ABSTRACT
Semen coagulation is achieved by a series of biochemical processes designed to protect
and guide the sperm during its migration through the female genital tract so that
spermatozoa reach the ovum successfully. Thus, semen coagulation promotes fertilization.
The mechanism of semen coagulation is similar in principle to blood coagulation and
fibrinolysis because it requires the catalytic activity of proteases to convert a
soluble substrate to an insoluble gel, and then dissolve the gel over a longer period
of time. In fact, there are traces of most blood coagulation factors and fibrinolytic
factors in semen; the roles of these factors in semen coagulation are still to be
determined. This review focuses on two such proteins that have remarkably high levels
in semen: protein C inhibitor and tissue factor. Protein C inhibitor is a serine protease
inhibitor that modulates the activity of several blood-clotting factors and activated
protein C. Tissue factor (thromboplastin) is a membrane protein crucial for the initiation
of the extrinsic cascade of blood coagulation. The emerging roles of these two proteins
in semen coagulation and in fertilization processes are summarized.
KEYWORDS
Protein C inhibitor - tissue factor - fertilization - semen coagulation - kallikreins
REFERENCES
- 1
De Jonge C J.
An update on human fertilization.
Semin Reprod Endocrinol.
1998;
16
209-217
- 2
Luconi M, Baldi E.
How do sperm swim? Molecular mechanisms underlying sperm motility.
Cell Mol Biol.
2003;
49
357-369
- 3
De Jonge C.
Biological basis for human capacitation.
Hum Reprod Update.
2005;
11
205-214
- 4
Aitken R J.
The cell biology of fertilization.
Fate of the male germ cell. Advances in Experimental Medicine and Biology.
1997;
424
291-299
- 5
Jonsson M, Linse S, Frohm B, Lundwall A, Malm J.
Semenogelins I and II bind zinc and regulate the activity of prostate-specific antigen.
Biochem J.
2005;
387
447-453
- 6
Fung K YC, Glode L M, Green S, Duncan M W.
A comprehensive characterization of the peptide and protein constituents of human
seminal fluid.
Prostate.
2004;
61
171-181
- 7
Lwaleed B A, Greenfield R, Stewart A, Birch B, Cooper A J.
Seminal clotting and fibrinolytic balance: a possible physiological role in the male
reproductive system.
Thromb Haemost.
2004;
92
752-766
- 8
España F, Gilabert J, Estelles A et al..
Functionally active protein C inhibitor plasminogen-activator inhibitor-3 (PCI/PAI-3)
is secreted in seminal vesicles, occurs at high concentrations in human seminal plasma
and complexes with prostate-specific antigen.
Thromb Res.
1991;
64
309-320
- 9
Fernández J A, Heeb M J, Radtke K P, Griffin J H.
Potent blood coagulant activity of human semen due to prostasome-bound tissue factor.
Biol Reprod.
1997;
56
757-763
- 10
Suzuki K.
Protein C inhibitor (PAI-3): structure and multi-function.
Fibrinol Proteol.
2000;
14
133-145
- 11
Heeb M J, España F, Geiger M et al..
Immunological identity of heparin-dependent plasma and urinary protein C inhibitor
and plasminogen activator inhibitor-3.
J Biol Chem.
1987;
262
15813-15816
- 12
Meijers J CM, Chung D W.
Organization of the gene coding for human protein C inhibitor (plasminogen-activator
inhibitor-3): assignment of the gene to chromosome-14.
J Biol Chem.
1991;
266
15028-15034
- 13
Laurell M, Christensson A, Abrahamsson P A, Stenflo J, Lilja H.
Protein C inhibitor in human body fluids: Seminal plasma is rich in inhibitor antigen
deriving from cells throughout the male reproductive system.
J Clin Invest.
1992;
89
1094-1101
- 14
Anway M D, Show M D, Zirkin B R.
Protein C inhibitor expression by adult rat sertoli cells: Effects of testosterone
withdrawal and replacement.
J Androl.
2005;
26
578-585
- 15
Wakita T, Hayashi T, Yuasa H et al..
Molecular cloning, tissue distribution and androgen regulation of rat protein C inhibitor.
FEBS Lett.
1998;
429
263-268
- 16
Elisen M GLM, van Kooij R J, Nolte M A et al..
Protein C inhibitor may modulate human sperm-oocyte interactions.
Biol Reprod.
1998;
58
670-677
- 17
Kise H, Nishioka J, Kawamura J, Suzuki K.
Characterization of semenogelin II and its molecular interaction with prostate-specific
antigen and protein C inhibitor.
Eur J Biochem.
1996;
238
88-96
- 18
España F, Fink E, Sanchez-Cuenca J et al..
Complexes of tissue kallikrein with protein C inhibitor in human semen and urine.
