SELP

Official Full Name

selectin P

Organism

Homo sapiens

GeneID

6403

Background

This gene encodes a 140 kDa protein that is stored in the alpha-granules of platelets and Weibel-Palade bodies of endothelial cells. This protein redistributes to the plasma membrane during platelet activation and degranulation and mediates the interaction of activated endothelial cells or platelets with leukocytes. The membrane protein is a calcium-dependent receptor that binds to sialylated forms of Lewis blood group carbohydrate antigens on neutrophils and monocytes. Alternative splice variants may occur but are not well documented. [provided by RefSeq, Jul 2008]

Synonyms

CD62; GRMP; PSEL; CD62P; GMP140; LECAM3; PADGEM;

Protein Sequence

MANCQIAILYQRFQRVVFGISQLLCFSALISELTNQKEVAAWTYHYSTKAYSWNISRKYCQNRYTDLVAIQNKNEIDYLNKVLPYYSSYYWIGIRKNNKTWTWVGTKKALTNEAENWADNEPNNKRNNEDCVEIYIKSPSAPGKWNDEHCLKKKHALCYTASCQDMSCSKQGECLETIGNYTCSCYPGFYGPECEYVRECGELELPQHVLMNCSHPLGNFSFNSQCSFHCTDGYQVNGPSKLECLASGIWTNKPPQCLAAQCPPLKIPERGNMTCLHSAKAFQHQSSCSFSCEEGFALVGPEVVQCTASGVWTAPAPVCKAVQCQHLEAPSEGTMDCVHPLTAFAYGSSCKFECQPGYRVRGLDMLRCIDSGHWSAPLPTCEAISCEPLESPVHGSMDCSPSLRAFQYDTNCSFRCAEGFMLRGADIVRCDNLGQWTAPAPVCQALQCQDLPVPNEARVNCSHPFGAFRYQSVCSFTCNEGLLLVGASVLQCLATGNWNSVPPECQAIPCTPLLSPQNGTMTCVQPLGSSSYKSTCQFICDEGYSLSGPERLDCTRSGRWTDSPPMCEAIKCPELFAPEQGSLDCSDTRGEFNVGSTCHFSCDNGFKLEGPNNVECTTSGRWSATPPTCKGIASLPTPGLQCPALTTPGQGTMYCRHHPGTFGFNTTCYFGCNAGFTLIGDSTLSCRPSGQWTAVTPACRAVKCSELHVNKPIAMNCSNLWGNFSYGSICSFHCLEGQLLNGSAQTACQENGHWSTTVPTCQAGPLTIQEALTYFGGAVASTIGLIMGGTLLALLRKRFRQKDDGKCPLNPHSHLGTYGVFTNAAFDPSP

Open

Disease

Allergic/hypersensitivity disorder, Arterial occlusive disease, Asthma, Circulatory system disease, Graft-versus-host disease, Hypertension, Influenza, Sickle-cell disorder, Solid tumour/cancer, Thrombosis

Approved Drug

1 +

Clinical Trial Drug

7 +

Discontinued Drug

4 +

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Detailed Information

The SELP gene is located on human chromosome 1q24.2 and lies in close linkage with SELE as part of the selectin gene cluster. It spans about 50 kb and contains 17 exons, producing a 4.2 kb mRNA transcript that encodes a 789-amino acid precursor protein. After post-translational processing, the mature protein, known as P-selectin (also CD62P or GMP-140), is a 140 kDa type I transmembrane glycoprotein. Its extracellular region consists of a C-type lectin domain that binds sialylated Lewis antigens (sLeˣ/sLeᵃ), an EGF-like domain that stabilizes protein conformation, and nine complement regulatory protein repeats (SCRs), the largest number among selectins. The short cytoplasmic tail, though only 35 amino acids, plays a critical role in subcellular localization and signaling regulation.

Expression and Regulation

P-selectin is primarily expressed in platelet α-granules and endothelial Weibel-Palade bodies. In resting cells, it is stored intracellularly and minimally expressed on the surface. Upon stimulation by thrombin, histamine, or reactive oxygen species, granules fuse with the plasma membrane, causing rapid P-selectin surface expression within minutes. This mobilization makes it an early responder in thrombosis and acute inflammation. P-selectin can also be cleaved to form a soluble 100 kDa fragment (sP-selectin) released into circulation, serving as a biomarker of platelet and endothelial activation.

