The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

PROS1  -  protein S (alpha)

Homo sapiens

Synonyms: PROS, PS21, PS22, PS23, PS24, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of PROS1

  • In the course of investigating the molecular basis of protein S deficiency in 31 index cases with thrombophilia, we identified seven kindred where the underlying defect was a novel A to G transition 9 bp upstream of exon 12 in intron K of the PROS1 gene [1].
  • Our data suggest that the determination of protein S levels will be useful in the evaluation of patients with recurrent thrombosis [2].
  • Using this test, we have now identified six unrelated persons with severe recurrent venous thrombosis who were deficient in protein S, with levels between 15 and 37 per cent while they were not receiving warfarin therapy [2].
  • Recurrent venous thromboembolism in patients with a partial deficiency of protein S [2].
  • When 20 normal plasmas were tested using this clotting assay, apoA-I levels correlated with anticoagulant response to APC/protein S (r = 0.47, P = 0.035), but not with activated partial thromboplastin time-based APC resistance ratios [3].

Psychiatry related information on PROS1


High impact information on PROS1

  • This article reviews the salient features of PSA, with particular emphasis on strategies to improve its utility in the diagnosis of prostate cancer [9].
  • Prostate-specific antigen (PSA) is the most important of all tumor markers in that it has significant applications in all aspects of the management of men with prostatic disease [9].
  • If a slightly more specific PSA assay is developed, the higher prevalence of clinically detectable prostate cancer could also make screening less costly than breast cancer screening [10].
  • Reporting in this issue of Cell, Kasper and colleagues (Mazmanian et al., 2005) reveal that a bacterial polysaccharide, PSA, produced by the commensal bacterium Bacteroides fragilis directs development of the immune system of the mouse host [11].
  • Plasma levels, protein C antigen, protein S antigen, and antithrombin antigen were lower than those in the controls [12].

Chemical compound and disease context of PROS1


Biological context of PROS1

  • By contrast, no cosegregating PROS1 mutation has been found in any of the six families with only type III phenotypes [18].
  • DNA sequence analysis of the protein S gene (PROS1) in 22 Spanish probands with type I or III PS deficiency, has allowed the identification of 10 different mutations and 2 new sequence variants in 15 probands [18].
  • Haplotype analysis using 7 microsatellite markers flanking PROS1 was consistent with a common founder for this mutation [19].
  • A novel mutation in intron K of the PROS1 gene causes aberrant RNA splicing and is a common cause of protein S deficiency in a UK thrombophilia cohort [1].
  • IL-6 exerts its effect through Signal Transducer and Activator of Transcription 3 (STAT3) that interacts with the PROS1 promoter at a binding site in between nucleotides 229 to 207 upstream from the translational start [20].

Anatomical context of PROS1

  • Protein S binding to neutrophils decreased approximately twofold in the presence of saturating concentrations of C4bBP [21].
  • Two different mapping approaches were used to determine the human chromosomal location of the gene for protein S. A human protein S cDNA was used as a hybridization probe to analyze a panel of somatic cell hybrids containing different human chromosomes [22].
  • Free PS has recently been shown to enhance phagocytosis of apoptotic cells by macrophages [23].
  • Using Jurkat cells as a model system for apoptosis, we now show protein S to bind to apoptotic cells [24].
  • The high recurrence rate (60% spontaneous recurrence) and the relatively high frequency of mesenteric vein thrombosis as a recurrent event favor introduction of long-term oral anticoagulant treatment after the first thrombotic event in patients with a documented hereditary deficiency of AT-III, PC, or PS [25].

Associations of PROS1 with chemical compounds

  • Protein S acted by binding to phosphatidylserine expressed on the apoptotic cell surface [26].
  • Tumor necrosis factor production during human renal allograft rejection is associated with depression of plasma protein C and free protein S levels and decreased intragraft thrombomodulin expression [27].
  • The heavy chain of Factor VIII was cleaved by APC and protein S did not alter the degradation pattern [13].
  • In contrast to the other vitamin K-dependent plasma proteins, the COOH-terminal portion of human protein S does not show any resemblance to serine proteases [28].
  • A major proportion of C4b-binding protein in plasma is in complex with protein S. The complex is a major and previously unrecognized component of the group of plasma proteins that adsorbs to barium citrate [29].

