* 600646

PROTEIN C RECEPTOR; PROCR


Alternative titles; symbols

ENDOTHELIAL PROTEIN C RECEPTOR; EPCR
CELL CYCLE, CENTROSOME-ASSOCIATED PROTEIN; CCCA
CCD41


HGNC Approved Gene Symbol: PROCR

Cytogenetic location: 20q11.22     Genomic coordinates (GRCh38): 20:35,171,096-35,216,259 (from NCBI)


TEXT

Description

Protein C (612283), a vitamin K-dependent serine protease zymogen, plays a major role in blood coagulation and may also prevent the lethal effects of gram-negative sepsis. Deficiency of protein C leads to life-threatening thrombophilia. Protein C is activated when thrombin (F2; 176930), the terminal enzyme of the coagulation system, binds to an endothelial cell surface protein, thrombomodulin (THBD; 188040).


Cloning and Expression

By fluorescence-activated cell sorting (FACS) analysis, Fukudome and Esmon (1994) determined that activated protein C (APC) specifically binds to cultured endothelial cells in a calcium-dependent manner that is not influenced by protein S (PROS1; 176880). The authors screened an endothelial cell library for APC-binding partners and isolated a cDNA encoding PROCR, which they termed EPCR. Sequence analysis predicted that the 238-amino acid type 1 transmembrane protein has a 15-amino acid N-terminal signal sequence; an extracellular domain with 4 potential N-glycosylation sites and 4 cys residues; a C-terminal 25-amino acid transmembrane region; and a short cytoplasmic tail containing only 3 amino acids. Northern blot analysis detected high levels of a 1.3-kb EPCR transcript only in endothelial cell lines. Flow cytometric and Northern blot analyses determined that exposure of endothelial cells to tumor necrosis factor (TNF; 191160) reduced APC binding and EPCR expression in parallel.


Gene Function

Using immunohistochemical analysis, Ye et al. (1999) demonstrated that EPCR is expressed strongly in the endothelial cells of arteries and veins in heart and lung, less intensely in capillaries in the lung and skin, and not at all in the endothelium of small vessels of the liver and kidney. Immunoblot analysis showed that EPCR is expressed as a 49-kD protein that is reduced to the predicted 25 kD by deglycosylation. Antibodies to EPCR could inhibit binding of protein C and APC to cultured endothelial cells and inhibited the activation of protein C.

Simmonds and Lane (1999) pointed out that THBD is uniformly expressed on endothelial cells, significantly reducing its effective concentration on large vessels, whereas EPCR, with its high affinity for protein C, is preferentially expressed on large vessels.

Riewald et al. (2002) demonstrated that activated protein C uses the endothelial cell protein C receptor (EPCR) as a coreceptor for cleavage of protease-activated receptor 1 (PAR1; 187930) on endothelial cells. Gene profiling demonstrated that PAR1 signaling could account for all activated protein C-induced protective genes, including the immunomodulatory monocyte chemoattractant protein-1 (MCP1; 158105), which was selectively induced by activation of PAR1, but not PAR2 (600933). Thus, Riewald et al. (2002) concluded that the prototypic thrombin receptor is the target for EPCR-dependent APC signaling, suggesting a role for this receptor cascade in protection from sepsis.

By screening an array of full-length plasma membrane proteins expressed on human embryonic kidney cells, Turner et al. (2013) identified EPCR as a binding partner of domain cassette-8 of the Plasmodium falciparum erythrocyte membrane protein-1 (DC8-PfEMP1). They mapped the PfEMP1 EPCR-binding domain by ELISA with DC8-PfEMP1C8 variants. Further analysis confirmed that PfEmp1 proteins have diverged into CD36 (173510)- and EPCR-binding subtypes. DC8-PfEMP1-expressing and parasitized erythrocytes bound to brain endothelial cells and were inhibited by recombinant EPCR or anti-EPCR antibodies. Turner et al. (2013) proposed that PfEMP1-EPCR-mediated cytoadhesion is the major virulence phenotype for severe malaria (see 611162).

