GO:0050732 negative regulation of peptidyl-tyrosine phosphorylation: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0050732 describes any process that stops, prevents, or reduces the phosphorylation of peptidyl-tyrosine residues on proteins.
• This regulatory process is central to controlling tyrosine kinase signaling, which is frequently dysregulated in cancer and other diseases.
• Key negative regulators include protein tyrosine phosphatases such as PTPN1, which remove phosphate groups from tyrosine residues.
• Dysregulation of this process contributes to glioma progression, testicular developmental defects, and heterotopic ossification.
• CRISPR-based knockout, point mutation, and knock-in models are essential for dissecting the causal roles of genes in this pathway.
• Network pharmacology and bioinformatics analyses have identified FYN, PTPN1, and other genes as core components of this regulatory network.
Description
Reversible phosphorylation of tyrosine residues is a fundamental mechanism for transmitting signals within and between cells. The addition of a phosphate group to tyrosine, catalyzed by protein tyrosine kinases, can activate or modulate protein function, but this modification must be tightly controlled. GO:0050732, negative regulation of peptidyl-tyrosine phosphorylation, encompasses all biological processes that stop, prevent, or reduce the frequency, rate, or extent of this phosphorylation event. This regulation is critical because excessive or inappropriate tyrosine phosphorylation can drive uncontrolled cell proliferation, survival, and migration, hallmarks of cancer and other diseases. Research into this GO term spans multiple disciplines, from cancer biology to developmental biology. For example, in glioma, differential methylation of genes involved in tyrosine phosphorylation regulation has been linked to tumorigenesis. In testicular development, the phosphatase PTPN1 (encoded by Ptpn1) acts as a negative regulator of tyrosine phosphorylation to control spermatogenesis. Similarly, in heterotopic ossification, aberrant signaling through tyrosine kinase pathways is modulated by negative regulators, and their dysregulation contributes to pathological bone formation. Understanding how these negative regulators function at the molecular level is essential for developing targeted therapies. This article synthesizes authoritative QuickGO data and verified PubMed literature to provide a comprehensive overview of GO:0050732. We cover the definition, biological importance, key genes, regulatory mechanisms, disease associations, and state-of-the-art research methods, including CRISPR-based models. By focusing on real, published findings, we aim to equip researchers with a reliable resource for studying this critical regulatory process.
negative regulation of peptidyl-tyrosine phosphorylation At A Glance
| GO ID | GO:0050732 |
|---|---|
| GO term | negative regulation of peptidyl-tyrosine phosphorylation |
| Ontology | biological_process |
| Synonym | down regulation of peptidyl-tyrosine phosphorylation, down-regulation of peptidyl-tyrosine phosphorylation, downregulation of peptidyl-tyrosine phosphorylation, inhibition of peptidyl-tyrosine phosphorylation |
| Major function | Stops, prevents, or reduces the phosphorylation of tyrosine residues on proteins, thereby modulating signal transduction pathways. |
| Related molecular function | Protein tyrosine phosphatase activity; protein tyrosine kinase inhibitor activity. |
| Related biological processes | Regulation of cell proliferation, differentiation, migration, and apoptosis. |
| Disease relevance | Cancer, developmental disorders, heterotopic ossification, and metabolic diseases. |
What Is GO:0050732?
According to the Gene Ontology, GO:0050732 (negative regulation of peptidyl-tyrosine phosphorylation) is defined as any process that stops, prevents, or reduces the frequency, rate or extent of the phosphorylation of peptidyl-tyrosine. In simpler terms, it includes all cellular mechanisms that put the brakes on the addition of phosphate groups to tyrosine residues on proteins. This can occur through the action of protein tyrosine phosphatases that remove phosphates, through inhibition of tyrosine kinases, or through sequestration of substrates. The term is a biological process and has synonyms such as down regulation of peptidyl-tyrosine phosphorylation, inhibition of peptidyl-tyrosine phosphorylation, and downregulation of peptidyl-tyrosine phosphorylation.
Why Is negative regulation of peptidyl-tyrosine phosphorylation Important in Cell Biology?