Physical interactions of PROS1

  • C4BP beta chain antigen levels, measured using a new ELISA, averaged 218 nmol/L, a value indistinguishable from the molar concentrations of bound protein S (215 nmol/L) and bound C4BP (227 nmol/L) [30].
  • These results allowed us to infer that this method evaluates the ability of protein C to interact with protein S, phospholipids, calcium ions and factor Va [31].
  • Activated protein C (APC)-mediated cleavages of factors VIIIa and Va occur on negatively charged phospholipid membranes and involve protein cofactors, protein S and factor V. APC also has anti-inflammatory and anti-apoptotic activities that involve binding of APC to EPCR and cleavage of PAR-1 (protease-activated receptor-1) [32].
  • APC-Mie and normal APC bound equally to protein S and to biotinyl-factor Va [33].
  • It was also observed that exogenous sIL-6R could also upregulate protein S by forming a complex with IL-6 constitutively produced by the endothelial cell [34].

Enzymatic interactions of PROS1

  • VWF-cleaving protease activity (VWF:CP) and protein S (PS) levels (total and free antigen and activity) were within the conventional FFP reference range for test and control CSP [35].

Regulatory relationships of PROS1

  • These data show that protein S has an anticoagulant function which is independent of activated protein C and, at least in part, that this is because of its competition with prothrombin for direct binding to Factor Va [36].
  • At high tissue-factor concentrations, protein S hardly expressed APC-independent anticoagulant activity but exerted potent APC-cofactor activity when thrombomodulin or APC were added to plasma [37].
  • It was suggested that the metabolism of C4bp might be regulated by the plasma PS level, although this hypothesis needs further exploration [38].
  • APC inactivates the activated form of coagulation factors V and VIII in the presence of protein S. Administration of APC reduced the pulmonary vascular injury and hypotension as well as the coagulation abnormalities by inhibiting production of the tumor necrosis factor-alpha (TNF-alpha) in rats given endotoxin (ET) [39].
  • The thrombin-mediated cleavage of protein S could be inhibited by HPS 7 [40].

Other interactions of PROS1

  • Inactivation of human factor VIII by activated protein C. Cofactor activity of protein S and protective effect of von Willebrand factor [13].
  • Four patients had concurrent regulatory protein abnormalities: three protein C deficiencies, one protein S deficiency, and one plasminogen deficiency [41].
  • This prediction was recently supported by the demonstration of binding of the PS-C4BP complex to apoptotic cells [42].
  • The proteolytic cleavage and subsequent inactivation of recombinant human factor VIII (rhFVIII) and human factor VIIIa (rhFVIIIa) by recombinant human activated protein C (rAPC) was analyzed in the presence and absence of human protein S and human factor V (FV) [43].
  • The native and recombinant Gas6, but not protein S, stimulated tyrosine phosphorylation of Sky ectopically expressed in Chinese hamster ovary cells [44].

