Affinage

PROS1

Vitamin K-dependent protein S · UniProt P07225

Round 2 corrected
Length
676 aa
Mass
75.1 kDa
Annotated
2026-04-28
130 papers in source corpus 20 papers cited in narrative 20 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PROS1 encodes Protein S, a vitamin K-dependent plasma glycoprotein that functions as a central anticoagulant regulator and immunomodulatory ligand. As a cofactor for activated protein C (APC), Protein S promotes inactivation of factors Va and VIIIa; it also directly inhibits Factor Xa and prothrombinase independently of APC, and enhances TFPI-mediated suppression of the tissue factor pathway by reducing the Ki of the FXa/TFPI complex approximately 10-fold (PMID:6239102, PMID:8428962, PMID:8146182, PMID:16488980). Approximately 60% of circulating Protein S is complexed with C4b-binding protein (C4BP), which abrogates its APC cofactor activity; loss-of-function mutations and copy number variations in PROS1 cause hereditary protein S deficiency and recurrent venous thromboembolism (PMID:6454142, PMID:1534488, PMID:19466456). Beyond hemostasis, Protein S binds phosphatidylserine on apoptotic cells to stimulate macrophage phagocytosis and signals through Mer and Tyro3 TAM receptors to suppress inflammatory cytokine production in dendritic cells and macrophages, thereby restraining innate and adaptive immune activation and modulating tumor immune evasion (PMID:12447359, PMID:23850380, PMID:29708510, PMID:33848267).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1981 High

    The discovery that Protein S circulates in both free and C4BP-complexed forms established that its bioavailability is regulated by a stoichiometric interaction with complement component C4BP, linking coagulation and complement systems.

    Evidence Biochemical fractionation, barium citrate adsorption, and SDS-PAGE of human plasma

    PMID:6454142

    Open questions at the time
    • Functional consequence of C4BP binding on Protein S activity was not yet determined
    • Identity of the C4BP subunit mediating the interaction was unknown
  2. 1984 High

    Demonstration that Protein S is an essential cofactor for APC-mediated inactivation of factors Va and VIIIa, and that its deficiency causes venous thromboembolism, established the physiological anticoagulant role of PROS1.

    Evidence Functional protein S activity assay in plasma from deficient patients, clinical phenotyping

    PMID:6239102

    Open questions at the time
    • Mechanism of cofactor enhancement of APC activity was unresolved
    • Whether Protein S had APC-independent anticoagulant activity was unknown
  3. 1986 High

    Cloning of human and bovine PROS1 cDNA revealed a unique multi-domain architecture—Gla domain, thrombin-sensitive region, four EGF-like repeats, and an SHBG-homologous C-terminus—that distinguishes it from serine protease coagulation factors and explains its non-enzymatic cofactor function.

    Evidence cDNA cloning from human and bovine liver libraries, direct protein sequencing (bovine)

    PMID:2940598 PMID:2944113

    Open questions at the time
    • Functions of individual domains (e.g., SHBG-like domain) were not mapped
    • Molecular basis for C4BP and APC interactions remained undefined
  4. 1991 High

    Detailed biochemical characterization established that the C4BP beta-chain is the sole Protein S binding site, that C4BP complexation abolishes APC cofactor activity, and that calcium binding to EGF-like domains is required for structural integrity, resolving how Protein S bioavailability is regulated.

    Evidence Domain-level binding studies, post-translational modification mapping, cofactor reconstitution assays

    PMID:1534488 PMID:1833851

    Open questions at the time
    • Structural basis for how C4BP binding neutralizes APC cofactor function was unknown
    • In vivo regulation of C4BP beta-chain expression was not addressed
  5. 1994 High

    Discovery that Protein S directly binds and inhibits Factor Xa and Factor Va and suppresses prothrombinase activity independently of APC revealed a second, autonomous anticoagulant mechanism.

    Evidence Reconstituted binding assays (solid-phase and fluid-phase), FXa amidolytic activity assay, prothrombin conversion assay with purified components

    PMID:8146182 PMID:8428962

    Open questions at the time
    • Relative physiological contribution of APC-independent vs APC-dependent anticoagulant activity was unclear
    • Structural determinants of the Protein S–FXa interaction were not mapped
  6. 2002 High

    Identification of Protein S as the serum factor that binds phosphatidylserine on apoptotic cells and stimulates macrophage phagocytosis extended its function beyond hemostasis into innate immune clearance.

