PTPRD: The Overlooked Signaling Hub from Neurodevelopment to Cancer Suppression

1. PTPRD Overview: Structure, Expression, and Core Physiological Functions

1.1 Molecular Structural Characteristics and Classification of PTPRD

PTPRD belongs to the protein tyrosine phosphatase (PTP) family, which comprises 107 members classified into receptor-type and non-receptor types based on structural features ^[3]. Receptor-type PTPs possess a single transmembrane domain and a variable extracellular domain related to cell adhesion, while their intracellular portion contains two tandem PTP domains (D1 and D2) ^[3]. PTPRD is a member of the leukocyte common antigen-related (LAR) subfamily of receptor-type PTPs, constituting, along with PTPRF and PTPRS, the human members of this subfamily ^[1].

Structurally, PTPRD consists of three key parts: First, the extracellular region, containing 3 immunoglobulin-like (Ig-like) domains and 8 type III fibronectin-like domains, which confer functions akin to cell adhesion molecules, enabling participation in cell-cell interactions ^{[1, 3]}. Second, a single transmembrane region, responsible for anchoring the protein to the cell membrane. Third, the intracellular region, containing two tandem catalytic domains (D1 and D2). D1 is the core domain mediating cytosolic protein phosphatase activity; although D2 shares sequence homology with phosphatases, it exhibits very low enzymatic activity and primarily serves a regulatory role, downregulating the phosphatase activity of D1 ^[1].

1.2 Tissue Distribution and Expression Characteristics of PTPRD

PTPRD expression exhibits a degree of tissue specificity. Analysis of human RNA sequencing data reveals its highest expression level in the brain (RPKM value 18.0), followed by the kidney (RPKM value 8.8), with varying levels of expression also detected in 14 other tissues, including the colon and breast ^{[1, 3]}. Within the nervous system, PTPRD expression is crucial for neurodevelopment. For instance, it can bind to SLIT- and NTRK-like family (SLITRK) proteins, promoting the accumulation of the vesicular GABA transporter (VGAT), a marker of synaptic specification, indicating PTPRD's role as a ligand in neuronal cell adhesion ^[1].

1.3 Core Physiological Functions of PTPRD: From Neurodevelopment to Metabolic Regulation

Under physiological conditions, PTPRD performs widespread and critical functions. At the cellular level, it participates in various processes such as cell proliferation, differentiation, migration, and apoptosis by regulating cell signal transduction ^[3]. At the tissue and organ level, beyond nervous system development, PTPRD plays a role in liver metabolic regulation. For example, in the fetal liver, PTPRD is involved in regulating pathways like glucose metabolism and amino acid degradation, maintaining normal metabolic homeostasis ^[8]. Furthermore, PTPRD is closely associated with cell adhesion functions. By interacting with cell adhesion molecules such as E-cadherin and β-catenin, it maintains the stability of intercellular junctions, thereby regulating epithelial cell contacts ^{[1, 3]}.

1.4 Association of PTPRD Abnormal Expression with Disease

Substantial recent evidence confirms that aberrant expression or functional loss of PTPRD is closely linked to the pathogenesis and progression of numerous diseases. In the field of cancer, PTPRD is frequently inactivated due to genetic mutations, deletions, copy number loss, or epigenetic modifications (such as promoter hypermethylation). Downregulated expression or functional loss of PTPRD has been observed in various malignancies including hepatocellular carcinoma, gastric cancer, glioblastoma, and breast cancer, suggesting its potential role as a tumor suppressor gene ^{[1, 2, 4, 6]}. In metabolic diseases, epigenetic silencing of PTPRD can lead to impaired insulin receptor signaling, subsequently causing insulin resistance, which is closely associated with the development of type 2 diabetes ^{[3, 5]}. In neurological diseases, PTPRD gene knockout may lead to cognitive impairment, and can also cause hearing loss, reduced sensitivity to diabetes, and increased risk of hypertension, indicating its importance for maintaining normal function in the nervous, endocrine, and cardiovascular systems ^[1].

2. Core Signaling Pathways and Molecular Mechanisms Regulated by PTPRD

PTPRD participates in physiological and pathological processes by regulating multiple key signaling pathways. These pathways are interconnected and interact, collectively forming the PTPRD signaling regulatory network.