GO:0050732 is critically important because tyrosine phosphorylation is a central switch in cellular signaling, and its negative regulation prevents aberrant activation of growth, survival, and motility pathways. Dysregulation of this process is implicated in numerous human diseases, including glioma, where altered methylation of regulatory genes drives tumor progression, and testicular developmental defects, where loss of PTPN1 function disrupts spermatogenesis. Moreover, understanding negative regulation provides a framework for therapeutic intervention: restoring the brakes on tyrosine phosphorylation could counteract oncogenic signaling. As such, researchers across cancer biology, developmental biology, and pharmacology focus on identifying and characterizing the enzymes, adaptors, and regulatory networks that execute this process.
• Prevents uncontrolled cell proliferation by dampening growth factor receptor signaling.
• Maintains tissue homeostasis by balancing kinase and phosphatase activities.
• Its dysregulation is a hallmark of many cancers, including glioma and non-small cell lung cancer.
• Plays a role in developmental processes such as spermatogenesis and bone formation.
• Serves as a target for therapeutic intervention, e.g., phosphatase activators or kinase inhibitors.
• Involved in immune cell signaling and inflammatory responses.
• Modulates neuronal signaling and synaptic plasticity.
• Contributes to metabolic regulation, including insulin signaling.
• Provides biomarkers for prognosis, such as FYN in low-grade glioma.
• Essential for understanding off-target effects of tyrosine kinase inhibitors.
What Happens During negative regulation of peptidyl-tyrosine phosphorylation?
Dephosphorylation by Protein Tyrosine Phosphatases
In simple terms: Enzymes called phosphatases remove phosphate groups from tyrosine, acting as the primary brakes on tyrosine phosphorylation.
The most direct mechanism of negative regulation is the removal of phosphate groups from phosphorylated tyrosine residues by protein tyrosine phosphatases (PTPs). For example, PTPN1 (also known as PTP1B) dephosphorylates activated tyrosine kinases and their substrates, thereby terminating or attenuating signaling. In testicular development, Ptpn1 expression is regulated by miR-124-3p, and its activity is required for normal spermatogenesis; loss of Ptpn1 leads to hyperphosphorylation and defective germ cell development. Similarly, in glioma, differential methylation of genes such as PTPN1 may alter phosphatase activity, contributing to tumorigenesis.
Inhibition of Tyrosine Kinase Activity
In simple terms: Negative regulation can also occur by blocking the enzymes that add phosphate groups, either directly or indirectly.
Tyrosine kinases are the enzymes that catalyze peptidyl-tyrosine phosphorylation. Negative regulation can be achieved by inhibiting their activity through binding of endogenous inhibitors, such as suppressor of cytokine signaling (SOCS) proteins, or through phosphorylation of inhibitory sites on the kinases themselves. For instance, FYN, a Src-family kinase, is a key mediator of tyrosine phosphorylation, and its activity can be negatively regulated by C-terminal Src kinase (CSK)-mediated phosphorylation. In low-grade glioma, FYN overexpression is associated with poor prognosis, suggesting that loss of negative regulation contributes to disease.
Sequestration and Degradation of Signaling Components
In simple terms: Cells can reduce tyrosine phosphorylation by removing the kinases or their substrates from the signaling compartment.
Negative regulation can also occur through the sequestration of tyrosine kinases or their substrates away from the plasma membrane, or through their targeted degradation. For example, endocytosis of activated receptor tyrosine kinases (RTKs) followed by lysosomal degradation reduces the pool of available receptors for phosphorylation. Additionally, ubiquitin ligases such as CBL promote the ubiquitination and degradation of RTKs, thereby dampening downstream tyrosine phosphorylation. In heterotopic ossification, aberrant expression of genes involved in ubiquitin-mediated proteolysis may contribute to dysregulated tyrosine phosphorylation.
Feedback Loops and Crosstalk with Other Signaling Pathways
In simple terms: Signaling pathways are interconnected, and activation of one can trigger negative feedback that reduces tyrosine phosphorylation.
Many growth factor signaling pathways are subject to negative feedback loops. For instance, activation of the MAPK/ERK pathway downstream of RTKs can lead to phosphorylation of RTKs at inhibitory sites or induce expression of phosphatases such as DUSP (dual-specificity phosphatases) and SPRY proteins, which attenuate RTK signaling. In non-small cell lung cancer, network pharmacology analysis of fucosterol revealed that its anti-cancer effects involve modulation of multiple tyrosine phosphorylation-related pathways, highlighting the importance of crosstalk. Similarly, in glioma, core differentially methylated genes include those involved in feedback regulation of tyrosine kinase signaling.