Analytical, diagnostic and therapeutic context of PROS1


  1. A novel mutation in intron K of the PROS1 gene causes aberrant RNA splicing and is a common cause of protein S deficiency in a UK thrombophilia cohort. Beauchamp, N.J., Daly, M.E., Makris, M., Preston, F.E., Peake, I.R. Thromb. Haemost. (1998) [Pubmed]
  2. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. Comp, P.C., Esmon, C.T. N. Engl. J. Med. (1984) [Pubmed]
  3. High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C. Griffin, J.H., Kojima, K., Banka, C.L., Curtiss, L.K., Fernández, J.A. J. Clin. Invest. (1999) [Pubmed]
  4. Early drop in protein C and antithrombin III is a predictor for the development of venoocclusive disease in patients undergoing hematopoietic stem cell transplantation. Tabbara, I.A., Ghazal, C.D., Ghazal, H.H. Journal of hematotherapy. (1996) [Pubmed]
  5. Alexia without agraphia following cerebral venous thrombosis associated with protein C and protein S deficiency. Celebisoy, N., Sagduyu, A., Atac, C. Clinical neurology and neurosurgery. (2005) [Pubmed]
  6. Patients' perceptions of quality of life after treatment for early prostate cancer. Clark, J.A., Inui, T.S., Silliman, R.A., Bokhour, B.G., Krasnow, S.H., Robinson, R.A., Spaulding, M., Talcott, J.A. J. Clin. Oncol. (2003) [Pubmed]
  7. The effect of parenteral testosterone replacement on prostate specific antigen in hypogonadal men with erectile dysfunction. Svetec, D.A., Canby, E.D., Thompson, I.M., Sabanegh, E.S. J. Urol. (1997) [Pubmed]
  8. Radiotherapy after radical prostatectomy: does transient androgen suppression improve outcomes? King, C.R., Presti, J.C., Gill, H., Brooks, J., Hancock, S.L. Int. J. Radiat. Oncol. Biol. Phys. (2004) [Pubmed]
  9. Prostate-specific antigen: current status. Brawer, M.K. CA: a cancer journal for clinicians. (1999) [Pubmed]
  10. The benefit and cost of prostate cancer early detection. The Investigators of the American Cancer Society-National Prostate Cancer Detection Project. Littrup, P.J., Goodman, A.C., Mettlin, C.J. CA: a cancer journal for clinicians. (1993) [Pubmed]
  11. Sugar-coated regulation of T cells. Eynon, E.E., Zenewicz, L.A., Flavell, R.A. Cell (2005) [Pubmed]
  12. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. Faust, S.N., Levin, M., Harrison, O.B., Goldin, R.D., Lockhart, M.S., Kondaveeti, S., Laszik, Z., Esmon, C.T., Heyderman, R.S. N. Engl. J. Med. (2001) [Pubmed]
  13. Inactivation of human factor VIII by activated protein C. Cofactor activity of protein S and protective effect of von Willebrand factor. Koedam, J.A., Meijers, J.C., Sixma, J.J., Bouma, B.N. J. Clin. Invest. (1988) [Pubmed]
  14. The factor V Leiden mutation, high factor VIII, and high plasminogen activator inhibitor activity: etiologies for sporadic miscarriage. Glueck, C.J., Pranikoff, J., Aregawi, D., Haque, M., Zhu, B., Tracy, T., Wang, P. Metab. Clin. Exp. (2005) [Pubmed]
  15. Roles of protein C, protein S, and antithrombin III in acute leukemia. Dixit, A., Kannan, M., Mahapatra, M., Choudhry, V.P., Saxena, R. Am. J. Hematol. (2006) [Pubmed]
  16. Evaluation of natural coagulation inhibitor levels in various hypertensive states of pregnancy. Sayin, M., Varol, F.G., Sayin, N.C. Eur. J. Obstet. Gynecol. Reprod. Biol. (2005) [Pubmed]
  17. Norepinephrine down-regulates the activity of protein S on endothelial cells. Brett, J.G., Steinberg, S.F., deGroot, P.G., Nawroth, P.P., Stern, D.M. J. Cell Biol. (1988) [Pubmed]
  18. Protein S gene analysis reveals the presence of a cosegregating mutation in most pedigrees with type I but not type III PS deficiency. Espinosa-Parrilla, Y., Morell, M., Souto, J.C., Tirado, I., Fontcuberta, J., Estivill, X., Sala, N. Hum. Mutat. (1999) [Pubmed]
  19. Characterization and structural impact of five novel PROS1 mutations in eleven protein S-deficient families. Andersen, B.D., Bisgaard, M.L., Lind, B., Philips, M., Villoutreix, B., Thorsen, S. Thromb. Haemost. (2001) [Pubmed]
  20. Interleukin-6 induction of protein s is regulated through signal transducer and activator of transcription 3. de Wolf, C.J., Cupers, R.M., Bertina, R.M., Vos, H.L. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
  21. Protein S enhances C4b binding protein interaction with neutrophils. Furmaniak-Kazmierczak, E., Hu, C.Y., Esmon, C.T. Blood (1993) [Pubmed]
  22. The gene for protein S maps near the centromere of human chromosome 3. Watkins, P.C., Eddy, R., Fukushima, Y., Byers, M.G., Cohen, E.H., Dackowski, W.R., Wydro, R.M., Shows, T.B. Blood (1988) [Pubmed]
  23. The C4b-binding protein-protein S complex inhibits the phagocytosis of apoptotic cells. Kask, L., Trouw, L.A., Dahlbäck, B., Blom, A.M. J. Biol. Chem. (2004) [Pubmed]