    Evidence Immunodepletion of Protein S from serum, reconstituted macrophage phagocytosis assay with apoptotic lymphoma cells

    PMID:12447359

    Open questions at the time
    • Receptor on macrophages mediating Protein S-stimulated phagocytosis was not identified
    • Whether this function operates in vivo and its relationship to autoimmunity was unresolved
  7. 2006 High

    Protein S was shown to enhance TFPI-mediated inhibition of the tissue factor pathway by reducing the Ki of TFPI for Factor Xa ~10-fold, identifying a third distinct anticoagulant mechanism independent of APC.

    Evidence Purified component coagulation assays, kinetic analysis of FXa inhibition by TFPI ± Protein S

    PMID:16488980

    Open questions at the time
    • Domain of Protein S responsible for TFPI enhancement was not mapped
    • In vivo significance relative to APC cofactor function was not established
  8. 2009 High

    Demonstration that gross PROS1 copy number variations account for approximately one-third of mutation-negative hereditary protein S deficiency cases expanded the genetic basis of this thrombophilia beyond point mutations.

    Evidence MLPA and quantitative PCR in hereditary protein S-deficient families

    PMID:19466456

    Open questions at the time
    • Genotype–phenotype correlations for specific CNV types were limited
    • Prevalence of CNVs across diverse populations was not determined
  9. 2013 High

    Conditional knockout of Pros1 in T cells revealed that T cell-derived Protein S signals through TAM receptors on dendritic cells to limit DC activation, establishing Protein S as a homeostatic negative feedback ligand bridging adaptive and innate immunity.

    Evidence T cell-specific Pros1 conditional KO mouse, DC activation assays, colitis model, confirmed PROS1 expression in human activated T cells

    PMID:23850380

    Open questions at the time
    • Specific TAM receptor (Mer vs Tyro3 vs Axl) mediating DC suppression was not fully resolved
    • Downstream signaling cascade in DCs was not defined
  10. 2018 High

    CRISPR deletion of Pros1 in tumor cells and receptor-KO macrophage studies demonstrated that tumor-secreted Protein S suppresses macrophage M1 polarization via Mer and Tyro3 (not Axl), requiring PTP1b, directly linking Protein S to tumor immune evasion.

    Evidence CRISPR Pros1-KO tumor cells, Mer/Tyro3/Axl-KO and PTP1b-KO macrophages, in vivo tumor models

    PMID:29708510

    Open questions at the time
    • Structural determinants of Protein S selectivity for Mer/Tyro3 over Axl were unknown
    • Whether pharmacological targeting of Protein S–TAM axis is therapeutically viable was untested
  11. 2021 High

    Myeloid-specific Pros1 deletion showed that macrophage-derived Protein S suppresses metastatic seeding by restraining pro-inflammatory and pro-tumorigenic cytokine production via MERTK–Socs3/NF-κB signaling, revealing a cell-autonomous immunomodulatory role in the tumor microenvironment.

    Evidence Myeloid-specific Pros1 cKO mouse, lung and breast metastasis models, BMDM conditioned medium assays, MERTK kinase inhibition

    PMID:33848267

    Open questions at the time
    • Relative contribution of myeloid vs tumor-derived PROS1 to net immunosuppression in tumors was not dissected
    • PROS1-mediated regulation of IL-10, which was MERTK-independent, remains mechanistically unexplained
  12. 2022 High

    In uveal melanoma, BAP1 loss was shown to epigenetically upregulate PROS1 (via H3K27ac accumulation), and elevated tumor-secreted PROS1 activates MERTK on CD163+ macrophages to promote an immunosuppressive M2 microenvironment, linking epigenetic deregulation to Protein S-mediated immune evasion.

    Evidence ChIP-seq, scRNA-seq, co-culture MERTK phosphorylation assay, siRNA depletion, patient tumor IHC

    PMID:35954340

    Open questions at the time
    • Whether BAP1-driven PROS1 upregulation is generalizable to other BAP1-mutant cancers is unknown
    • Therapeutic blockade of PROS1–MERTK axis in uveal melanoma has not been tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • High-resolution structural data for Protein S—including full-length structure, the Protein S–APC interface, and the Protein S–TFPI–FXa ternary complex—remain unavailable, limiting rational drug design and a unified structural understanding of its multi-partner interactions.
  • No full-length crystal or cryo-EM structure of Protein S
  • Structural basis of selectivity for Mer/Tyro3 versus Axl as TAM ligand is not resolved
  • Mechanism by which C4BP binding neutralizes APC cofactor function at the structural level is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 4 GO:0008289 lipid binding 2
Localization
GO:0005576 extracellular region 6
Pathway
R-HSA-109582 Hemostasis 5 R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-5357801 Programmed Cell Death 3
Partners
C4BPBF10F5MERTKPROCTFPITYRO3
Complex memberships
Protein S–C4BP complex