Biological Functions and Mechanisms

The central role of P-selectin is to mediate interactions between activated platelets or endothelial cells and leukocytes, particularly in thromboinflammatory processes. Following vascular injury, activated platelets expose P-selectin, which binds leukocyte PSGL-1 (encoded by SELPLG), driving platelet-leukocyte aggregate formation. Similarly, endothelial P-selectin mediates leukocyte rolling and recruitment under inflammatory stimuli, a process highly dependent on shear stress. Binding requires both glycosylation and tyrosine sulfation of PSGL-1, ensuring specificity. Beyond adhesion, P-selectin signaling activates β2 integrins, reactive oxygen production, and cytokine release in leukocytes, while promoting coagulation and fibrin deposition through platelet signaling.

Pathological Roles

Aberrant P-selectin activation contributes to multiple diseases. In thrombotic disorders, platelet P-selectin enhances platelet-leukocyte aggregates that stabilize clots and promote coagulation. During ischemia-reperfusion injury, rapid endothelial P-selectin upregulation drives neutrophil infiltration and oxidative damage. In sepsis and disseminated intravascular coagulation, systemic platelet and endothelial activation leads to widespread P-selectin expression, fueling microvascular thrombosis and organ failure. P-selectin is also implicated in cancer progression by promoting tumor-associated thrombosis and protecting circulating tumor cells through platelet binding, thereby facilitating metastasis.

Figure 1. Illustration showing the different roles of SELP in cancer progression. (Yeini E, et al., 2022)

Genetic Associations and Clinical Correlates

Genetic studies link SELP polymorphisms to cardiovascular risk. Variants such as rs6136 alter glycosylation and are associated with early myocardial infarction, while promoter mutations influence gene expression and predispose to venous thrombosis. Circulating sP-selectin levels correlate with atherosclerosis severity and predict future cardiovascular events. In acute coronary syndromes, platelet-leukocyte aggregates are elevated and linked to poor outcomes. Imaging studies using labeled anti-P-selectin antibodies demonstrate its potential as a diagnostic marker of active atherosclerotic plaques.

Disease Associations and Clinical Applications

In sickle cell disease (SCD), persistent endothelial and platelet activation leads to high P-selectin expression, driving vaso-occlusive crises (VOC). Clinical trials demonstrated that the monoclonal antibody crizanlizumab significantly reduced VOC frequency, leading to its FDA approval in 2019 as the first selectin-targeting therapy. In oncology, high baseline sP-selectin predicts venous thromboembolism risk, and inhibition of P-selectin reduces metastasis in preclinical models. Trials are ongoing to evaluate P-selectin inhibitors such as rivipansel in cancer. Preclinical studies also suggest therapeutic potential in autoimmune diseases, ischemia-reperfusion injury, and cardiovascular disorders.

Targeted Strategies and Challenges

P-selectin targeting strategies include monoclonal antibodies, small-molecule antagonists, and nucleic acid aptamers. Beyond crizanlizumab, inclacumab has shown promise in reducing myocardial injury in coronary artery disease. Small molecules like PSI-697 and rivipansel mimic sLeˣ and competitively block ligand binding, though efficacy has been limited in advanced trials. Aptamers, developed through SELEX, demonstrate high affinity and specificity, with applications in drug delivery, imaging, and gene regulation.

Key challenges remain in balancing physiological roles with therapeutic inhibition, overcoming compensatory mechanisms such as E-selectin upregulation, and optimizing delivery methods. Future directions emphasize spatiotemporally controlled delivery systems, including shear-sensitive nanoparticles and environment-responsive inhibitors, alongside AI-driven molecular design to improve the specificity and durability of inhibition.

Reference

Gupta P, Choudhari V, Kumar R. Exploring the genetic mechanisms: SELP gene's contribution to alleviating vaso-occlusive crisis in sickle cell disease. Gene. 2024 Nov 30;928:148805.
Alexander J. Selenium. Novartis Found Symp. 2007;282:143-9; discussion 149-53, 212-8.
Yeini E, Satchi-Fainaro R. The role of P-selectin in cancer-associated thrombosis and beyond. Thromb Res. 2022 May;213 Suppl 1:S22-S28.

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