2.1 STAT3 Pathway: A Key Action Target of PTPRD in Cancer

The STAT3 signaling pathway is one of the core pathways regulated by PTPRD and plays a pivotal role in various pathological processes, including cancer and inflammation ^{[1, 3, 6]}. STAT3, a cytoplasmic transcription factor, can be activated by external stimuli such as cytokines (e.g., IL-6) and growth factors. PTPRD primarily regulates the STAT3 pathway through negative feedback. PTPRD can directly interact with STAT3 and, via its D1 domain, dephosphorylate STAT3 at the Y705 site, inhibiting STAT3 dimerization and nuclear translocation, thereby blocking the expression of its downstream target genes ^{[1, 3]}. In hepatocellular carcinoma, PTPRD inactivation leads to sustained STAT3 phosphorylation, activating target genes like MMP-2 and MMP-9, and promoting tumor cell proliferation and invasion ^[1]; in glioblastoma, PTPRD loss causes aberrant STAT3 activation, maintaining tumor stem cell properties and enhancing the malignant phenotype ^[6]; in gastric cancer, PTPRD inhibits STAT3 activation, downregulating CXCL8 expression and thereby suppressing tumor angiogenesis ^[2]. Furthermore, in non-alcoholic fatty liver disease, PTPRD can attenuate STAT3 (Tyr705) phosphorylation, participating in disease pathogenesis ^[1].

2.2 Insulin Receptor Pathway: How PTPRD Regulates Glucose Metabolism and Diabetes

The insulin receptor signaling pathway is crucial for regulating glucose metabolism, and PTPRD helps maintain metabolic homeostasis by modulating this pathway ^{[3, 5]}. On one hand, PTPRD can directly regulate the activation state of the insulin receptor and support the initiation and transmission of insulin signals ^[3]; on the other hand, PTPRD can indirectly regulate this pathway by activating PPARγ2, a nuclear receptor that activates the expression of insulin sensitivity-related genes, enhancing cellular response to insulin ^[5]. When PTPRD is silenced due to DNA hypermethylation, its promotive effect on insulin receptor phosphorylation is weakened, and PPARγ2 activation becomes insufficient. This leads to impaired insulin receptor signaling, decreased cellular insulin sensitivity, insulin resistance, and ultimately the development of type 2 diabetes ^[5]. In the fetal liver under intrauterine growth restriction, downregulated PTPRD expression also affects the normal function of the insulin receptor signaling pathway, leading to disordered glucose metabolism ^[8].

2.3 NF-κB Pathway: PTPRD's Negative Regulation of Inflammation and Cancer

The NF-κB signaling pathway is important for regulating inflammatory responses and tumor progression. PTPRD suppresses the occurrence and development of inflammation and cancer by negatively regulating this pathway ^{[6, 7]}. Firstly, PTPRD can directly interact with the IKK complex, inhibiting IKK activity, thereby reducing IκB phosphorylation and degradation, and maintaining NF-κB in an inactive state ^[6]. Secondly, PTPRD can indirectly affect NF-κB activity by regulating the STAT3 signaling pathway; STAT3 can interact with NF-κB, cooperatively activating downstream genes. By inhibiting STAT3 activation, PTPRD indirectly attenuates NF-κB transcriptional activity ^[6]. Additionally, PTPRD can influence NF-κB pathway activation by regulating the expression of inflammatory factors like IL-6. IL-6 can indirectly activate NF-κB via the JAK/STAT3 pathway; by suppressing IL-6 expression, PTPRD reduces NF-κB activation ^[7]. In glioblastoma, PTPRD inactivation leads to enhanced NF-κB activity, promoting the release of inflammatory factors, creating a pro-tumor microenvironment, and increasing tumor cell resistance to radiotherapy and chemotherapy ^[6]; in hepatocellular carcinoma, PTPRD inhibits the NF-κB signaling pathway, reducing the expression of inflammation-related genes and suppressing tumorigenesis and development ^[1].

2.4 CXCL8/Angiogenesis Signaling Pathway: Mechanism of PTPRD in Inhibiting Tumor Metastasis

The CXCL8/angiogenesis signaling pathway is key for regulating tumor angiogenesis. PTPRD influences tumor growth and metastasis by modulating this pathway ^[2]. Under normal conditions, PTPRD can reduce the transcription and secretion of CXCL8 by inhibiting the ERK and STAT3 signaling pathways ^[2]. In gastric cancer, PTPRD is inactivated due to gene mutation, deletion, or methylation, weakening its inhibitory effect on ERK and STAT3. This leads to sustained activation of ERK and STAT3, subsequently upregulating CXCL8 expression. Upon binding to receptors on the surface of vascular endothelial cells, CXCL8 activates the tube-forming capacity of these cells, promoting tumor angiogenesis to supply nutrients and oxygen for tumor growth. Simultaneously, it can promote the migration and invasion of gastric cancer cells, accelerating tumor metastasis ^[2]. Furthermore, in hepatocellular carcinoma, loss of PTPRD can also lead to increased CXCL8 expression, further promoting angiogenesis and progression of liver cancer ^[1].