  24. Vitamin K-dependent protein S localizing complement regulator C4b-binding protein to the surface of apoptotic cells. Webb, J.H., Blom, A.M., Dahlbäck, B. J. Immunol. (2002) [Pubmed]
  25. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. A cooperative, retrospective study. Gesellschaft fur Thrombose- und Hamostaseforschung (GTH) Study Group on Natural Inhibitors. Pabinger, I., Schneider, B. Arterioscler. Thromb. Vasc. Biol. (1996) [Pubmed]
  26. Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Anderson, H.A., Maylock, C.A., Williams, J.A., Paweletz, C.P., Shu, H., Shacter, E. Nat. Immunol. (2003) [Pubmed]
  27. Tumor necrosis factor production during human renal allograft rejection is associated with depression of plasma protein C and free protein S levels and decreased intragraft thrombomodulin expression. Tsuchida, A., Salem, H., Thomson, N., Hancock, W.W. J. Exp. Med. (1992) [Pubmed]
  28. Isolation and sequence of the cDNA for human protein S, a regulator of blood coagulation. Lundwall, A., Dackowski, W., Cohen, E., Shaffer, M., Mahr, A., Dahlbäck, B., Stenflo, J., Wydro, R. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  29. High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein. Dahlbäck, B., Stenflo, J. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  30. Reevaluation of total, free, and bound protein S and C4b-binding protein levels in plasma anticoagulated with citrate or hirudin. Griffin, J.H., Gruber, A., Fernández, J.A. Blood (1992) [Pubmed]
  31. A novel functional assay of protein C in human plasma and its comparison with amidolytic and anticoagulant assays. Guglielmone, H.A., Vides, M.A. Thromb. Haemost. (1992) [Pubmed]
  32. The anticoagulant protein C pathway. Dahlbäck, B., Villoutreix, B.O. FEBS Lett. (2005) [Pubmed]
  33. The Gla26 residue of protein C is required for the binding of protein C to thrombomodulin and endothelial cell protein C receptor, but not to protein S and factor Va. Nishioka, J., Ido, M., Hayashi, T., Suzuki, K. Thromb. Haemost. (1996) [Pubmed]
  34. Endothelial cell protein S synthesis is upregulated by the complex of IL-6 and soluble IL-6 receptor. Hooper, W.C., Phillips, D.J., Evatt, B.L. Thromb. Haemost. (1997) [Pubmed]
  35. Coagulation factor levels in cryosupernatant prepared from plasma treated with amotosalen hydrochloride (S-59) and ultraviolet A light. Yarranton, H., Lawrie, A.S., Mackie, I.J., Pinkoski, L., Corash, L., Machin, S.J. Transfusion (2005) [Pubmed]
  36. Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C. Heeb, M.J., Mesters, R.M., Tans, G., Rosing, J., Griffin, J.H. J. Biol. Chem. (1993) [Pubmed]
  37. Inhibition of thrombin generation by protein S at low procoagulant stimuli: implications for maintenance of the hemostatic balance. Seré, K.M., Rosing, J., Hackeng, T.M. Blood (2004) [Pubmed]
  38. Behavior of protein S during long-term oral anticoagulant therapy. Takahashi, H., Wada, K., Hayashi, S., Hanano, M., Tatewaki, W., Shibata, A. Thromb. Res. (1988) [Pubmed]
  39. Regulation of inflammatory responses by activated protein C: the molecular mechanism(s) and therapeutic implications. Okajima, K. Clin. Chem. Lab. Med. (2004) [Pubmed]
  40. Inhibition of human vitamin-K-dependent protein-S-cofactor activity by a monoclonal antibody specific for a Ca2+-dependent epitope. Malm, J., Persson, U., Dahlbäck, B. Eur. J. Biochem. (1987) [Pubmed]
  41. Lupus-like anticoagulants and lower extremity arterial occlusive disease. Eldrup-Jorgensen, J., Brace, L., Flanigan, D.P., Schwarcz, T.H., Fritsma, G., Meyer, J.P., Schuler, J.J. Circulation (1989) [Pubmed]
  42. Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex. Rezende, S.M., Simmonds, R.E., Lane, D.A. Blood (2004) [Pubmed]
  43. Comparison of activated protein C/protein S-mediated inactivation of human factor VIII and factor V. Lu, D., Kalafatis, M., Mann, K.G., Long, G.L. Blood (1996) [Pubmed]
  44. Stimulation of sky receptor tyrosine kinase by the product of growth arrest-specific gene 6. Ohashi, K., Nagata, K., Toshima, J., Nakano, T., Arita, H., Tsuda, H., Suzuki, K., Mizuno, K. J. Biol. Chem. (1995) [Pubmed]
  45. Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism of residue 460. Bertina, R.M., Ploos van Amstel, H.K., van Wijngaarden, A., Coenen, J., Leemhuis, M.P., Deutz-Terlouw, P.P., van der Linden, I.K., Reitsma, P.H. Blood (1990) [Pubmed]
  46. Absence of linkage between type III protein S deficiency and the PROS1 and C4BP genes in families carrying the protein S Heerlen allele. Espinosa-Parrilla, Y., Morell, M., Souto, J.C., Borrell, M., Heine-Suñer, D., Tirado, I., Volpini, V., Estivill, X., Sala, N. Blood (1997) [Pubmed]
  47. Familial protein S deficiency with a variant protein S molecule in plasma and platelets. Schwarz, H.P., Heeb, M.J., Lottenberg, R., Roberts, H., Griffin, J.H. Blood (1989) [Pubmed]
WikiGenes - Universities