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1981 Protein S (encoded by PROS1) exists in two forms in plasma: free protein and in a high-molecular-weight complex with complement component C4b-binding protein (C4BP), held together by noncovalent bonds; a major proportion of C4BP in plasma is complexed with protein S, establishing that protein S is a binding partner for C4BP. Barium citrate adsorption, SDS-PAGE with and without reduction, biochemical fractionation Proceedings of the National Academy of Sciences of the United States of America High 6454142
1984 Protein S functions as a cofactor for activated protein C (APC), which inhibits blood clotting at the levels of factors V and VIII; deficiency of protein S leads to inadequate anticoagulant regulation and recurrent venous thromboembolism, establishing protein S's essential role in the protein C anticoagulant pathway. Functional assay for protein S activity in plasma, clinical phenotype in protein S-deficient patients The New England journal of medicine High 6239102
1986 Human protein S is a single-chain 635-amino-acid vitamin K-dependent plasma protein with an N-terminal Gla domain, a thrombin-sensitive region, four EGF-like repeat domains, and a C-terminal region homologous to androgen-binding proteins/SHBG; it is structurally distinct from other vitamin K-dependent coagulation proteins in lacking a serine protease domain. cDNA cloning and sequencing of human liver cDNA library, comparison to bovine protein S sequence Proceedings of the National Academy of Sciences of the United States of America High 2944113
1986 Bovine protein S primary structure confirmed by cDNA sequencing and protein sequencing: single polypeptide of 634 amino acids, one asparagine-linked carbohydrate, a Gla domain, thrombin-sensitive region (residues 42–75), four EGF-like cysteine-rich repeats, and a C-terminal SHBG-homologous domain; cofactor function for activated protein C in inactivation of coagulation factors Va and VIIIa established. Full-length cDNA sequencing from bovine liver library and direct protein sequencing (95% coverage) Proceedings of the National Academy of Sciences of the United States of America High 2940598
1990 The human protein S expressed gene (PROS1/PS-alpha) spans >80 kb with 15 exons and 14 introns; exons I–VIII encode the vitamin K-dependent module (Gla domain, EGF-like repeats) with intron positions identical to other vitamin K-dependent coagulation proteins, while exons IX–XV encode the SHBG-homologous domain with identical intron positions as the SHBG gene, revealing its mosaic evolutionary origin. A pseudogene (PS-beta) with 97% coding identity but multiple frameshifts/stop codons was also characterized. Genomic clone isolation, restriction mapping, exon–intron sequencing, comparative genomic analysis Biochemistry High 2148110
1991 Protein S acts as a cofactor for activated protein C (APC) in the degradation of phospholipid-bound coagulation factors Va and VIIIa; protein S contains post-translational modifications including 11 Gla residues, beta-hydroxylated Asp in EGF1 and beta-hydroxylated Asn in EGF2–4; calcium binds with high affinity to EGF-like domains playing a structural/stabilizing role; the C4BP-complexed form of protein S lacks APC cofactor function; C4BP beta-chain contains the single protein S binding site. Protein biochemistry, domain characterization, complex reconstitution, cofactor activity assays Thrombosis and haemostasis High 1833851
1992 In plasma, free protein S (~38% of total, ~131 nmol/L) and C4BP-bound protein S (~62%) coexist in a 1:1 molar stoichiometry with C4BP beta-chain; free C4BP predominantly lacks the beta-chain; plasma levels of C4BP beta-chain directly and stoichiometrically regulate free protein S levels; free protein S antigen correlates with protein S anticoagulant activity. Immunoadsorption with anti-C4BP and anti-protein S antibody-Sepharose columns, ELISA quantitation in human plasma samples Blood High 1534488
