SRPX2, or Sushi Repeat-Containing Protein X-Linked 2, has emerged at the forefront of molecular biology as a multifunctional regulatory protein implicated in a wide array of pathological processes ranging from cancer progression to neurological disorders and fibrosis. The surge of interest in SRPX2 arises from its intricate structural features and its influential role in diverse cellular pathways that underpin critical biological functions and disease mechanisms. Recent comprehensive reviews dissect the molecular underpinnings by which SRPX2 orchestrates these complex processes, shedding light on its multifaceted contributions and highlighting its promise as a therapeutic target.
Originally identified as SRPUL in 1999, denoting its initial discovery as sushi-repeat protein upregulated in leukemia, SRPX2 is located on the X chromosome (Xp22.1). It is expressed broadly across human tissues but exhibits particularly high neuronal expression within regions of the brain such as the Rolandic cortex. This tissue-specific prominence suggests pivotal involvement in neurodevelopmental regulation and language processing. Structurally, SRPX2 belongs to the sushi repeat protein family, characterized by three distinct sushi or complement control protein (CCP) domains and a HYR domain, conferring unique biochemical properties relevant to its function.
The clinical significance of SRPX2 is underscored by the identification of specific mutations—such as p.Tyr72Ser and p.Asn327Ser—that have been linked to neurodevelopmental disorders including Rolandic epilepsy, intellectual disability, and speech dyspraxia. However, the pathogenic status of these variants, particularly p.Asn327Ser, remains subject to debate due to their prevalence in general populations and potential modulation by epistatic interactions, notably with GRIN2A mutations. Functionally, these mutations disrupt essential post-translational modifications like glycosylation and proper protein folding, ultimately impairing neuronal functionality.
A crucial biochemical aspect of SRPX2 is its classification as a novel chondroitin sulfate proteoglycan (CSPG). Its glycosylation status is pivotal in determining protein stability, interaction dynamics, and downstream signaling capacities. SRPX2’s ability to bind hepatocyte growth factor (HGF) amplifies its role in promoting angiogenesis, a hallmark of tumor growth and repair mechanisms. Moreover, its interaction with the FOXP2 transcription factor places SRPX2 within the regulatory framework of synaptic development and vocalization pathways, linking molecular pathology with observable neurobehavioral phenotypes.
In oncology, SRPX2 functions prominently as an oncogenic driver across a spectrum of malignancies. These include but are not limited to gastric, pancreatic, thyroid (both papillary and anaplastic types), colorectal, osteosarcoma, esophageal and oral squamous cell carcinomas, glioblastoma, acute myeloid leukemia, and skin melanoma. Elevated SRPX2 levels correlate strongly with aggressive tumor characteristics, including enhanced proliferation, migration, invasion, metastatic capability, angiogenesis, and resistance to chemotherapy and immune checkpoint therapies. Mechanistically, SRPX2 perturbes multiple signaling networks, including TGF-β, PI3K/AKT/mTOR, Wnt/β-catenin, Hippo/YAP, and FAK/SRC/ERK pathways, as well as its interaction with uPAR (urokinase plasminogen activator receptor). These intersections position SRPX2 as both a robust prognostic biomarker and a promising target for molecularly guided therapeutic interventions.
Beyond oncogenesis, SRPX2’s role extends into neurological disease frameworks. It is intricately involved in the FOXP2-SRPX2/uPAR axis, critical in perisylvian polymicrogyria-associated epilepsy and speech disorders. Interaction with glutamatergic receptor subunits such as GRIN2A further implicates SRPX2 in synaptic plasticity and cortical circuit maturation that underlie language acquisition and higher cognitive functions. The convergence of these pathways highlights SRPX2’s centrality in neurodevelopmental conditions, positioning it as a molecular lynchpin for understanding and potentially modulating epilepsy and speech impairments.
Emerging genetic and animal model data also associate SRPX2 with Autism Spectrum Disorder (ASD). Loss-of-function mutations, including splice site alterations, lead to reduced synaptic density and impairments in social communication. This is partially mediated by disrupted complement cascade regulation, particularly involving C1q-mediated synaptic pruning, a process essential for neurodevelopmental circuit refinement. These findings provide a crucial molecular link between SRPX2 deficiency and the synaptic anomalies characteristic of ASD.
In trauma contexts, acute downregulation of SRPX2 following traumatic brain injury (TBI) suggests it as a sensitive biomarker for hypothalamic-pituitary axis dysfunction. This regulatory decline may reflect disrupted neuroendocrine signaling critical for homeostatic recovery, presenting new avenues for early diagnostic strategies and post-injury therapeutic monitoring.
Fibrotic diseases also feature SRPX2 prominently. In idiopathic pulmonary fibrosis (IPF), SRPX2 expression is elevated and engages in a TGF-β1/SMAD3 positive feedback loop that accelerates the transition of fibroblasts to collagen-producing myofibroblasts. Targeted silencing of SRPX2 in experimental models attenuates fibrotic progression, highlighting its potential as a therapeutic intervention candidate for fibrogenic pathologies.
Cardiovascular injury models reveal that SRPX2 expression decreases following ischemia-reperfusion injury in myocardial infarction. Notably, SRPX2 exerts cardioprotective effects by modulating apoptotic pathways and reducing endoplasmic reticulum stress through inhibition of PI3K/Akt/mTOR signaling, suggesting a nuanced role in cardiac tissue resilience and repair processes.
Angiogenesis, a critical process in both normal physiology and tumorigenesis, is positively regulated by SRPX2 via its interaction with uPAR and integrin αvβ3. This engagement activates PI3K/Akt and Ras/MAPK/FAK pathways, leading to enhanced endothelial cell migration and sprouting, thereby facilitating neovascularization in diverse biological contexts.
SRPX2 also influences embryonic stem cell differentiation, functioning as a downstream effector of transcription factors NFATc3 and c-JUN. Its regulatory impact on lineage commitment and epithelial-mesenchymal transition (EMT) underscores its broader role in developmental biology and tissue homeostasis, linking early development mechanisms with adult tissue pathophysiology.
Additional research implicates SRPX2 in immunologically and metabolically related diseases such as IgA nephropathy and diabetic peripheral neuropathy. In IgA nephropathy, SRPX2 is identified as a secretory gene correlated with tubulointerstitial fibrosis. In diabetic peripheral neuropathy, bioinformatics analyses highlight SRPX2 as a hub gene involved in inflammation, extracellular matrix remodeling, and immune modulation, emphasizing its systemic relevance.
Collectively, the expanding body of evidence firmly establishes SRPX2 as a crucial biomolecule with diverse functional repertoires impacting oncology, neurology, fibrosis, cardiovascular health, and beyond. Its unique combination of structural domains, interaction partners, and regulatory functions grants it a central role in disease progression and presents opportunities for innovative diagnostic and therapeutic strategies. Future investigations focusing on structural biology, integrated computational drug design, and translational applications are imperative to harness SRPX2’s full clinical potential, ultimately enabling precision medicine approaches for complex diseases marked by SRPX2 dysregulation.
Subject of Research: Not applicable
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Web References: http://dx.doi.org/10.1016/j.glycos.2025.100005
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Image Credits: Qifei Cong, et al
Keywords: Molecular biology, Health and medicine, Cancer, Pancreatic cancer, Neuroscience