Using single-cell RNA sequencing analysis of mouse Th17 cells (see IL17A, 603149) differentiated in vitro under pathogenic versus nonpathogenic conditions or of Th17 cells isolated ex vivo from lymph nodes or central nervous system of mice undergoing experimental autoimmune encephalomyelitis (EAE), Kishi et al. (2016) showed that expression of Procr correlated inversely with Th17-cell pathogenicity. Procr expression was regulated by transcription factors critical for Th17 differentiation, including Stat3 (102582), Irf4 (601900), and Rorgt (602943). Procr overexpression reduced expression of the Th17 proinflammatory module, including Il1r (IL1R1; 147810) and Il23r (607562). Using different EAE mouse models, Kishi et al. (2016) found that loss or reduction of Procr expression led to increased Th17 pathogenicity and enhanced EAE in vivo. Kishi et al. (2016) concluded that PROCR is a negative regulator of Th17 pathogenicity.

Using RNA and protein expression profiling at single-cell resolution in mouse cells, Chihara et al. (2018) identified a module of coinhibitory receptors that includes not only several known coinhibitory receptors but many novel surface receptors. Chihara et al. (2018) functionally validated 2 novel coinhibitory receptors, activated PROCR and podoplanin (PDPN; 608863). The module of coinhibitory receptors is coexpressed in both CD4+ and CD8+ T cells and is part of a larger coinhibitory gene program that is shared by nonresponsive T cells in several physiologic contexts and is driven by the immunoregulatory cytokine IL27 (608273). Computational analysis identified the transcription factors PRDM1 (603423) and c-MAF (177075) as cooperative regulators of the coinhibitory module, and this was validated experimentally. This molecular circuit underlies the coexpression of coinhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumor immunity.


Gene Structure

Using genomic sequence and 5-prime RACE analysis Simmonds and Lane (1999) and Hayashi et al. (1999) determined that the EPCR gene contains 4 exons and spans 6 kb. The transcription initiation point is 79 bp upstream of the translation initiation (met) codon and 84 bp downstream of a TATA box element. Hayashi et al. (1999) identified putative AP1 (165160)-, SP1 (189906)-, and AP2 (107580)-binding sites in the promoter region. Simmonds and Lane (1999) determined that exon 1 encodes the 5-prime untranslated region (UTR) and the signal peptide, exons 2 and 3 encode most of the extracellular region, and exon 4 encodes the transmembrane domain, cytoplasmic tail, and most of the 3-prime UTR. Secondary structure analysis predicted that EPCR has similarity to CD1 (see 188410) and MHC class I (see 142800) proteins and folds with a beta-sheet platform supporting 2 alpha-helical regions that collectively form a potential binding pocket for protein C and APC.


Mapping

The mouse CCD41 protein is a centrosome-associated antigen occupying a compact structure inside the centrosome. It is prevalent in the G2 and M phases of the cell cycle, where it is found not only in centrosomes but also accumulated in perinuclear vesicles (Rothbarth et al., 1993). The epitope in the centrosome is exposed throughout the cell cycle except for a brief period immediately after the formation of the daughter centrosomes. On the basis of these observations, it was suggested that the protein plays an essential role in the centrosome function regarding cell cycle progression. Mutations in this gene might be expected to result in severe phenotypic abnormalities. To identify candidate mouse disorders, Mincheva et al. (1995) mapped the gene to mouse chromosome 2 (band H) by fluorescence in situ hybridization. The homologous human gene was predicted to be on 20q. Rothbarth et al. (1999) showed that EPCR and CCD41 have identical cDNA sequences. Mutation analysis and fluorescence microscopy suggested that the preferential transmembrane expression of EPCR compared with the centrosomal localization of CCD41 may be due to a posttranslational deletion of the signal peptide in the latter.

By radiation hybrid analysis and FISH, Simmonds and Lane (1999) and Hayashi et al. (1999) mapped the PROCR gene to 20q11.2.


Molecular Genetics

Franchi et al. (2001) found an excess of mutations in the EPCR gene and in the thrombomodulin gene in women who had experienced late fetal loss. They cited work in mice indicating that this disruption of the Epcr gene causes early embryonic lethality in mice. One of the mutations found in the EPCR gene by Franchi et al. (2001) was a 23-bp insertion leading to the formation of a truncated receptor that lacked the extracellular and transmembrane domains and was thus rendered unable to sustain protein C activation. Franchi et al. (2001) stated that this mutation had previously been described in patients with venous thromboembolism and myocardial infarction.