1993 Protein S directly binds to Factor Va in a calcium-dependent, saturable, and reversible manner (Kd ~33 nM in fluid phase); protein S competes with prothrombin for binding to Factor Va; protein S inhibits prothrombinase activity independently of activated protein C, by a mixed inhibition mechanism, with ~50% inhibition at ~16 nM protein S. Solid-phase binding assay (immobilized factor Va/protein S), fluid-phase binding with biotin-labeled factors, prothrombinase activity assay with purified clotting factors The Journal of biological chemistry High 8428962
1994 Protein S directly binds to Factor Xa (Kd ~18–19 nM), inhibits Factor Xa amidolytic activity (~50% at 33 nM), and inhibits prothrombin conversion to thrombin by Factor Xa in a phospholipid-independent, Ca2+-stimulated manner; these anticoagulant mechanisms are independent of activated protein C and involve direct interactions with both Factor Xa and Factor Va. Ligand blotting, solid-phase and fluid-phase binding assays, factor Xa amidolytic activity assay, prothrombin conversion assay, one-stage clotting assay in protein S-depleted plasma Proceedings of the National Academy of Sciences of the United States of America High 8146182
2001 Four novel PROS1 missense mutations (W108C, W342R, E349K, L485S) and one 4-bp deletion causing frameshift in codons 632–633 cause Type I or III protein S deficiency; platelet mRNA analysis showed mutant transcripts are expressed, suggesting the primary molecular mechanism is defective protein folding/instability and impaired secretion with intracellular degradation, rather than absence of mRNA. DNA sequencing of PROS1, haplotype analysis with microsatellite markers, platelet mRNA analysis, computer-based structural modeling of protein S Thrombosis and haemostasis Medium 11776305
2002 Protein S binds to phosphatidylserine (PS) exposed on the surface of apoptotic cells and stimulates macrophage phagocytosis of apoptotic cells; immunodepletion of protein S from serum eliminated the pro-phagocytic activity of serum, identifying protein S as the serum factor responsible for serum-enhanced clearance of apoptotic cells. Protein purification from serum, immunodepletion of protein S, macrophage phagocytosis assay with apoptotic lymphoma cells, phosphatidylserine binding assay Nature immunology High 12447359
2003 Protein S circulates ~40% as free PS and ~60% complexed with C4BP; the PS–C4BP complex binds to apoptotic cells, positioning C4BP as a bridge between coagulation and complement regulation; complexed protein S loses APC cofactor function while C4BP modulates APC anticoagulant activity. Review/synthesis of biochemical binding studies, complement activation assays, apoptotic cell binding experiments Blood Medium 12907438
2006 Protein S specifically stimulates inhibition of the tissue factor (TF) pathway by promoting the interaction between full-length TF pathway inhibitor (TFPI) and Factor Xa (FXa); protein S causes a 10-fold reduction in the Ki of the FXa/TFPI complex (from 4.4 nM to 0.5 nM), accelerating feedback inhibition of the TF-mediated coagulation pathway and acting in concert with TFPI independently of activated protein C. Purified component in vitro coagulation assays, kinetic analysis of FXa inhibition by TFPI in presence/absence of protein S, thrombin generation assays Proceedings of the National Academy of Sciences of the United States of America High 16488980
2009 Gross copy number variations (CNVs) in PROS1—including complete gene deletions, partial deletions (exons 4–9 or 9–11), and partial duplications—account for protein S deficiency in approximately one-third of point mutation-negative hereditary PS-deficient patients, identified by MLPA and confirmed by quantitative PCR. Multiplex ligation-dependent probe amplification (MLPA), quantitative PCR confirmation, family member testing Human genetics High 19466456