2.5 Wnt/β-catenin Pathway: Role of PTPRD in Cell Adhesion and Migration

The Wnt/β-catenin/TCF signaling pathway plays significant roles in embryonic development and tumorigenesis. PTPRD regulates the Wnt/β-catenin/TCF pathway primarily through interaction with β-catenin. PTPRD can interact with cell adhesion molecules like β-catenin and E-cadherin via its D2 domain, while simultaneously dephosphorylating β-catenin, inhibiting the activation of the β-catenin/TCF signaling pathway, thereby suppressing cell migration and tumor progression ^[1]. In colon cancer, PTPRD acts synergistically with CD44, inhibiting the β-catenin/TCF pathway by dephosphorylating β-catenin, thus inhibiting colon cancer cell migration ^[1]; in hepatocellular carcinoma, PTPRD inactivation leads to aberrant activation of the β-catenin/TCF pathway, upregulation of downstream target genes, and promotion of liver cancer cell proliferation and invasion ^[1]. Additionally, PTPRD can further inhibit β-catenin nuclear translocation and attenuate its transcriptional activity by maintaining intercellular adhesion junctions ^[3].

3. PTPRD and Disease Therapy: From Cancer to Metabolic and Neurological Diseases

Aberrant expression or functional loss of PTPRD is closely associated with the pathogenesis and progression of various diseases, involving cancer, metabolic diseases, neurological disorders, and others. Although its mechanisms of action differ across diseases, they all involve influencing disease processes by regulating key signaling pathways.

3.1 The Tumor Suppressor Role and Mechanisms of PTPRD in Various Cancers

3.1.1 Hepatocellular Carcinoma (HCC)

Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide, with limited effective treatment options, making the exploration of new molecular targets crucial for its diagnosis and treatment ^[1]. Studies have found that PTPRD is significantly downregulated in HCC tissues, primarily through promoter hypermethylation. The expression level of PTPRD is closely related to the pathological features of HCC, with lower PTPRD expression in high-grade compared to low-grade tumors ^[1]. As a tumor suppressor gene, PTPRD inhibits HCC pathogenesis through multiple mechanisms: on one hand, it can dephosphorylate STAT3, inhibiting STAT3-mediated pro-tumor signaling and reducing the expression of pro-proliferation and pro-angiogenesis genes like MMP-2 and MMP-9; on the other hand, PTPRD can inhibit HCC cell migration and invasion by regulating the PI3K/Akt/mTOR signaling pathway; furthermore, PTPRD can also maintain intercellular adhesion junctions and inhibit malignant transformation of HCC cells by negatively regulating the Wnt/β-catenin/TCF signaling pathway ^[1]. Clinical studies indicate that HCC patients with high PTPRD expression have lower postoperative tumor recurrence rates and better survival, suggesting PTPRD's potential as a prognostic biomarker for HCC ^[1].

3.1.2 Gastric Cancer (GC)

Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related deaths globally. Despite advances in diagnosis and treatment, the prognosis for patients with advanced gastric cancer remains poor ^[2]. In gastric cancer, PTPRD expression is frequently downregulated, occurring in approximately 69% of GC tissues (24% low expression, 45% moderate expression). Loss of PTPRD expression is associated with advanced disease stage, poorer overall survival, and higher risk of distant metastasis ^[2]. The tumor suppression mechanisms of PTPRD in gastric cancer mainly include: inhibiting the ERK and STAT3 signaling pathways to downregulate CXCL8 expression, thereby suppressing tumor angiogenesis; interacting with cell adhesion molecules like CD44 and β-catenin to maintain intercellular adhesion junctions, inhibiting GC cell migration and invasion; additionally, PTPRD can promote GC cell apoptosis by regulating apoptosis-related pathways ^[2].