Animal Model

By homologous targeting in embryonic stem cells, Gu et al. (2002) developed Epcr-deficient mice. Homozygous null embryos died on or before embryonic day 10.5, however, embryos removed from extra-embryonic membranes and tissues at day 7.5 and cultured in vitro developed beyond day l0.5, suggesting a role for Epcr in the placenta or at the maternal-embryonic interface. Immunohistochemistry revealed the lack of Epcr and increased fibrin deposition around trophoblast giant cells from Epcr-null embryos. These cells normally express Epcr and are in direct contact with maternal circulation and its clotting factors. Subcutaneous treatment of heterozygous Epcr-crossed female mice with an antithrombin compound delayed midgestational lethality, but yielded no Epcr-null pups. Gu et al. (2002) concluded that Epcr is essential for normal embryonic development and plays a key role in preventing thrombosis at the maternal-embryonic interface.


REFERENCES

  1. Chihara, N., Madi, A., Kondo, T., Zhang, H., Acharya, N., Singer, M., Nyman, J., Marjanovic, N. D., Kowalczyk, M. S., Wang, C., Kurtulus, S., Law, T., and 9 others. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 558: 454-459, 2018. [PubMed: 29899446, related citations] [Full Text]

  2. Franchi, F., Biguzzi, E., Cetin, I., Facchetti, F., Radaelli, T., Bozzo, M., Pardi, G., Faioni, E. M. Mutations in the thrombomodulin and endothelial protein C receptor genes in women with late fetal loss. Brit. J. Haemat. 114: 641-646, 2001. [PubMed: 11552992, related citations] [Full Text]

  3. Fukudome, K., Esmon, C. T. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J. Biol. Chem. 269: 26486-26491, 1994. [PubMed: 7929370, related citations]

  4. Gu, J. M, Crawley, J. T., Ferrell, G., Zhang, F., Li, W., Esmon, N. L., Esmon, C. T. Disruption of the endothelial cell protein C receptor gene in mice causes placental thrombosis and early embryonic lethality. J. Biol. Chem. 277: 43335-43343, 2002. [PubMed: 12218060, related citations] [Full Text]

  5. Hayashi, T., Nakamura, H., Okada, A., Takebayashi, S., Wakita, T., Yuasa, H., Okumura, K., Suzuki, K. Organization and chromosomal localization of the human endothelial protein C receptor gene. Gene 238: 367-373, 1999. [PubMed: 10570964, related citations] [Full Text]

  6. Kishi, Y., Kondo, T., Xiao, S., Yosef, N., Gaublomme, J., Wu, C., Wang, C., Chihara, N., Regev, A., Joller, N., Kuchroo, V. K. Protein C receptor (PROCR) is a negative regulator of Th17 pathogenicity. J. Exp. Med. 213: 2489-2501, 2016. [PubMed: 27670590, related citations] [Full Text]

  7. Mincheva, A., Rothbarth, K., Werner, D., Lichter, P. Assignment of the gene encoding centrosome-associated protein CCD41 to mouse chromosome 2H. Mammalian Genome 6: 444 only, 1995. [PubMed: 7647473, related citations] [Full Text]

  8. Riewald, M., Petrovan, R. J., Donner, A., Mueller, B. M., Ruf, W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296: 1880-1882, 2002. [PubMed: 12052963, related citations] [Full Text]

  9. Rothbarth, K., Dabaghian, A. R. H., Stammer, H., Werner, D. One single mRNA encodes the centrosomal protein CCD41 and the endothelial cell protein C receptor (EPCR). FEBS Lett. 458: 77-80, 1999. [PubMed: 10518938, related citations] [Full Text]

  10. Rothbarth, K., Petzelt, C., Lu, X., Todorov, I. T., Joswig, G., Pepperkok, R., Ansorge, W., Werner, D. cDNA-derived molecular characteristics and antibodies to a new centrosome-associated and G2/M phase-prevalent protein. J. Cell Sci. 104: 19-30, 1993. [PubMed: 8449997, related citations] [Full Text]

  11. Simmonds, R. E., Lane, D. A. Structural and functional implications of the intron/exon organization of the human endothelial cell protein C/activated protein C receptor (EPCR) gene: comparison with the structure of CD1/major histocompatibility complex alpha-1 and alpha-2 domains. Blood 94: 632-641, 1999. [PubMed: 10397730, related citations]

