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Gene Review

PROC  -  protein C (inactivator of coagulation...

Homo sapiens

Synonyms: APC, Anticoagulant protein C, Autoprothrombin IIA, Blood coagulation factor XIV, PC, ...
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Disease relevance of PROC


Psychiatry related information on PROC

  • Measurements of protein C, protein S, and AT III levels were obtained prior to conditioning therapy and weekly thereafter for 2-3 weeks [6].
  • Alexia without agraphia following cerebral venous thrombosis associated with protein C and protein S deficiency [7].
  • RESULTS: After 1 month of treatment, protein C activity increased by 9.6% and 11.4% of the initial value (p < 0.05), fibrinogen level decreased by 7.8% and 6.1% of the initial value (p < 0.05) and PAI-1 decreased by 19.4% and 14.3% of the initial value (p < 0.05) in the CEE therapy group and the CEE/MPA therapy group, respectively [8].
  • Previous measurements of label accessibility to externally added ascorbate had been considered to suggest an external-internal transition of protein-bound labels, coupled with ion translocation [Tonomura, Y. & Morales, M.F. (1974) Proc. Natl. Acad. Sci. USA 71, 3687-3691] [9].
  • Cardiac myosin binding protein C gene is specifically expressed in heart during murine and human development [10].

High impact information on PROC

  • Plasma levels, protein C antigen, protein S antigen, and antithrombin antigen were lower than those in the controls [11].
  • We studied the expression of thrombomodulin and the endothelial protein C receptor in the dermal microvasculature of children with severe meningococcemia and purpuric or petechial lesions [11].
  • BACKGROUND: Impairment of the protein C anticoagulation pathway is critical to the thrombosis associated with sepsis and to the development of purpura fulminans in meningococcemia [11].
  • Dysfunction of endothelial protein C activation in severe meningococcal sepsis [11].
  • CONCLUSIONS: In severe meningococcal sepsis, protein C activation is impaired, a finding consistent with down-regulation of the endothelial thrombomodulin-endothelial protein C receptor pathway [11].

Chemical compound and disease context of PROC


Biological context of PROC

  • Molecular genetic analysis of the PROC and PROS gene segregating in the family then yielded one PROC gene lesion in the father and two PROS gene lesions, one in each parent [1].
  • We have identified one frameshift (3363 ins C) and two missense mutations (R178Q and T298M) in 7 French Canadian families with type I PROC deficiency [17].
  • The frequency of the CG allele associated with lower PC concentrations was slightly but not significantly lower in 82 heterozygotes for detrimental PROC gene mutations than in 36 patients with no identified detrimental mutations [18].
  • Our data suggest that these patients carry a common haplotype at the PROC locus [17].
  • In order to demonstrate a possible founder effect for the 3363 ins C mutation, we have constructed a high-resolution genetic map to locate several highly polymorphic markers close to PROC locus [17].

Anatomical context of PROC


Associations of PROC with chemical compounds

  • Genotypic analysis of the second child showed a PROC mutation, but neither PROS mutation consistent with its possession of normal protein S levels and a low/borderline protein C level [1].
  • The sequencing of all exons and splice junctions of the PROC gene led to the identification of a new, unpublished G-->A transition at nt 8490, leading to an exchange of alanine 259 by threonine [3].
  • In this study we have investigated the effects of Factor Va and its light chain on the activation of protein C in the presence of cultured endothelial cells [5].
  • Activation rates of the protein C derivative lacking the gamma-carboxyglutamic acid domain, which is required for binding to EPCR, are not altered by the anti-EPCR antibodies [21].
  • Protein C, an anticoagulant zymogen, has Asp residues in positions P3 and P'3 [22].

Physical interactions of PROC

  • Thrombomodulin changes the molecular surface of interaction and the rate of complex formation between thrombin and protein C [23].
  • EPCR binds to both protein C and activated protein C (APC) with high affinity [24].
  • The normal level of PC inhibitor and APC:PCI complex found in this study provided no evidence of increased consumption of protein C in thalassemia patients [25].
  • The endothelial PC receptor binds the Gla domain of PC and stimulates the activation [26].
  • Eight of these were novel, including a gross gene deletion, three missense mutations, two micro-deletions, a splicing mutation and a single base-pair substitution in the HNF-3 binding site in the PROC gene promoter [27].

Enzymatic interactions of PROC


Regulatory relationships of PROC


Other interactions of PROC

  • Here we present the 2.3 A crystal structure of human alpha-thrombin bound to the smallest thrombomodulin fragment required for full protein-C co-factor activity, TME456 [33].
  • By these mechanisms, EPCR appears to enable significant levels of protein C activation in large vessels [20].
  • We studied the relation between heritable thrombophilic defects and fetal loss in a cohort of women with factor V Leiden or deficiency of antithrombin, protein C, or protein S. METHODS: We studied 1384 women enrolled in the European Prospective Cohort on Thrombophilia (EPCOT) [34].
  • Addition of PCI to normal plasma and protein C-deficient plasma resulted in a minor prolongation of the clotting time [35].
  • When the TFPI concentration was reduced to 1.25 nM, thrombin generation is still curtailed in the presence of normal factor V. In contrast, under similar conditions using factor VLEIDEN, the protein C pathway totally failed to down-regulate thrombin generation [36].