Key Genes Involved in GO:0050732 negative regulation of peptidyl-tyrosine phosphorylation
The following genes and proteins are key players in the negative regulation of peptidyl-tyrosine phosphorylation, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PTPN1 | Protein tyrosine phosphatase that dephosphorylates tyrosine residues on target proteins. | Regulates testicular development and spermatogenesis; potential tumor suppressor. |
| FYN | Src-family tyrosine kinase; its activity is subject to negative regulation. | Overexpressed in low-grade glioma; biomarker for prognosis. |
| PTPN11 | Protein tyrosine phosphatase involved in dephosphorylation of RTKs. | Mutations cause Noonan syndrome and leukemia; negative regulator of Ras/MAPK signaling. |
| PTPRC | CD45, a receptor-type phosphatase that regulates Src-family kinases. | Modulates immune cell signaling; negative regulator of cytokine receptor signaling. |
| CSK | C-terminal Src kinase; phosphorylates inhibitory site of Src-family kinases. | Negative regulator of FYN and other Src kinases. |
| CBL | E3 ubiquitin ligase that targets RTKs for degradation. | Negatively regulates tyrosine phosphorylation by promoting RTK turnover. |
| SOCS1 | Suppressor of cytokine signaling; inhibits JAK tyrosine kinase activity. | Negative regulator of cytokine signaling; implicated in inflammation and cancer. |
| SOCS3 | Suppressor of cytokine signaling; inhibits JAK/STAT pathway. | Negative regulator of tyrosine phosphorylation in immune and metabolic cells. |
| PTPN6 | SHP-1, a phosphatase that negatively regulates hematopoietic signaling. | Tumor suppressor in leukemias and lymphomas. |
| PTPN2 | TCPTP, a phosphatase that dephosphorylates RTKs and JAKs. | Negative regulator of inflammation and cancer; target in immunotherapy. |
| DUSP1 | Dual-specificity phosphatase that dephosphorylates MAPK. | Indirectly reduces tyrosine phosphorylation by feedback inhibition. |
| SPRY2 | Sprouty homolog 2; inhibits RTK-mediated Ras/MAPK signaling. | Negative regulator of tyrosine phosphorylation in development and cancer. |
| ERRFI1 | MIG6, a negative regulator of EGFR; binds and inhibits EGFR kinase. | Feedback inhibitor of EGFR tyrosine phosphorylation. |
| LRIG1 | Leucine-rich repeats and immunoglobulin-like domains 1; enhances EGFR degradation. | Negative regulator of RTK signaling. |
| PTPRJ | DEP-1, a receptor-type phosphatase that dephosphorylates RTKs. | Tumor suppressor in breast and colon cancer. |
| PTPRO | Protein tyrosine phosphatase receptor type O; dephosphorylates RTKs. | Negative regulator of tumor growth; methylation-silenced in cancers. |
| PTPN13 | PTP-BAS, a large phosphatase involved in cell adhesion and signaling. | Negative regulator of tyrosine phosphorylation; implicated in cancer. |
| PTPN14 | Protein tyrosine phosphatase non-receptor type 14; regulates cell adhesion. | Negative regulator of YAP/TAZ signaling; tumor suppressor. |
How Is negative regulation of peptidyl-tyrosine phosphorylation Regulated?
The process of negative regulation of peptidyl-tyrosine phosphorylation is itself tightly regulated at multiple levels. Transcriptionally, expression of phosphatases such as PTPN1 can be induced by cytokines or growth factors as part of feedback loops. Post-translationally, phosphatase activity can be modulated by phosphorylation, oxidation, or SUMOylation. For example, reactive oxygen species can reversibly inhibit PTPs by oxidizing their catalytic cysteine, thereby transiently enhancing tyrosine phosphorylation. Additionally, microRNAs such as miR-124-3p can target phosphatases; in testicular development, miR-124-3p regulates Ptpn1 expression, thereby influencing the balance of tyrosine phosphorylation. In cancer, epigenetic silencing of phosphatase genes via promoter methylation, as seen for PTPRO and PTPRJ, can lead to loss of negative regulation and hyperactivation of tyrosine kinase signaling. Thus, the negative regulation of tyrosine phosphorylation is controlled by a complex interplay of genetic, epigenetic, and signaling mechanisms.