  12. Turner, L., Lavstsen, T., Berger, S. S., Wang, C. W., Petersen, J. E. V., Avril, M., Brazier, A. J., Freeth, J., Jespersen, J. S., Nielsen, M. A., Magistrado, P., Lusingu, J., Smith, J. D., Higgins, M. K., Theander, T. G. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature 498: 502-505, 2013. [PubMed: 23739325, images, related citations] [Full Text]

  13. Ye, X., Fukudome, K., Tsuneyoshi, N., Satoh, T., Tokunaga, O., Sugawara, K., Mizokami, H., Kimoto, M. The endothelial cell protein C receptor (EPCR) functions as a primary receptor for protein C activation on endothelial cells in arteries, veins, and capillaries. Biochem. Biophys. Res. Commun. 259: 671-677, 1999. [PubMed: 10364477, related citations] [Full Text]


Ada Hamosh - updated : 08/06/2018
Paul J. Converse - updated : 01/03/2018
Paul J. Converse - updated : 07/29/2013
Patricia A. Hartz - updated : 5/7/2003
Ada Hamosh - updated : 7/12/2002
Victor A. McKusick - updated : 11/9/2001
Paul J. Converse - updated : 11/13/2000
Creation Date:
Victor A. McKusick : 7/12/1995
alopez : 08/06/2018
mgross : 01/03/2018
alopez : 07/29/2013
carol : 10/8/2008
wwang : 4/23/2008
cwells : 5/7/2003
alopez : 7/15/2002
alopez : 7/15/2002
terry : 7/12/2002
carol : 11/28/2001
mcapotos : 11/26/2001
terry : 11/14/2001
terry : 11/9/2001
mgross : 11/13/2000
jamie : 5/8/1997
terry : 7/28/1995
mark : 7/12/1995

* 600646

PROTEIN C RECEPTOR; PROCR


Alternative titles; symbols

ENDOTHELIAL PROTEIN C RECEPTOR; EPCR
CELL CYCLE, CENTROSOME-ASSOCIATED PROTEIN; CCCA
CCD41


HGNC Approved Gene Symbol: PROCR

Cytogenetic location: 20q11.22     Genomic coordinates (GRCh38): 20:35,171,096-35,216,259 (from NCBI)


TEXT

Description

Protein C (612283), a vitamin K-dependent serine protease zymogen, plays a major role in blood coagulation and may also prevent the lethal effects of gram-negative sepsis. Deficiency of protein C leads to life-threatening thrombophilia. Protein C is activated when thrombin (F2; 176930), the terminal enzyme of the coagulation system, binds to an endothelial cell surface protein, thrombomodulin (THBD; 188040).


Cloning and Expression

By fluorescence-activated cell sorting (FACS) analysis, Fukudome and Esmon (1994) determined that activated protein C (APC) specifically binds to cultured endothelial cells in a calcium-dependent manner that is not influenced by protein S (PROS1; 176880). The authors screened an endothelial cell library for APC-binding partners and isolated a cDNA encoding PROCR, which they termed EPCR. Sequence analysis predicted that the 238-amino acid type 1 transmembrane protein has a 15-amino acid N-terminal signal sequence; an extracellular domain with 4 potential N-glycosylation sites and 4 cys residues; a C-terminal 25-amino acid transmembrane region; and a short cytoplasmic tail containing only 3 amino acids. Northern blot analysis detected high levels of a 1.3-kb EPCR transcript only in endothelial cell lines. Flow cytometric and Northern blot analyses determined that exposure of endothelial cells to tumor necrosis factor (TNF; 191160) reduced APC binding and EPCR expression in parallel.


Gene Function

Using immunohistochemical analysis, Ye et al. (1999) demonstrated that EPCR is expressed strongly in the endothelial cells of arteries and veins in heart and lung, less intensely in capillaries in the lung and skin, and not at all in the endothelium of small vessels of the liver and kidney. Immunoblot analysis showed that EPCR is expressed as a 49-kD protein that is reduced to the predicted 25 kD by deglycosylation. Antibodies to EPCR could inhibit binding of protein C and APC to cultured endothelial cells and inhibited the activation of protein C.

