gpcr ligand binding` ([R-HSA-500792](https://reactome.org/content/detail/R-HSA-500792)) and `G alpha (s) signalling events` ([R-HSA-418555](https://reactome.org/content/detail/R-HSA-418555)). The annotation for `epidermis development` ([GO:0008544](https://www.ebi.ac.uk/QuickGO/term/GO:0008544)) aligns with its high significance in multiple `epithelial cell` ([CL:0000066]) and `basal cell` ([CL:0000646]) types, suggesting it is a key paracrine factor in skin and other epithelial tissues. Some studies also suggest it can translocate to the nucleus and function as an intracrine factor, directly participating in the `regulation of gene expression` ([GO:0010468](https://www.ebi.ac.uk/QuickGO/term/GO:0010468)) ([Link](https://doi.org/10.1210/en.2002-220818)). ## Research Directions The broad expression pattern of [PTHLH](/details-gene/5744) suggests functions beyond its established roles, opening several avenues for future investigation. Its association with cancer provides a strong rationale for exploring its context-specific activities as a potential therapeutic target. **Testable Hypotheses:** 1. Given its high significance in `glial cell`s ([CL:0000125]), `neural progenitor cell`s ([CL:0011020]), and `GABAergic neuron`s ([CL:0000617]), [PTHLH](/details-gene/5744) likely functions as a local neuromodulator or developmental factor within the central nervous system, regulating neurogenesis or glial-neuronal interactions independently of systemic calcium regulation. 2. The prominent expression of [PTHLH](/details-gene/5744) in `respiratory basal cell`s ([CL:0002633]) and `bronchus fibroblast of lung` ([CL:2000093]) suggests it is a critical paracrine signaling molecule that governs epithelial homeostasis and repair in the lung. Dysregulation of this axis may contribute to the pathogenesis of lung diseases, including cancer. **Proposed Experiment:** To test the role of [PTHLH](/details-gene/5744) in lung epithelial homeostasis (Hypothesis 2), a co-culture system using primary human `respiratory basal cell`s ([CL:0002633]) and `bronchus fibroblast of lung` ([CL:2000093]) could be employed to form 3D bronchial organoids. Specific knockout or knockdown of [PTHLH](/details-gene/5744) in the fibroblast population using CRISPR-Cas9 or shRNA would elucidate its paracrine role. The effects on basal cell proliferation (Ki-67 staining), differentiation into ciliated and secretory cells (immunofluorescence for lineage markers), and overall organoid morphology would be assessed via confocal microscopy and single-cell RNA sequencing to define its specific impact on the epithelial stem/progenitor niche. **Therapeutic Potential:** As the primary mediator of humoral hypercalcemia of malignancy, [PTHLH](/details-gene/5744) is a well-validated therapeutic target. Because it is a secreted protein, it is highly amenable to **inhibition** by biologic therapies. Neutralizing monoclonal antibodies that bind and sequester circulating [PTHLH](/details-gene/5744) could effectively treat this paraneoplastic syndrome. Such a strategy would not target the tumor directly but would alleviate a major source of morbidity and mortality in patients with certain cancers, particularly squamous cell carcinomas of the lung, head, and neck.

Genular Protein ID: 2609766213

Symbol: PTHR_HUMAN

Name: Parathyroid hormone-related protein

UniProtKB Accession Codes:

P12272 Q15251 Q6FH74

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CPTC 1 CTD 1 ChEMBL 1 DMDM 1 DNASU 1 DisGeNET 1 DisProt 1 EMBL 16 EMDB 3 Ensembl 7 EvolutionaryTrace 1 ExpressionAtlas 1 GO 22 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HPA 1 IDEAL 1 InParanoid 1 IntAct 1 InterPro 2 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 11 PDBsum 11 PIR 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 RNAct 1 Reactome 2 RefSeq 8 SIGNOR 1 SMART 1 SMR 1 STRING 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 3616618

Title: A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression.

PubMed ID: 3616618

DOI: 10.1126/science.3616618

PubMed ID: 2829195

Title: Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy.

PubMed ID: 2829195

DOI: 10.1073/pnas.85.2.597

PubMed ID: 2708388

Title: Characterization of the human parathyroid hormone-like peptide gene. Functional and evolutionary aspects.

PubMed ID: 2708388

DOI: 10.1016/s0021-9258(18)83294-x

PubMed ID: 3290897

Title: Human renal carcinoma expresses two messages encoding a parathyroid hormone-like peptide: evidence for the alternative splicing of a single-copy gene.

PubMed ID: 3290897

DOI: 10.1073/pnas.85.13.4605

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: 2744490

Title: Structure of the 5' flanking region of the gene encoding human parathyroid-hormone-related protein (PTHrP).