Analytical, diagnostic and therapeutic context of PROC

  • Using a highly sensitive RT-PCR assay, we show here that aberrant splicing is a frequent occurrence during expression of the protein C (PROC) and protein S (PROS) genes [37].
  • PROC and PROS deficiency were documented by functional and immunologic tests [3].
  • Plasma samples (n = 454) were collected three times/week from all patients (n = 25) undergoing renal transplantation during a 9-month consecutive period, and assayed by ELISA and functional assays for TNF, PC, and free PS (FPS) [4].
  • Using specific radioimmunoassays, 8 day cultures of Hep G2 cells were shown to contain in their supernatants 16, 74, and 828 ng/mL and in their cell lysates, 8, 55, and 48 ng/2 X 10(8) cells of factor VII, protein C, and protein S, respectively [38].
  • No significant differences exist between survivors and nonsurvivors with respect to baseline PC levels, F1 + 2 levels, and APACHE II (acute physiology and chronic health evaluation) scores [39].


  1. Severe perinatal thrombosis in double and triple heterozygous offspring of a family segregating two independent protein S mutations and a protein C mutation. Formstone, C.J., Hallam, P.J., Tuddenham, E.G., Voke, J., Layton, M., Nicolaides, K., Hann, I.M., Cooper, D.N. Blood (1996) [Pubmed]
  2. A novel homozygous missense mutation in the protein C (PROC) gene causing recurrent venous thrombosis. Grundy, C.B., Chisholm, M., Kakkar, V.V., Cooper, D.N. Hum. Genet. (1992) [Pubmed]
  3. Combined occurrence of a heterozygous missense mutation in the protein C gene and allelic exclusion of one protein S allele leading to severe venous thrombosis. Knoll, B., Hach-Wunderle, V., Rieger, S., Häring, D., Mannhalter, C. Thromb. Res. (2001) [Pubmed]
  4. 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]
  5. Coagulation factor Va binds to human umbilical vein endothelial cells and accelerates protein C activation. Maruyama, I., Salem, H.H., Majerus, P.W. J. Clin. Invest. (1984) [Pubmed]
  6. 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]
  7. 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]
  8. Changes in coagulation factors and fibrinolytic components of postmenopausal women receiving continuous hormone replacement therapy. Nozaki, M., Ogata, R., Koera, K., Hashimoto, K., Nakano, H. Climacteric : the journal of the International Menopause Society. (1999) [Pubmed]
  9. Calcium translocation mechanism in sarcoplasmic reticulum vesicles, deduced from location studies of protein-bound spin labels. Champeil, P., Rigaud, J.L., Gary-Bobo, C.M. Proc. Natl. Acad. Sci. U.S.A. (1980) [Pubmed]
  10. Cardiac myosin binding protein C gene is specifically expressed in heart during murine and human development. Fougerousse, F., Delezoide, A.L., Fiszman, M.Y., Schwartz, K., Beckmann, J.S., Carrier, L. Circ. Res. (1998) [Pubmed]
  11. 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]
  12. Protein C inhibitor and other components of the protein C pathway in patients with acute deep vein thrombosis during heparin treatment. Tabernero, D., España, F., Vicente, V., Estellés, A., Gilabert, J., Aznar, J. Thromb. Haemost. (1990) [Pubmed]
  13. 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]
  14. Coumarin necrosis, neonatal purpura fulminans, and protein C deficiency. Gladson, C.L., Groncy, P., Griffin, J.H. Archives of dermatology. (1987) [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. Frequency of hereditary thrombophilia: an AKUH experience. Khalid, S., Sajid, R., Adil, S.N., Khurshid, M. JPMA. The Journal of the Pakistan Medical Association. (2004) [Pubmed]
  17. Type I protein C deficiency in French Canadians: evidence of a founder effect and association of specific protein C gene mutations with plasma protein C levels. Couture, P., Demers, C., Morissette, J., Delage, R., Jomphe, M., Couture, L., Simard, J. Thromb. Haemost. (1998) [Pubmed]
  18. Thirty-three novel mutations in the protein C gene. French INSERM network on molecular abnormalities responsible for protein C and protein S. Alhenc-Gelas, M., Gandrille, S., Aubry, M.L., Aiach, M. Thromb. Haemost. (2000) [Pubmed]
  19. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Cheng, T., Liu, D., Griffin, J.H., Fernández, J.A., Castellino, F., Rosen, E.D., Fukudome, K., Zlokovic, B.V. Nat. Med. (2003) [Pubmed]