3.1.3 Glioblastoma (GBM)

Glioblastoma is the most common and malignant primary brain tumor, with a median patient survival of only 12-15 months ^[6]. Approximately 50% of glioblastomas exhibit PTPRD inactivation, primarily through gene deletion, epigenetic silencing, or inactivating mutations ^[6]. The tumor suppressor role of PTPRD in GBM is mediated through the following mechanisms: directly interacting with STAT3, dephosphorylating and inhibiting its activity, reducing the expression of STAT3 downstream target genes, and inhibiting tumor cell proliferation and cancer stem cell maintenance; negatively regulating the NF-κB pathway, reducing the release of inflammatory factors, inhibiting the formation of a pro-tumor microenvironment, while enhancing tumor cell sensitivity to radiotherapy and chemotherapy; furthermore, PTPRD can inhibit glioblastoma cell invasion by regulating the expression of cell adhesion molecules ^[6]. Research shows that GBM patients with PTPRD loss are more sensitive to STAT3 inhibitors, suggesting PTPRD could serve as a biomarker for treatment selection in glioblastoma ^[6].

3.1.4 Breast Cancer

Breast cancer is one of the most common malignancies in women, and PTPRD also plays a tumor suppressor role in breast cancer ^{[1, 3]}. Studies have found that PTPRD expression is downregulated in breast cancer tissues, and its loss is closely associated with breast cancer progression and metastasis ^[1]. PTPRD inhibits breast cancer cell proliferation and metastasis by dephosphorylating STAT3 and suppressing the IL-6/STAT3 signaling pathway; simultaneously, PTPRD can further enhance its inhibitory effect on breast cancer progression by downregulating the expression of ETK (epithelial and endothelial tyrosine kinase) ^[1]. In breast cancer animal models, exogenous expression of PTPRD significantly inhibits tumor growth and metastasis, indicating PTPRD's potential as a therapeutic target for breast cancer ^[1].

3.1.5 Other Cancers

Beyond the cancers mentioned above, PTPRD also functions as a tumor suppressor in various other cancers, including colon cancer, melanoma, and head and neck squamous cell carcinoma ^{[1, 3]}. In colon cancer, PTPRD acts synergistically with CD44, inhibiting the β-catenin/TCF pathway by dephosphorylating β-catenin, thereby suppressing colon cancer cell migration ^[1]; in melanoma, loss of PTPRD expression promotes melanoma cell migration, while exogenous PTPRD expression significantly reduces melanoma cell growth and viability and increases apoptosis ^[1]; in head and neck squamous cell carcinoma, epigenetic alterations of PTPRD can lead to STAT3 overactivation, and patients with PTPRD loss are more sensitive to STAT3 inhibitors, suggesting PTPRD's potential as a biomarker for prognosis and treatment selection in HNSCC ^[3].

3.2 Role of PTPRD in Metabolic Diseases

3.2.1 Type 2 Diabetes

Type 2 diabetes is a metabolic disease characterized by insulin resistance and inadequate insulin secretion. PTPRD abnormality is closely associated with the development of T2D ^{[3, 5]}. Genome-wide association studies (GWAS) have found that PTPRD gene polymorphisms are associated with susceptibility to type 2 diabetes in the Han Chinese population ^[5]. Mechanistically, PTPRD maintains normal glucose metabolism by activating the insulin receptor signaling pathway; it enhances insulin receptor phosphorylation, promotes insulin signal transduction, and can also activate PPARγ2, enhancing cellular insulin sensitivity ^[5]. In patients with type 2 diabetes, PTPRD is silenced due to DNA hypermethylation, leading to significantly reduced expression levels, impaired insulin receptor signaling, decreased cellular insulin sensitivity, and the emergence of insulin resistance ^[5]. Clinical studies show that PTPRD mRNA expression levels in the peripheral blood of T2D patients are significantly lower than in healthy individuals, and its expression level is negatively correlated with disease duration—the longer the duration, the lower the PTPRD expression ^[5].

3.2.2 Non-alcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic fatty liver disease is a metabolic liver disorder associated with insulin resistance and obesity. PTPRD also plays a role in NAFLD ^{[1, 3]}. Research has found that single nucleotide polymorphisms (SNPs) in PTPRD are associated with the occurrence of NAFLD. PTPRD can participate in the pathological process of NAFLD by attenuating STAT3 (Tyr705) phosphorylation ^[1]. In NAFLD patients, reduced PTPRD expression leads to sustained STAT3 activation, promoting the release of inflammatory factors and hepatic steatosis, thereby exacerbating disease progression ^[1]. Furthermore, PTPRD can also influence lipid accumulation in hepatocytes by regulating the expression of lipid metabolism-related genes, further participating in the pathogenesis of NAFLD ^[3].