negative regulation of peptidyl-tyrosine phosphorylation and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| FYN | Low-grade glioma (LGG); prognosis biomarker | U251 or U87 glioma cell lines with FYN knockout or overexpression; xenograft mouse models. |
| PTPN1 | Testicular development and spermatogenesis defects | Mouse spermatogonial cell lines with Ptpn1 knockout; miR-124-3p mimic/inhibitor. |
| PTPN1 | Type 2 diabetes and obesity | Hepatocyte or adipocyte cell lines with PTPN1 knockout; insulin resistance models. |
| PTPN11 | Noonan syndrome and juvenile myelomonocytic leukemia | HEK293T or hematopoietic cell lines with point mutations (e.g., E76K); zebrafish models. |
| PTPRO | Breast and colon cancer; methylation-silenced tumor suppressor | MCF-7 or HCT116 cells with PTPRO overexpression or knockout; methylation-specific PCR. |
Cancer
Dysregulation of negative regulation of peptidyl-tyrosine phosphorylation is a common feature of many cancers. In glioma, differential methylation of core genes involved in this process, such as PTPN1 and FYN, has been associated with tumor progression and poor prognosis. FYN, a tyrosine kinase, is overexpressed in low-grade glioma and serves as a biomarker for unfavorable outcomes. In non-small cell lung cancer, network pharmacology studies have identified fucosterol as a compound that modulates multiple tyrosine phosphorylation-related pathways, suggesting that targeting negative regulators could be therapeutically beneficial. Loss of phosphatases like PTPRO and PTPRJ through promoter methylation leads to sustained tyrosine phosphorylation and oncogenic signaling.
Developmental and Reproductive Disorders
Proper negative regulation of tyrosine phosphorylation is essential for normal development. In mouse testis, the phosphatase PTPN1 is required for spermatogenesis; its expression is regulated by miR-124-3p, and disruption of this axis leads to defective germ cell development. This highlights how precise control of tyrosine phosphorylation is critical for reproductive biology. Additionally, in heterotopic ossification, aberrant tyrosine phosphorylation signaling contributes to pathological bone formation, and negative regulators may be dysregulated.
Metabolic and Inflammatory Diseases
PTPN1 (PTP1B) is a well-known negative regulator of insulin and leptin signaling. Its overexpression contributes to insulin resistance and obesity, making it a therapeutic target for type 2 diabetes. Similarly, PTPN2 and SOCS proteins negatively regulate cytokine signaling, and their dysregulation is linked to inflammatory bowel disease and autoimmune conditions. Thus, the negative regulation of tyrosine phosphorylation plays a broad role in metabolic and immune homeostasis.
From negative regulation of peptidyl-tyrosine phosphorylation-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of PTPN1 increase tyrosine phosphorylation in spermatogenesis? | Ptpn1 knockout mouse model or CRISPR-Cas9 knockout in GC-1 spermatogonial cells. |
| Does FYN overexpression drive glioma progression? | FYN overexpression in U87 glioma cells; orthotopic xenograft in mice. |
| Does a point mutation in PTPN11 affect phosphatase activity? | Knock-in of E76K or other mutations in HEK293T cells using CRISPR. |
| Can restoration of PTPRO suppress tumor growth? | PTPRO knock-in or overexpression in breast cancer cell lines; cell proliferation and migration assays. |
| What is the role of miR-124-3p in regulating Ptpn1? | miR-124-3p mimic/inhibitor transfection in mouse testicular cells; luciferase reporter assays. |
| Does fucosterol modulate tyrosine phosphorylation pathways in NSCLC? | A549 or H1299 cells treated with fucosterol; phospho-tyrosine proteomics. |
How to Study the negative regulation of peptidyl-tyrosine phosphorylation Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Phospho-tyrosine proteomics | Global levels of tyrosine phosphorylation on thousands of proteins | Discovering substrates of PTPN1 or other phosphatases. |
| Western blot with 4G10 antibody | Overall tyrosine phosphorylation levels | Validating changes after gene knockout or drug treatment. |
| CRISPR knockout screen | Genes whose loss increases tyrosine phosphorylation | Identifying novel negative regulators. |
| RNA-seq | Transcriptional changes in response to altered tyrosine phosphorylation | Pathway analysis in glioma or testicular cells. |
| Methylation-specific PCR | DNA methylation status of phosphatase promoters | Epigenetic silencing of PTPRO in cancer. |
| Luciferase reporter assay | miRNA-target interaction | Validating miR-124-3p regulation of Ptpn1. |
| Network pharmacology | Predicted compound-target-pathway interactions | Repurposing drugs like fucosterol for NSCLC. |
| Immunoprecipitation | Protein-protein interactions | Identifying binding partners of FYN or PTPN1. |
Phospho-Tyrosine Proteomics
Mass spectrometry-based phosphoproteomics allows global profiling of tyrosine phosphorylation sites. By comparing cells with and without a candidate negative regulator (e.g., PTPN1 knockout), researchers can identify specific tyrosine phosphorylation events that are regulated. This method is powerful for unbiased discovery of substrates and pathways.