2013 T cell-derived Protein S (Pros1) signals through TAM receptor tyrosine kinases (specifically on dendritic cells) to limit the magnitude of DC activation; genetic ablation of Pros1 in mouse T cells increased expression of costimulatory molecules and cytokines in DCs, enhanced immune responses to T cell-dependent antigens, and increased colitis severity, revealing a homeostatic negative feedback mechanism between adaptive and innate immunity. Conditional Pros1 knockout in T cells (mouse), DC activation assays, cytokine measurement, colitis model, human PROS1 expression in activated T cells confirmed Immunity High 23850380
2016 PROS1 knockdown in LN18 glioblastoma cells (siRNA) induces apoptosis via activation of both extrinsic (FasL/death receptor) and intrinsic apoptotic pathways, reduces migration and invasion (by up to 82%), and reduces proliferation; PROS1 silencing also downregulates GAS6 and other TAM family receptors, suggesting PROS1 promotes GBM cell survival through the TAM signaling axis. siRNA knockdown in LN18 GBM cells, apoptosis assays, wound-healing assay, invasion assay, proliferation assay, expression analysis International journal of oncology Medium 27840905
2018 Tumor-secreted Protein S (Pros1) inhibits macrophage M1 polarization (suppressing IFN-γ/LPS-induced M1 cytokine expression) via Mer and Tyro3 (but not Axl) TAM receptors; this suppressive action requires PTP1b complexing with Mer; CRISPR deletion of Pros1 in tumor cells abrogated M1 suppression; IFN-γ induces Pros1 transcription and secretion in tumor cells; Pros1-deficient tumors showed increased innate and adaptive immune infiltration and improved survival in mice. CRISPR-based Pros1 deletion in tumor cells, Mer/Tyro3/Axl-KO macrophages, PTP1b-KO macrophages, in vitro M1 polarization assay, in vivo tumor survival experiments, cytokine measurement The Journal of clinical investigation High 29708510
2019 Tumor-secreted ProS1 activates Tyro3 and stimulates Erk phosphorylation more potently than Gas6; in cells expressing Tyro3 alone (MGH-U3), ProS1 additionally activates Akt; Gas6 is the sole stimulator of Axl and Akt in cells co-expressing Axl; ProS1 protects cancer cells from staurosporine-induced and serum starvation-induced apoptosis through Tyro3–Erk (and Akt where Tyro3 is sole TAM receptor) signaling. Western blotting of kinase phosphorylation, conditioned medium experiments, ProS1 ligand traps and warfarin specificity controls, apoptosis assays in multiple cancer cell lines Cancers Medium 31766614
2021 Myeloid cell-derived PROS1 suppresses metastatic seeding in lung and breast cancer models; PROS1 deletion in myeloid cells (cKO) elevated TNF-α, IL-6, Nos2, and IL-10 via modulation of Socs3/NF-κB; cKO BMDM conditioned medium enhanced EMT and activated ERK, AKT, and STAT3 in tumor cells promoting IL-10-dependent invasion; MERTK kinase activity mediates PROS1 suppression of TNF-α and IL-6 but not IL-10; PROS1/MERTK axis in macrophages modulates T cell proliferation and DC costimulatory molecule expression. Myeloid-specific Pros1 conditional knockout mouse, BMDM conditioned medium experiments, lung and breast metastasis models, cytokine and signaling pathway analysis, MERTK kinase inhibition The Journal of clinical investigation High 33848267
2022 BAP1 loss in uveal melanoma leads to epigenetic upregulation of PROS1 (accumulation of H3K27ac at the PROS1 locus per ChIP-seq); elevated tumor-secreted PROS1 activates MERTK (increased phosphorylation) in CD163+ macrophages, promoting an immunosuppressive M2-polarized tumor microenvironment; PROS1 depletion in BAP1-/- uveal melanocytes blocked MERTK phosphorylation in co-cultured macrophages. ChIP-seq (H3K27ac), RNA-seq and single-cell RNA-seq, co-culture MERTK phosphorylation assay, siRNA PROS1 depletion, multicolor immunohistochemistry on patient tumors Cancers High 35954340