  20. Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor. Fukudome, K., Ye, X., Tsuneyoshi, N., Tokunaga, O., Sugawara, K., Mizokami, H., Kimoto, M. J. Exp. Med. (1998) [Pubmed]
  21. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Stearns-Kurosawa, D.J., Kurosawa, S., Mollica, J.S., Ferrell, G.L., Esmon, C.T. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  22. Glu-192----Gln substitution in thrombin mimics the catalytic switch induced by thrombomodulin. Le Bonniec, B.F., Esmon, C.T. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  23. Thrombomodulin changes the molecular surface of interaction and the rate of complex formation between thrombin and protein C. Xu, H., Bush, L.A., Pineda, A.O., Caccia, S., Di Cera, E. J. Biol. Chem. (2005) [Pubmed]
  24. Mechanisms by which soluble endothelial cell protein C receptor modulates protein C and activated protein C function. Liaw, P.C., Neuenschwander, P.F., Smirnov, M.D., Esmon, C.T. J. Biol. Chem. (2000) [Pubmed]
  25. Hemostatic alterations in beta-thalassemia/hemoglobin E patients. Opartkiattikul, N., Tatsumi, N., Funahara, Y., Shirahata, A., Wongtiraporn, W., Tientadakul, P., Fucharoen, S. Southeast Asian J. Trop. Med. Public Health (1999) [Pubmed]
  26. Molecular recognition in the protein C anticoagulant pathway. Dahlbäck, B., Villoutreix, B.O. J. Thromb. Haemost. (2003) [Pubmed]
  27. Molecular genetic analysis of severe protein C deficiency. Millar, D.S., Johansen, B., Berntorp, E., Minford, A., Bolton-Maggs, P., Wensley, R., Kakkar, V., Schulman, S., Torres, A., Bosch, N., Cooper, D.N. Hum. Genet. (2000) [Pubmed]
  28. Proline at the P2 position in protein C is important for calcium-mediated regulation of protein C activation and secretion. Rezaie, A.R., Esmon, C.T. Blood (1994) [Pubmed]
  29. Gene structure of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for thrombin-catalyzed activation of protein C. Suzuki, K. Nippon Ketsueki Gakkai Zasshi (1988) [Pubmed]
  30. Protein S is a cofactor for activated protein C neutralization of an inhibitor of plasminogen activation released from platelets. D'Angelo, A., Lockhart, M.S., D'Angelo, S.V., Taylor, F.B. Blood (1987) [Pubmed]
  31. Platelet factor 4 binds to glycanated forms of thrombomodulin and to protein C. A potential mechanism for enhancing generation of activated protein C. Dudek, A.Z., Pennell, C.A., Decker, T.D., Young, T.A., Key, N.S., Slungaard, A. J. Biol. Chem. (1997) [Pubmed]
  32. Activation of thrombin-activable fibrinolysis inhibitor requires epidermal growth factor-like domain 3 of thrombomodulin and is inhibited competitively by protein C. Kokame, K., Zheng, X., Sadler, J.E. J. Biol. Chem. (1998) [Pubmed]
  33. Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex. Fuentes-Prior, P., Iwanaga, Y., Huber, R., Pagila, R., Rumennik, G., Seto, M., Morser, J., Light, D.R., Bode, W. Nature (2000) [Pubmed]
  34. Increased fetal loss in women with heritable thrombophilia. Preston, F.E., Rosendaal, F.R., Walker, I.D., Briët, E., Berntorp, E., Conard, J., Fontcuberta, J., Makris, M., Mariani, G., Noteboom, W., Pabinger, I., Legnani, C., Scharrer, I., Schulman, S., van der Meer, F.J. Lancet (1996) [Pubmed]
  35. Protein C inhibitor acts as a procoagulant by inhibiting the thrombomodulin-induced activation of protein C in human plasma. Elisen, M.G., von dem Borne, P.A., Bouma, B.N., Meijers, J.C. Blood (1998) [Pubmed]
  36. Increased tissue factor-initiated prothrombin activation as a result of the Arg506 --> Gln mutation in factor VLEIDEN. van 't Veer, C., Kalafatis, M., Bertina, R.M., Simioni, P., Mann, K.G. J. Biol. Chem. (1997) [Pubmed]
  37. Aberrant RNA splicing of the protein C and protein S genes in healthy individuals. Berg, L.P., Soria, J.M., Formstone, C.J., Morell, M., Kakkar, V.V., Estivill, X., Sala, N., Cooper, D.N. Blood Coagul. Fibrinolysis (1996) [Pubmed]
  38. Biosynthesis and secretion of factor VII, protein C, protein S, and the Protein C inhibitor from a human hepatoma cell line. Fair, D.S., Marlar, R.A. Blood (1986) [Pubmed]
  39. Patients with severe sepsis vary markedly in their ability to generate activated protein C. Liaw, P.C., Esmon, C.T., Kahnamoui, K., Schmidt, S., Kahnamoui, S., Ferrell, G., Beaudin, S., Julian, J.A., Weitz, J.I., Crowther, M., Loeb, M., Cook, D. Blood (2004) [Pubmed]
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