Western Blotting with Phospho-Specific Antibodies
Immunoblotting using antibodies against phosphotyrosine (e.g., 4G10) or site-specific phospho-tyrosine antibodies provides a direct measure of phosphorylation levels on specific proteins. This is commonly used to validate findings from proteomics or to assess the impact of genetic perturbations.
CRISPR-Based Genetic Screens
Genome-wide CRISPR knockout or activation screens can identify genes that negatively regulate tyrosine phosphorylation. For example, a screen could use a phospho-tyrosine reporter to sort cells with high or low phosphorylation, followed by sequencing to identify enriched sgRNAs. This approach has been used to discover novel phosphatases and adaptors.
Network Pharmacology and Bioinformatics
Computational analyses integrating gene expression, methylation, and pathway databases can predict key negative regulators and their disease associations. For instance, network pharmacology identified fucosterol as a modulator of tyrosine phosphorylation pathways in NSCLC, and methylation analyses highlighted core genes in glioma. These methods guide experimental validation.
How CRISPR Can Be Used to Study GO:0050732 negative regulation of peptidyl-tyrosine phosphorylation
Knockout
CRISPR-Cas9 knockout is used to completely ablate a candidate negative regulator gene, such as PTPN1 or FYN, to assess its role in controlling tyrosine phosphorylation. For example, Ptpn1 knockout in mouse testicular cells leads to increased tyrosine phosphorylation and defective spermatogenesis. In glioma, FYN knockout reduces tumor cell proliferation and migration. Knockout models are essential for establishing causality.
Point Mutation
Point mutations can be introduced via CRISPR base editing or homology-directed repair to mimic disease-associated variants or to ablate catalytic activity. For instance, mutating the catalytic cysteine of PTPN1 to serine (C215S) creates a phosphatase-dead mutant, which can be used to dissect the importance of its enzymatic activity in negative regulation. Similarly, point mutations in PTPN11 (e.g., E76K) found in leukemia can be knocked into cell lines to study gain-of-function effects.
Knock-in
Knock-in of reporter tags (e.g., GFP, HA) or of entire genes at endogenous loci allows for real-time tracking of protein expression and localization. For example, knocking in a GFP tag on PTPN1 enables live-cell imaging of its dynamics during signaling. Knock-in of a constitutively active or dominant-negative allele can also be used to probe pathway function without altering endogenous regulation.
Overexpression
CRISPR activation (CRISPRa) or lentiviral overexpression is used to increase the levels of a negative regulator to test whether it can suppress tyrosine phosphorylation and downstream phenotypes. Overexpressing PTPRO in breast cancer cells reduces tyrosine phosphorylation and inhibits tumor growth. Overexpression of miR-124-3p, which targets Ptpn1, can downregulate the phosphatase and increase phosphorylation. These models are valuable for therapeutic target validation.
How EDITGENE Supports negative regulation of peptidyl-tyrosine phosphorylation Research
Researchers studying negative regulation of peptidyl-tyrosine phosphorylation-related genes often need to determine whether a candidate gene is causally involved in the process or merely correlated. This requires precise genetic manipulation, such as knockout, point mutation, knock-in, or overexpression, followed by functional assays. EDITGENE provides end-to-end CRISPR services to accelerate such discoveries.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of peptidyl-tyrosine phosphorylation research.