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2008 The proPO-system: pros and cons for its role in invertebrate immunity. Trends in immunology 804 18457993
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2004 The human plasma proteome: a nonredundant list developed by combination of four separate sources. Molecular & cellular proteomics : MCP 658 14718574
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 616 14630798
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
1984 Recurrent venous thromboembolism in patients with a partial deficiency of protein S. The New England journal of medicine 532 6239102
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
2014 PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. American journal of medical genetics. Part A 423 25557259
2010 The pros and cons of phytoestrogens. Frontiers in neuroendocrinology 417 20347861
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1981 High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein. Proceedings of the National Academy of Sciences of the United States of America 407 6454142
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2019 The Pros and Cons of Mesenchymal Stem Cell-Based Therapies. Cell transplantation 386 31018669
2022 Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons. Cell communication and signaling : CCS 377 35392976
1987 Hereditary protein S deficiency: clinical manifestations. Annals of internal medicine 372 2952034
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
2002 Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nature immunology 336 12447359
1991 Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant system. Thrombosis and haemostasis 330 1833851
2006 Nanoparticles: health effects--pros and cons. Environmental health perspectives 293 17185269
2014 Adding Molecules to Food, Pros and Cons: A Review on Synthetic and Natural Food Additives. Comprehensive reviews in food science and food safety 270 33412697
2006 Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proceedings of the National Academy of Sciences of the United States of America 261 16488980
2003 Inhibition of fibrocyte differentiation by serum amyloid P. Journal of immunology (Baltimore, Md. : 1950) 252 14607961
2017 Blocking CGRP in migraine patients - a review of pros and cons. The journal of headache and pain 216 28948500
1993 Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C. The Journal of biological chemistry 211 8428962
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
1986 Isolation and sequence of the cDNA for human protein S, a regulator of blood coagulation. Proceedings of the National Academy of Sciences of the United States of America 202 2944113
2008 Are tests of sperm DNA damage clinically useful? Pros and cons. Journal of andrology 197 19059901
2015 From in vitro Experiments to in vivo and Clinical Studies; Pros and Cons. Current drug discovery technologies 191 26778084
1994 Protein S binds to and inhibits factor Xa. Proceedings of the National Academy of Sciences of the United States of America 160 8146182
2003 Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex. Blood 155 12907438
2013 T cell-derived protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response. Immunity 153 23850380
2018 Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response. The Journal of clinical investigation 146 29708510
1990 Organization of the human protein S genes. Biochemistry 142 2148110
1986 Primary structure of bovine vitamin K-dependent protein S. Proceedings of the National Academy of Sciences of the United States of America 142 2940598
2013 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. Proteomics 138 23533145
2018 Pros and cons of different therapeutic antibody formats for recombinant antivenom development. Toxicon : official journal of the International Society on Toxinology 135 29534892
2017 Statins: pros and cons. Medicina clinica 135 29292104
1992 Reevaluation of total, free, and bound protein S and C4b-binding protein levels in plasma anticoagulated with citrate or hirudin. Blood 129 1534488
2019 Genome-Editing Technologies: Concept, Pros, and Cons of Various Genome-Editing Techniques and Bioethical Concerns for Clinical Application. Molecular therapy. Nucleic acids 126 30965277
2006 Cannabinoids and cancer: pros and cons of an antitumour strategy. British journal of pharmacology 124 16501583
2021 Engineered TCR-T Cell Immunotherapy in Anticancer Precision Medicine: Pros and Cons. Frontiers in immunology 116 33859650
2002 The pros and cons of apoptosis assays for use in the study of cells, tissues, and organs. Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada 100 12533214
2017 Maillard reaction in food allergy: Pros and cons. Critical reviews in food science and nutrition 97 26980434
2015 The pros and cons of vertebrate animal models for functional and therapeutic research on inherited retinal dystrophies. Progress in retinal and eye research 93 25936606
2013 Lysosomal multienzyme complex: pros and cons of working together. Cellular and molecular life sciences : CMLS 93 24337808
2016 CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS). Clinical genetics 90 27426476