Simmonds and Lane (1999) pointed out that THBD is uniformly expressed on endothelial cells, significantly reducing its effective concentration on large vessels, whereas EPCR, with its high affinity for protein C, is preferentially expressed on large vessels.

Riewald et al. (2002) demonstrated that activated protein C uses the endothelial cell protein C receptor (EPCR) as a coreceptor for cleavage of protease-activated receptor 1 (PAR1; 187930) on endothelial cells. Gene profiling demonstrated that PAR1 signaling could account for all activated protein C-induced protective genes, including the immunomodulatory monocyte chemoattractant protein-1 (MCP1; 158105), which was selectively induced by activation of PAR1, but not PAR2 (600933). Thus, Riewald et al. (2002) concluded that the prototypic thrombin receptor is the target for EPCR-dependent APC signaling, suggesting a role for this receptor cascade in protection from sepsis.

By screening an array of full-length plasma membrane proteins expressed on human embryonic kidney cells, Turner et al. (2013) identified EPCR as a binding partner of domain cassette-8 of the Plasmodium falciparum erythrocyte membrane protein-1 (DC8-PfEMP1). They mapped the PfEMP1 EPCR-binding domain by ELISA with DC8-PfEMP1C8 variants. Further analysis confirmed that PfEmp1 proteins have diverged into CD36 (173510)- and EPCR-binding subtypes. DC8-PfEMP1-expressing and parasitized erythrocytes bound to brain endothelial cells and were inhibited by recombinant EPCR or anti-EPCR antibodies. Turner et al. (2013) proposed that PfEMP1-EPCR-mediated cytoadhesion is the major virulence phenotype for severe malaria (see 611162).

Using single-cell RNA sequencing analysis of mouse Th17 cells (see IL17A, 603149) differentiated in vitro under pathogenic versus nonpathogenic conditions or of Th17 cells isolated ex vivo from lymph nodes or central nervous system of mice undergoing experimental autoimmune encephalomyelitis (EAE), Kishi et al. (2016) showed that expression of Procr correlated inversely with Th17-cell pathogenicity. Procr expression was regulated by transcription factors critical for Th17 differentiation, including Stat3 (102582), Irf4 (601900), and Rorgt (602943). Procr overexpression reduced expression of the Th17 proinflammatory module, including Il1r (IL1R1; 147810) and Il23r (607562). Using different EAE mouse models, Kishi et al. (2016) found that loss or reduction of Procr expression led to increased Th17 pathogenicity and enhanced EAE in vivo. Kishi et al. (2016) concluded that PROCR is a negative regulator of Th17 pathogenicity.

Using RNA and protein expression profiling at single-cell resolution in mouse cells, Chihara et al. (2018) identified a module of coinhibitory receptors that includes not only several known coinhibitory receptors but many novel surface receptors. Chihara et al. (2018) functionally validated 2 novel coinhibitory receptors, activated PROCR and podoplanin (PDPN; 608863). The module of coinhibitory receptors is coexpressed in both CD4+ and CD8+ T cells and is part of a larger coinhibitory gene program that is shared by nonresponsive T cells in several physiologic contexts and is driven by the immunoregulatory cytokine IL27 (608273). Computational analysis identified the transcription factors PRDM1 (603423) and c-MAF (177075) as cooperative regulators of the coinhibitory module, and this was validated experimentally. This molecular circuit underlies the coexpression of coinhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumor immunity.


Gene Structure

Using genomic sequence and 5-prime RACE analysis Simmonds and Lane (1999) and Hayashi et al. (1999) determined that the EPCR gene contains 4 exons and spans 6 kb. The transcription initiation point is 79 bp upstream of the translation initiation (met) codon and 84 bp downstream of a TATA box element. Hayashi et al. (1999) identified putative AP1 (165160)-, SP1 (189906)-, and AP2 (107580)-binding sites in the promoter region. Simmonds and Lane (1999) determined that exon 1 encodes the 5-prime untranslated region (UTR) and the signal peptide, exons 2 and 3 encode most of the extracellular region, and exon 4 encodes the transmembrane domain, cytoplasmic tail, and most of the 3-prime UTR. Secondary structure analysis predicted that EPCR has similarity to CD1 (see 188410) and MHC class I (see 142800) proteins and folds with a beta-sheet platform supporting 2 alpha-helical regions that collectively form a potential binding pocket for protein C and APC.