Frequently Asked Questions About negative regulation of peptidyl-tyrosine phosphorylation
What is GO:0050732?
GO:0050732 is the Gene Ontology term for negative regulation of peptidyl-tyrosine phosphorylation, defined as any process that stops, prevents, or reduces the phosphorylation of tyrosine residues on proteins.
What genes are involved in negative regulation of peptidyl-tyrosine phosphorylation?
Key genes include protein tyrosine phosphatases such as PTPN1, PTPN11, PTPRC, and PTPRO, as well as kinases like FYN and CSK, and adaptors such as CBL and SOCS proteins.
How does PTPN1 negatively regulate tyrosine phosphorylation?
PTPN1 is a phosphatase that removes phosphate groups from tyrosine residues on target proteins, thereby terminating or attenuating signaling. Its activity is essential for processes like spermatogenesis.
Why is negative regulation of tyrosine phosphorylation important in cancer?
Loss of negative regulation leads to sustained tyrosine phosphorylation, which drives uncontrolled cell growth and survival. For example, FYN overexpression in glioma is associated with poor prognosis.
What diseases are linked to dysregulation of this process?
Diseases include glioma, non-small cell lung cancer, testicular developmental defects, heterotopic ossification, type 2 diabetes, and inflammatory disorders.
How can CRISPR be used to study negative regulation of tyrosine phosphorylation?
CRISPR knockout, point mutation, knock-in, and overexpression models allow researchers to manipulate candidate genes and assess effects on tyrosine phosphorylation and downstream phenotypes.
What methods are used to measure tyrosine phosphorylation?
Common methods include phospho-tyrosine western blotting, mass spectrometry-based phosphoproteomics, and immunoprecipitation followed by kinase assays.
What is the role of FYN in glioma?
FYN is a tyrosine kinase that is overexpressed in low-grade glioma and serves as a biomarker for poor prognosis; its activity is normally kept in check by negative regulators like CSK.
How does miR-124-3p regulate PTPN1?
miR-124-3p targets Ptpn1 mRNA, reducing its expression and thereby increasing tyrosine phosphorylation, which affects testicular development.
Can network pharmacology identify drugs targeting this pathway?
Yes, network pharmacology has been used to show that compounds like fucosterol modulate multiple tyrosine phosphorylation-related pathways in non-small cell lung cancer.
Conclusion
GO:0050732, negative regulation of peptidyl-tyrosine phosphorylation, is a fundamental biological process that maintains cellular signaling homeostasis. Its dysregulation is implicated in a wide range of diseases, from cancer to developmental and metabolic disorders. Key genes such as PTPN1, FYN, and PTPN11 serve as critical nodes, and their functions are being dissected using advanced CRISPR models and phosphoproteomics. Continued research into this process promises to uncover new therapeutic targets and biomarkers. EDITGENE provides comprehensive CRISPR services, including knockout, point mutation, knock-in, overexpression, and library screening, to support researchers in exploring this pathway. By leveraging our expertise, scientists can accelerate the translation of basic findings into clinical applications.
References
- 1. Zhu J et al.. 2024. FYN as an emerging biological biomarker for prognosis and potential therapeutic target in LGG.. Neurol Res 46(9):787-795 PMID: 38752708
- 2. Xue J et al.. 2019. Identification of core differentially methylated genes in glioma.. Oncol Lett 18(6):6033-6045 PMID: 31788078
- 3. Luo L et al.. 2024. miR-124-3p regulates the involvement of Ptpn1 in testicular development and spermatogenesis in mouse.. Gene 893:147967 PMID: 37931856
- 4. Li X et al.. 2024. Genetic structure and selective sweeps in Kirghiz sheep using SNP50K bead chip.. Front Genet 15:1432105 PMID: 39233740
- 5. Li X et al.. 2021. Exploration in the mechanism of fucosterol for the treatment of non-small cell lung cancer based on network pharmacology and molecular docking.. Sci Rep 11(1):4901 PMID: 33649481
- 6. Yang Z et al.. 2021. Potential genes and pathways associated with heterotopic ossification derived from analyses of gene expression profiles.. J Orthop Surg Res 16(1):499 PMID: 34389038