2016 In vitro evolution of chemically-modified nucleic acid aptamers: Pros and cons, and comprehensive selection strategies. RNA biology 84 27715478
2018 The Properties of Cytokines in Multiple Sclerosis: Pros and Cons. The American journal of the medical sciences 81 30447707
2019 Pros and Cons of Chaperone-Mediated Autophagy in Cancer Biology. Trends in endocrinology and metabolism: TEM 75 31699565
2000 Pros and cons of inhibiting cholesteryl ester transfer protein. Current opinion in lipidology 71 11086331
2010 Radiolabelled proteins for positron emission tomography: Pros and cons of labelling methods. Biochimica et biophysica acta 67 20153401
2020 Pros and Cons of Denosumab Treatment for Osteoporosis and Implication for RANKL Aptamer Therapy. Frontiers in cell and developmental biology 64 32478071
2015 Pros and cons of using biomarkers versus clinical decisions in start and stop decisions for antibiotics in the critical care setting. Intensive care medicine 62 26194026
2021 Myeloid cell-derived PROS1 inhibits tumor metastasis by regulating inflammatory and immune responses via IL-10. The Journal of clinical investigation 60 33848267
2016 Circulating Tumor Cells Versus Circulating Tumor DNA in Colorectal Cancer: Pros and Cons. Current colorectal cancer reports 60 27516729
2015 Heat shock proteins and heat therapy for type 2 diabetes: pros and cons. Current opinion in clinical nutrition and metabolic care 56 26049635
2020 Current methods for diagnosis of human coronaviruses: pros and cons. Analytical and bioanalytical chemistry 44 33219449
2013 The pros and the cons of mTOR inhibitors in kidney transplantation. Expert review of clinical immunology 44 24377908
2023 Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons. Cells 41 37508559
2006 Bioartificial liver: its pros and cons. Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 41 16684219
2002 Pros and cons of existing treatment modalities in osteoporosis: a comparison between tibolone, SERMs and estrogen (+/-progestogen) treatments. The Journal of steroid biochemistry and molecular biology 39 12650712
2019 Models of Intracellular Transport: Pros and Cons. Frontiers in cell and developmental biology 37 31440506
2015 Pros and Cons of Antigen-Presenting Cell Targeted Tumor Vaccines. Journal of immunology research 37 26583156
2020 Wnt/β-Catenin Signaling Pathway as Chemotherapeutic Target in Breast Cancer: An Update on Pros and Cons. Clinical breast cancer 36 32416986
2019 The Yin and Yang of the Bone Marrow Microenvironment: Pros and Cons of Mesenchymal Stromal Cells in Acute Myeloid Leukemia. Frontiers in oncology 36 31709192
2012 Pregabalin in clinical psychiatry and addiction: pros and cons. Expert opinion on investigational drugs 35 22725618
2022 Liver-on-a-chip devices: the pros and cons of complexity. American journal of physiology. Gastrointestinal and liver physiology 34 35819853
2016 Pros and Cons of Clinical Basophil Testing (BAT). Current allergy and asthma reports 34 27411319
2014 Downstream processing of biopharmaceutical proteins produced in plants: the pros and cons of flocculants. Bioengineered 34 24637706
2014 Pros and cons of current approaches for detecting peroxynitrite and their applications. Biomedical journal 34 24923569
2009 Gross deletions/duplications in PROS1 are relatively common in point mutation-negative hereditary protein S deficiency. Human genetics 34 19466456
2022 BAP1 Loss Promotes Suppressive Tumor Immune Microenvironment via Upregulation of PROS1 in Class 2 Uveal Melanomas. Cancers 33 35954340
2015 Pros and cons of fatty acids in bone biology. Progress in lipid research 32 25835096
2015 Pros and cons of methylation-based enrichment methods for ancient DNA. Scientific reports 32 26134828
2014 Scrambling free combinatorial labeling of alanine-β, isoleucine-δ1, leucine-proS and valine-proS methyl groups for the detection of long range NOEs. Journal of biomolecular NMR 32 25430061
2008 Insulin delivery route for the artificial pancreas: subcutaneous, intraperitoneal, or intravenous? Pros and cons. Journal of diabetes science and technology 32 19885254
2022 Pros and cons of causative association between periodontitis and rheumatoid arthritis. Periodontology 2000 30 35262966
2016 Silencing of PROS1 induces apoptosis and inhibits migration and invasion of glioblastoma multiforme cells. International journal of oncology 30 27840905
2019 Tumour-Secreted Protein S (ProS1) Activates a Tyro3-Erk Signalling Axis and Protects Cancer Cells from Apoptosis. Cancers 28 31766614
2017 Multi-targeting Strategies for Alzheimer's Disease Therapeutics: Pros and Cons. Current topics in medicinal chemistry 28 28685694
2015 Emerging role for αB-crystallin as a therapeutic agent: pros and cons. Current molecular medicine 28 25601468
2011 Noise in biological systems: pros, cons, and mechanisms of control. Methods in molecular biology (Clifton, N.J.) 28 21863500
2018 Pros and Cons of the New Edition of TNM Classification of Head and Neck Squamous Cell Carcinoma. Oncology 27 29975952
2017 Acid-Suppressive Therapy and Risk of Infections: Pros and Cons. Clinical drug investigation 27 28361440
2021 Urea-Urease Reaction in Controlling Properties of Supramolecular Hydrogels: Pros and Cons. Chemistry (Weinheim an der Bergstrasse, Germany) 26 33861488