Mapping

The mouse CCD41 protein is a centrosome-associated antigen occupying a compact structure inside the centrosome. It is prevalent in the G2 and M phases of the cell cycle, where it is found not only in centrosomes but also accumulated in perinuclear vesicles (Rothbarth et al., 1993). The epitope in the centrosome is exposed throughout the cell cycle except for a brief period immediately after the formation of the daughter centrosomes. On the basis of these observations, it was suggested that the protein plays an essential role in the centrosome function regarding cell cycle progression. Mutations in this gene might be expected to result in severe phenotypic abnormalities. To identify candidate mouse disorders, Mincheva et al. (1995) mapped the gene to mouse chromosome 2 (band H) by fluorescence in situ hybridization. The homologous human gene was predicted to be on 20q. Rothbarth et al. (1999) showed that EPCR and CCD41 have identical cDNA sequences. Mutation analysis and fluorescence microscopy suggested that the preferential transmembrane expression of EPCR compared with the centrosomal localization of CCD41 may be due to a posttranslational deletion of the signal peptide in the latter.

By radiation hybrid analysis and FISH, Simmonds and Lane (1999) and Hayashi et al. (1999) mapped the PROCR gene to 20q11.2.


Molecular Genetics

Franchi et al. (2001) found an excess of mutations in the EPCR gene and in the thrombomodulin gene in women who had experienced late fetal loss. They cited work in mice indicating that this disruption of the Epcr gene causes early embryonic lethality in mice. One of the mutations found in the EPCR gene by Franchi et al. (2001) was a 23-bp insertion leading to the formation of a truncated receptor that lacked the extracellular and transmembrane domains and was thus rendered unable to sustain protein C activation. Franchi et al. (2001) stated that this mutation had previously been described in patients with venous thromboembolism and myocardial infarction.


Animal Model

By homologous targeting in embryonic stem cells, Gu et al. (2002) developed Epcr-deficient mice. Homozygous null embryos died on or before embryonic day 10.5, however, embryos removed from extra-embryonic membranes and tissues at day 7.5 and cultured in vitro developed beyond day l0.5, suggesting a role for Epcr in the placenta or at the maternal-embryonic interface. Immunohistochemistry revealed the lack of Epcr and increased fibrin deposition around trophoblast giant cells from Epcr-null embryos. These cells normally express Epcr and are in direct contact with maternal circulation and its clotting factors. Subcutaneous treatment of heterozygous Epcr-crossed female mice with an antithrombin compound delayed midgestational lethality, but yielded no Epcr-null pups. Gu et al. (2002) concluded that Epcr is essential for normal embryonic development and plays a key role in preventing thrombosis at the maternal-embryonic interface.


REFERENCES

  1. Chihara, N., Madi, A., Kondo, T., Zhang, H., Acharya, N., Singer, M., Nyman, J., Marjanovic, N. D., Kowalczyk, M. S., Wang, C., Kurtulus, S., Law, T., and 9 others. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 558: 454-459, 2018. [PubMed: 29899446] [Full Text: https://doi.org/10.1038/s41586-018-0206-z]

  2. Franchi, F., Biguzzi, E., Cetin, I., Facchetti, F., Radaelli, T., Bozzo, M., Pardi, G., Faioni, E. M. Mutations in the thrombomodulin and endothelial protein C receptor genes in women with late fetal loss. Brit. J. Haemat. 114: 641-646, 2001. [PubMed: 11552992] [Full Text: https://doi.org/10.1046/j.1365-2141.2001.02964.x]

  3. Fukudome, K., Esmon, C. T. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J. Biol. Chem. 269: 26486-26491, 1994. [PubMed: 7929370]

  4. Gu, J. M, Crawley, J. T., Ferrell, G., Zhang, F., Li, W., Esmon, N. L., Esmon, C. T. Disruption of the endothelial cell protein C receptor gene in mice causes placental thrombosis and early embryonic lethality. J. Biol. Chem. 277: 43335-43343, 2002. [PubMed: 12218060] [Full Text: https://doi.org/10.1074/jbc.M207538200]

