PDGFB

Official Full Name

platelet derived growth factor subunit B

Organism

Homo sapiens

GeneID

5155

Background

This gene encodes a member of the protein family comprised of both platelet-derived growth factors (PDGF) and vascular endothelial growth factors (VEGF). The encoded preproprotein is proteolytically processed to generate platelet-derived growth factor subunit B, which can homodimerize, or alternatively, heterodimerize with the related platelet-derived growth factor subunit A. These proteins bind and activate PDGF receptor tyrosine kinases, which play a role in a wide range of developmental processes. Mutations in this gene are associated with meningioma. Reciprocal translocations between chromosomes 22 and 17, at sites where this gene and that for collagen type 1, alpha 1 are located, are associated with dermatofibrosarcoma protuberans, a rare skin tumor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

Synonyms

SIS; SSV; IBGC5; PDGF2; c-sis; PDGF-2;

Bio Chemical Class

Growth factor

Protein Sequence

MNRCWALFLSLCCYLRLVSAEGDPIPEELYEMLSDHSIRSFDDLQRLLHGDPGEEDGAELDLNMTRSHSGGELESLARGRRSLGSLTIAEPAMIAECKTRTEVFEISRRLIDRTNANFLVWPPCVEVQRCSGCCNNRNVQCRPTQVQLRPVQVRKIEIVRKKPIFKKATVTLEDHLACKCETVAAARPVTRSPGGSQEQRAKTPQTRVTIRTVRVRRPPKGKHRKFKHTHDKTALKETLGA

Open

Disease

Cystic fibrosis, Diabetic foot ulcer, Retinopathy

Approved Drug

Clinical Trial Drug

4 +

Discontinued Drug

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Detailed Information

The PDGFB gene is located on chromosome 22q13.1 in humans and encodes the Platelet-Derived Growth Factor Subunit B (PDGFB). Its primary translation product is a precursor protein of 241 amino acids, which is processed proteolytically to generate the mature PDGFB composed of 109 amino acids. PDGFB forms homodimers (PDGF-BB) through disulfide bonds or heterodimers with PDGFA (PDGF-AB). PDGFB activates downstream signaling pathways by binding to tyrosine kinase receptors on the cell surface (PDGFRα/β), with high ligand-receptor specificity: PDGFB primarily binds PDGFRβ, while PDGF-AB can activate both PDGFRα and PDGFRβ. Upon receptor activation and autophosphorylation, adaptor proteins such as PI3K, PLCγ, and Ras-GAP are recruited, initiating multiple signaling cascades including MAPK/ERK, PI3K/AKT, and JAK/STAT pathways, which regulate cell proliferation, migration, and survival.

During embryonic development, PDGFB is a key regulator of angiogenesis. It promotes pericyte migration and proliferation around nascent endothelial vessels, stabilizing the microvascular network. Gene knockout studies have shown that Pdgfb⁻/⁻ mice die shortly after birth due to capillary aneurysms and microhemorrhages caused by deficient pericyte coverage. Beyond the vascular system, PDGFB also plays roles in kidney development (regulating mesangial cell differentiation), lung mesenchyme formation, and the maintenance of glial homeostasis in the central nervous system.

Pathological Mechanisms and Disease Associations

1. Tumorigenesis and Fusion Genes

Abnormal activation of PDGFB is strongly associated with various tumors. A hallmark example is Dermatofibrosarcoma Protuberans (DFSP), where approximately 90% of cases exhibit a t(17;22)(q22;q13) chromosomal translocation, resulting in the formation of the COL1A1-PDGFB fusion gene. This fusion retains the full-length growth factor domain of PDGFB but is driven by the COL1A1 promoter, leading to constitutive overexpression and autocrine activation of PDGFRβ signaling, which drives tumor cell proliferation. Clinical studies have confirmed that COL1A1-PDGFB fusions are highly specific diagnostic markers, with 86.96% (60 out of 69) of DFSP samples testing positive, while control samples are negative.

In hematological malignancies, PDGFB rearrangements (such as ETV6-PDGFB) define a subset of myeloid/lymphoid neoplasms associated with eosinophilia. These fusions cause constitutive activation of PDGFRβ tyrosine kinase, leading to abnormal eosinophil proliferation. Patients typically present with chronic myeloproliferative disorders that may progress to acute leukemia. Notably, these malignancies are highly sensitive to imatinib, which inhibits PDGFRβ kinase activity.

2. Novel Mechanisms in Neurological Disorders

In 2022, researchers at Zhejiang University uncovered a novel mechanism involving PDGFB in hypertension. Resting microglia were found to secrete PDGFB, which acts on PDGFRα receptors in presympathetic neurons of the paraventricular nucleus in the hypothalamus, activating potassium channel gene expression and preventing neuronal hyperexcitability. Specific ablation of microglia or inhibition of PDGFB signaling led to increased sympathetic tone and elevated blood pressure. This finding provides a mechanistic explanation for the hypertensive side effect (40% incidence) of the anticancer drug pazopanib, a PDGFR inhibitor, by blocking neuronal PDGFRα; the drug impairs potassium channel function, resulting in excessive sympathetic activation.

Clinical Translation and Challenges

Targeted therapies against the PDGFB signaling pathway fall into two main categories:

Tyrosine Kinase Inhibitors (TKIs): Agents like imatinib are used in DFSP and hematologic malignancies with PDGFR rearrangements. A phase III clinical trial demonstrated that imatinib achieved a 70% objective response rate in locally advanced DFSP, enabling a 50% reduction in the extent of surgical resection.
Ligand-Neutralizing Antibodies: Olaratumab, an anti-PDGFRα monoclonal antibody, was tested in combination with doxorubicin for soft tissue sarcomas. However, the phase III ANNOUNCE trial failed to meet its overall survival endpoint, indicating the need for improved biomarker-based patient selection.

Key challenges remain, including overcoming drug resistance and minimizing tissue-specific toxicity. Approximately 40% of DFSP patients develop secondary resistance to imatinib, often due to PDGFB gene amplification or downstream PI3K mutations. Cardiovascular side effects of PDGFR inhibitors, such as hypertension, limit long-term treatment. Novel approaches include the development of brain-impermeable TKIs (e.g., derivatives of nilotinib) to reduce central nervous system side effects, and the design of fusion gene-specific siRNAs targeting the COL1A1-PDGFB junction to enhance treatment selectivity.

References:

Panwar V, Liu Y, Gwin K, Chen H. COL1A1-PDGFB Fusion Associated Fibrosarcoma of the Uterine Corpus: A Case Report and Literature Review. Int J Gynecol Pathol. 2023 Mar 1;42(2):143-146.
Shah S, Sizemore GM. Diverse roles of tumor-stromal PDGFB-to-PDGFRβ signaling in breast cancer growth and metastasis. Adv Cancer Res. 2022;154:93-140.
Rota S, Franza A, Fabbroni C, et al. COL1A1::PDGFB fusion-associated uterine fibrosarcoma: A case report and review of the literature. Cancer Rep (Hoboken). 2024 Feb;7(2):e1969.

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