2023 CDK4/6 inhibitors: basics, pros, and major cons in breast cancer treatment with specific regard to cardiotoxicity - a narrative review. Therapeutic advances in medical oncology 25 37841752
2018 Inducible HIV RNA transcription assays to measure HIV persistence: pros and cons of a compromise. Retrovirology 25 29343255
2012 Is EPCR a multi-ligand receptor? Pros and cons. Thrombosis and haemostasis 25 22318610
2008 Treatment of type 2 diabetes with combined therapy: what are the pros and cons? Diabetes care 25 18227473
2024 Pros and Cons in Various Immobilization Techniques and Carriers for Enzymes. Applied biochemistry and biotechnology 24 38175415
2022 Pros and Cons of In Vitro Methods for Circular RNA Preparation. International journal of molecular sciences 23 36362032
2021 HtrA family proteases of bacterial pathogens: pros and cons for their therapeutic use. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 23 33359376
2013 Multipotent (adult) and pluripotent stem cells for heart regeneration: what are the pros and cons? Stem cell research & therapy 23 24476362
2017 Balancing Ethical Pros and Cons of Stem Cell Derived Gametes. Annals of biomedical engineering 22 28091967
2017 [PIK3CA-related overgrowth syndrome (PROS)]. Nephrologie & therapeutique 22 28577738
2016 Measurement of free light chains - pros and cons of current methods. Clinical chemistry and laboratory medicine 22 26812876
2015 Pros and cons of pDNA and mRNA transfection to study mRNA translation in mammalian cells. Gene 22 26680098
2021 Brain metastases in patients with oncogenic-driven non-small cell lung cancer: Pros and cons for early radiotherapy. Cancer treatment reviews 21 34587557
2020 Inflammation and Inflammasomes: Pros and Cons in Tumorigenesis. Journal of immunology research 21 33015196
2001 Pros and cons of splenectomy in patients with myelofibrosis undergoing stem cell transplantation. Leukemia 21 11237072
2023 ProS-GNN: Predicting effects of mutations on protein stability using graph neural networks. Computational biology and chemistry 20 37643501
2023 New insights in application of mesenchymal stem cells therapy in tumor microenvironment: pros and cons. Frontiers in cell and developmental biology 20 37849741
2022 Targeting C-Reactive Protein by Selective Apheresis in Humans: Pros and Cons. Journal of clinical medicine 20 35407379
2017 Protein Supplements: Pros and Cons. Journal of dietary supplements 20 28937838
1983 Antigen detection in cerebrospinal fluid--pros and cons. The American journal of medicine 20 6410914
2016 Minimal Residual Disease by Next-Generation Sequencing: Pros and Cons. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting 19 27249750
2022 Immunotherapy in liver transplantation for hepatocellular carcinoma: Pros and cons. World journal of gastrointestinal oncology 18 35116109
2022 Extracellular vesicles in cancer pros and cons: The importance of the evidence-based medicine. Seminars in cancer biology 18 35124195
2007 Leukotriene synthesis inhibitors versus antagonists: the pros and cons. Current allergy and asthma reports 17 17437683
2001 Characterization and structural impact of five novel PROS1 mutations in eleven protein S-deficient families. Thrombosis and haemostasis 17 11776305
2020 In Search of Effective Treatments Targeting α-Synuclein Toxicity in Synucleinopathies: Pros and Cons. Frontiers in cell and developmental biology 16 33015057
2019 The Pros and Cons of Using Oat in a Gluten-Free Diet for Celiac Patients. Nutrients 16 31581722
2018 Methylenedioxymethamphetamine (MDMA) in Psychiatry: Pros, Cons, and Suggestions. Journal of clinical psychopharmacology 16 30303861
2024 Administration of methylene blue in septic shock: pros and cons. Critical care (London, England) 15 38365828
2024 Neoadjuvant and Adjuvant Immune-based Approach for Renal Cell Carcinoma: Pros, Cons, and Future Directions. European urology oncology 15 39327187
2022 Unraveling the pros and cons of various in vitro methodologies for ruminant nutrition: a review. Translational animal science 15 36213308
2021 Early approval of COVID-19 vaccines: Pros and cons. Human vaccines & immunotherapeutics 15 34283001
2021 Pros and Cons of Pharmacological Manipulation of cGMP-PDEs in the Prevention and Treatment of Breast Cancer. International journal of molecular sciences 15 35008687
2020 Pros and Cons of Robotic Revisional Bariatric Surgery. Visceral medicine 15 32775356
2020 Recurrent PROC and novel PROS1 mutations in Vietnamese patients diagnosed with idiopathic deep venous thrombosis. International journal of laboratory hematology 15 32964666
1996 Oral vs inhaled asthma therapy. Pros, cons and combinations. Drugs 15 8941500
2022 EBCC-13 manifesto: Balancing pros and cons for contralateral prophylactic mastectomy. European journal of cancer (Oxford, England : 1990) 14 36641897
2020 Electrochemical Immuno- and Aptamer-Based Assays for Bacteria: Pros and Cons over Traditional Detection Schemes. Sensors (Basel, Switzerland) 14 32998409
2019 The Pros and Cons of Incorporating Transcriptomics in the Age of Precision Oncology. Journal of the National Cancer Institute 14 31165154
2012 B cell depletion in treating primary biliary cirrhosis: pros and cons. World journal of gastroenterology 14 22912543