3.3 PTPRD Dysfunction and Neurological Diseases

3.3.1 Cognitive Impairment

Cognitive impairment encompasses neurological disorders characterized by declining cognitive function. PTPRD abnormality is closely associated with the occurrence of cognitive impairment ^[1]. PTPRD is highly expressed in the brain and participates in neuronal migration, synapse formation, and neural signal transmission ^[1]. Studies have found that PTPRD knockout mice exhibit cognitive impairment, manifested as reduced learning and memory abilities ^[1]. Mechanistically, PTPRD can interact with neural cell adhesion molecules like SLITRK proteins, promoting the accumulation of the vesicular GABA transporter (VGAT) and maintaining synaptic specialization and stability. Its loss leads to abnormal synaptic structure and function, impairing normal neural signal transmission and consequently causing cognitive deficits ^[1]. Additionally, PTPRD can affect neuronal excitability by regulating the balance of neurotransmitters, and its functional abnormality may further aggravate cognitive impairment ^[1].

3.3.2 Hearing Loss

Hearing loss is a common sensory disorder, and PTPRD abnormality may also lead to hearing loss ^[1]. Studies have found that patients with homozygous microdeletions of the PTPRD gene present with symptoms including trigonocephaly, hearing loss, and intellectual disability ^[1]. Mechanistically, PTPRD plays a role in the development and functional maintenance of the auditory system, possibly by regulating the survival and synapse formation of auditory neurons to maintain normal auditory function. Loss of PTPRD leads to apoptosis of auditory neurons and disruption of synaptic connections, consequently causing hearing loss ^[1]. Furthermore, PTPRD can affect the conduction of sound signals by regulating the development and function of inner ear hair cells, and its dysfunction may further exacerbate hearing impairment ^[1].

3.4 Other Diseases: Potential Links from Fetal Development to Hypertension

3.4.1 Intrauterine Growth Restriction (IUGR)

Intrauterine growth restriction refers to delayed fetal growth in utero, with birth weight below the 10th percentile for normal fetuses of the same gestational age. PTPRD plays a role in liver metabolic regulation in IUGR fetuses ^[8]. Research has found that PTPRD expression is significantly reduced in the livers of IUGR fetuses, and this reduced expression is closely associated with metabolic disturbances in the fetal liver ^[8]. In the IUGR fetal liver, loss of PTPRD can lead to abnormalities in pathways such as glucose metabolism and amino acid degradation. For instance, it can affect the expression of gluconeogenesis-related genes by regulating the STAT3 signaling pathway, resulting in increased glucose production in the fetal liver, while also affecting amino acid degradation processes, leading to elevated amino acid concentrations in hepatocytes ^[8]. Additionally, PTPRD deficiency can lead to impaired mitochondrial function and reduced energy production in the fetal liver, further aggravating fetal growth restriction ^[8].

3.4.2 Hypertension

Hypertension is a common cardiovascular disease, and PTPRD abnormality may be associated with its occurrence ^[1]. Studies have found that PTPRD knockout mice develop hypertension, suggesting a role for PTPRD in blood pressure regulation ^[1]. Mechanistically, PTPRD may affect vascular dilation and contraction by regulating the function of vascular endothelial cells. Its loss leads to endothelial dysfunction, reduced vasodilatory capacity, and consequently increased blood pressure ^[1]. Furthermore, PTPRD may also influence water-sodium metabolism by regulating the activity of the renin-angiotensin-aldosterone system (RAAS), and its dysfunction could further exacerbate hypertension ^[1].

4. Targeting PTPRD: Drug Development and Novel Therapeutic Strategies

Research on PTPRD-targeting drugs has progressed in several areas. In cancer therapy, PTPRD is frequently downregulated in gastric cancer, and its loss of expression is associated with advanced disease, reduced overall survival, and increased risk of distant metastasis. Studies have found that metformin can effectively inhibit PTPRD inactivation-induced angiogenesis, reduce the activity of PTPRD-inactivated cancer cells, and reverse the decline in PTPRD expression. In the field of metabolic diseases, PTPRD maintains liver metabolic balance by inhibiting the STAT3 signaling pathway, and its loss of expression is closely related to the development of metabolic liver disease, providing an important theoretical basis for developing innovative therapies targeting the PTPRD-STAT3 axis. In the treatment of drug dependence, NHB1109, an inhibitor of PTPRD, demonstrates good oral bioavailability and tolerability and is being further developed as an anti-addiction agent.

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