  5. Hayashi, T., Nakamura, H., Okada, A., Takebayashi, S., Wakita, T., Yuasa, H., Okumura, K., Suzuki, K. Organization and chromosomal localization of the human endothelial protein C receptor gene. Gene 238: 367-373, 1999. [PubMed: 10570964] [Full Text: https://doi.org/10.1016/s0378-1119(99)00360-1]

  6. Kishi, Y., Kondo, T., Xiao, S., Yosef, N., Gaublomme, J., Wu, C., Wang, C., Chihara, N., Regev, A., Joller, N., Kuchroo, V. K. Protein C receptor (PROCR) is a negative regulator of Th17 pathogenicity. J. Exp. Med. 213: 2489-2501, 2016. [PubMed: 27670590] [Full Text: https://doi.org/10.1084/jem.20151118]

  7. Mincheva, A., Rothbarth, K., Werner, D., Lichter, P. Assignment of the gene encoding centrosome-associated protein CCD41 to mouse chromosome 2H. Mammalian Genome 6: 444 only, 1995. [PubMed: 7647473] [Full Text: https://doi.org/10.1007/BF00355652]

  8. Riewald, M., Petrovan, R. J., Donner, A., Mueller, B. M., Ruf, W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296: 1880-1882, 2002. [PubMed: 12052963] [Full Text: https://doi.org/10.1126/science.1071699]

  9. Rothbarth, K., Dabaghian, A. R. H., Stammer, H., Werner, D. One single mRNA encodes the centrosomal protein CCD41 and the endothelial cell protein C receptor (EPCR). FEBS Lett. 458: 77-80, 1999. [PubMed: 10518938] [Full Text: https://doi.org/10.1016/s0014-5793(99)01074-1]

  10. Rothbarth, K., Petzelt, C., Lu, X., Todorov, I. T., Joswig, G., Pepperkok, R., Ansorge, W., Werner, D. cDNA-derived molecular characteristics and antibodies to a new centrosome-associated and G2/M phase-prevalent protein. J. Cell Sci. 104: 19-30, 1993. [PubMed: 8449997] [Full Text: https://doi.org/10.1242/jcs.104.1.19]

  11. Simmonds, R. E., Lane, D. A. Structural and functional implications of the intron/exon organization of the human endothelial cell protein C/activated protein C receptor (EPCR) gene: comparison with the structure of CD1/major histocompatibility complex alpha-1 and alpha-2 domains. Blood 94: 632-641, 1999. [PubMed: 10397730]

  12. Turner, L., Lavstsen, T., Berger, S. S., Wang, C. W., Petersen, J. E. V., Avril, M., Brazier, A. J., Freeth, J., Jespersen, J. S., Nielsen, M. A., Magistrado, P., Lusingu, J., Smith, J. D., Higgins, M. K., Theander, T. G. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature 498: 502-505, 2013. [PubMed: 23739325] [Full Text: https://doi.org/10.1038/nature12216]

  13. Ye, X., Fukudome, K., Tsuneyoshi, N., Satoh, T., Tokunaga, O., Sugawara, K., Mizokami, H., Kimoto, M. The endothelial cell protein C receptor (EPCR) functions as a primary receptor for protein C activation on endothelial cells in arteries, veins, and capillaries. Biochem. Biophys. Res. Commun. 259: 671-677, 1999. [PubMed: 10364477] [Full Text: https://doi.org/10.1006/bbrc.1999.0846]


Contributors:
Ada Hamosh - updated : 08/06/2018
Paul J. Converse - updated : 01/03/2018
Paul J. Converse - updated : 07/29/2013
Patricia A. Hartz - updated : 5/7/2003
Ada Hamosh - updated : 7/12/2002
Victor A. McKusick - updated : 11/9/2001
Paul J. Converse - updated : 11/13/2000

Creation Date:
Victor A. McKusick : 7/12/1995

Edit History:
alopez : 08/06/2018
mgross : 01/03/2018
alopez : 07/29/2013
carol : 10/8/2008
wwang : 4/23/2008
cwells : 5/7/2003
alopez : 7/15/2002
alopez : 7/15/2002
terry : 7/12/2002
carol : 11/28/2001
mcapotos : 11/26/2001
terry : 11/14/2001
terry : 11/9/2001
mgross : 11/13/2000
jamie : 5/8/1997
terry : 7/28/1995
mark : 7/12/1995