PubMed ID: 2744490

DOI: 10.1016/0378-1119(89)90363-6

PubMed ID: 2885845

Title: Parathyroid hormone-related protein purified from a human lung cancer cell line.

PubMed ID: 2885845

DOI: 10.1073/pnas.84.14.5048

PubMed ID: 2928340

Title: Isolation and characterization of the human parathyroid hormone-like peptide gene.

PubMed ID: 2928340

DOI: 10.1073/pnas.86.7.2408

PubMed ID: 1915066

Title: A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts.

PubMed ID: 1915066

DOI: 10.1210/endo-129-4-1762

PubMed ID: 1954916

Title: A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein; PTHrP107-111.

PubMed ID: 1954916

DOI: 10.1210/endo-129-6-3424

PubMed ID: 9144344

Title: C-terminal parathyroid hormone-related protein inhibits proliferation and differentiation of human osteoblast-like cells.

PubMed ID: 9144344

DOI: 10.1359/jbmr.1997.12.5.778

PubMed ID: 9048639

Title: Parathyroid hormone-related protein-(107-139) inhibits bone resorption in vivo.

PubMed ID: 9048639

DOI: 10.1210/endo.138.3.4990

PubMed ID: 12852260

Title: Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles.

PubMed ID: 12852260

DOI: 10.1016/s0083-6729(03)01010-0

PubMed ID: 11401507

Title: Molecular dissection of the importin beta1-recognized nuclear targeting signal of parathyroid hormone-related protein.

PubMed ID: 11401507

DOI: 10.1006/bbrc.2001.4607

PubMed ID: 12538599

Title: Minireview: parathyroid hormone-related protein as an intracrine factor -- trafficking mechanisms and functional consequences.

PubMed ID: 12538599

DOI: 10.1210/en.2002-220818

PubMed ID: 20637541

Title: PTHrP promotes colon cancer cell migration and invasion in an integrin alpha6beta4-dependent manner through activation of Rac1.

PubMed ID: 20637541

DOI: 10.1016/j.canlet.2010.06.009

PubMed ID: 10050767

Title: The structure of human parathyroid hormone-related protein(1-34) in near-physiological solution.

PubMed ID: 10050767

DOI: 10.1016/s0014-5793(98)01658-5

PubMed ID: 12504010

Title: Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta.

PubMed ID: 12504010

DOI: 10.1016/s1097-2765(02)00727-x

PubMed ID: 19674967

Title: Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides.

PubMed ID: 19674967

DOI: 10.1074/jbc.m109.022905

PubMed ID: 16959974

Title: The consensus coding sequences of human breast and colorectal cancers.

PubMed ID: 16959974

DOI: 10.1126/science.1133427

PubMed ID: 20170896

Title: Deletion and point mutations of PTHLH cause brachydactyly type E.

PubMed ID: 20170896

DOI: 10.1016/j.ajhg.2010.01.023

Sequence Information:

  • Length: 177
  • Mass: 20194
  • Checksum: 449FDFEE954C51DB
  • Sequence:
    • MQRRLVQQWS VAVFLLSYAV PSCGRSVEGL SRRLKRAVSE HQLLHDKGKS IQDLRRRFFL 
HHLIAEIHTA EIRATSEVSP NSKPSPNTKN HPVRFGSDDE GRYLTQETNK VETYKEQPLK 
TPGKKKKGKP GKRKEQEKKK RRTRSAWLDS GVTGSGLEGD HLSDTSTTSL ELDSRRH

Genular Protein ID: 3182773271

Symbol: Q53XY9_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q53XY9

Database IDs:

ARBA 2 AlphaFoldDB 1 Antibodypedia 1 BioGRID-ORCS 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 6 ExpressionAtlas 1 GO 7 InterPro 2 NCBI Taxonomy 1 OMA 1 OrthoDB 1 PANTHER 2 PROSITE 1 Pfam 1 PharmGKB 1 RefSeq 2 RuleBase 1 SAM 2 SMART 1 SMR 1 UCSC 1 VEuPathDB 1

Citations:

PubMed ID: 11181995

Title: The sequence of the human genome.

PubMed ID: 11181995

DOI: 10.1126/science.1058040

Sequence Information:

  • Length: 175
  • Mass: 19901
  • Checksum: 4FEE954C51DB3E7D
  • Sequence:
    • MQRRLVQQWS VAVFLLSYAV PSCGRSVEGL SRRLKRAVSE HQLLHDKGKS IQDLRRRFFL 
HHLIAEIHTA EIRATSEVSP NSKPSPNTKN HPVRFGSDDE GRYLTQETNK VETYKEQPLK 
TPGKKKKGKP GKRKEQEKKK RRTRSAWLDS GVTGSGLEGD HLSDTSTTSL ELDSR