Eur J Biochem.
1995;
234
641-649
- 19
Heeb M J, España F.
Alpha2-macroglobulin and C1-inactivator are plasma inhibitors of human glandular kallikrein
(hK2).
Blood Cells Mol Dis.
1998;
24
411-418
- 20
Lovgren J, Airas K, Lilja H.
Enzymatic action of human glandular kallikrein 2 (hK2): Substrate specificity and
regulation by Zn2+ and extracellular protease inhibitors.
Eur J Biochem.
1999;
262
781-789
- 21
Uhrin P, Dewerchin M, Hilpert M et al..
Disruption of the protein C inhibitor gene results in impaired spermatogenesis and
male infertility.
J Clin Invest.
2000;
106
1531-1539
- 22
Odet F, Guyot R, Leduque P, Magueresse-Battistoni B.
Evidence for similar expression of protein C inhibitor and the urokinase-type plasminogen
activator system during mouse testis development.
Endocrinology.
2004;
145
1481-1489
- 23
España F, Estelles A, Hendl S M et al..
Evidence for the physiological regulation of urokinase and tissue-type plasminogen
activators by the serpin, protein C inhibitor, in semen, urine and blood.
Thromb Haemost.
1993;
70
989-994
- 24
Lison D, Tas S, Gennart J P et al..
Plasminogen activator activity and fertilizing ability of human spermatozoa.
Int J Androl.
1993;
16
201-206
- 25
Christensson A, Bjartell A, Lilja H.
The significance of serpins in the regulation of proteases in the male genital tract.
Chem Biol Serpins Advances in Experimental Medicine and Biology.
1997;
425
163-176
- 26
Zheng X L, Zechmeister-Machhart M, Uhrin P et al..
Effect of protein C inhibitor (PCI) on in vitro fertilization.
Immunopharmacology.
1996;
33
140-142
- 27
Zheng X L, Geiger M, Ecke S et al..
Inhibition of acrosin by protein C inhibitor and localization of protein C inhibitor
to spermatozoa.
Am J Physiol.
1994;
267
C466-C472
- 28
Tulsiani D RP, Abou-Haila A, Loeser C R, Pereira B MJ.
The biological and functional significance of the sperm acrosome and acrosomal enzymes
in mammalian fertilization.
Exp Cell Res.
1998;
240
151-164
- 29
España F, Sanchez-Cuenca J, Fernández P J et al..
Inhibition of human sperm-zona-free hamster oocyte binding and penetration by protein
C inhibitor.
Andrologia.
1999;
31
217-223
- 30
España F, Estelles A, Griffin J H, Aznar J.
Interaction of plasma kallikrein with protein C inhibitor in purified mixtures and
in plasma.
Thromb Haemost.
1991;
65
46-51
- 31
Christensson A, Lilja H.
Complex formation between protein C inhibitor and prostate-specific antigen in vitro
and in human semen.
Eur J Biochem.
1994;
220
45-53
- 32
España F, Sanchez-Cuenca J, Estelles A et al..
Quantitative immunoassay for complexes of prostate-specific antigen with alpha2-macroglobulin.
Clin Chem.
1996;
42
545-550
- 33
Riegman P HJ, Vlietstra R J, Klaassen P et al..
The prostate specific antigen gene and the human glandular kallikrein-1 gene are tandemly
located on chromosome-19.
FEBS Lett.
1989;
247
123-126
- 34
Lilja H.
Structure, Function, and regulation of the enzyme activity of prostate-specific antigen.
World J Urol.
1993;
11
188-191
- 35
Malm J, Hellman J, Hogg P, Lilja H.
Enzymatic action of prostate-specific antigen (PSA or hK3): substrate specificity
and regulation by Zn2+, a tight binding inhibitor.
Prostate.
2000;
45
132-139
- 36
Christensson A, Laurell C B, Lilja H.
Enzymatic activity of prostate-specific antigen and its reactions with extracellular
serine proteinase inhibitors.
Eur J Biochem.
1990;
194
755-763
- 37
Villoutreix B O, Lilja H, Pettersson K, Lovgren T, Teleman O.
Structural investigation of the alpha1-antichymotrypsin: prostate-specific antigen complex by comparative model building.
Protein Sci.
1996;
5
836-851
- 38
Seregni E, Botti C, Ballabio G, Bombardieri E.
Biochemical characteristics and recent biological knowledge on prostate-specific antigen.
Tumori.
1996;
82
72-77
- 39
Malm J, Hellman J, Magnusson H, Laurell C B, Lilja H.
Isolation and characterization of the major gel proteins in human semen, semenogelin
I and semenogelin II.
Eur J Biochem.
1996;
238
48-53
- 40
Takayama T K, Fujikawa K, Davie E W.
Characterization of the precursor of prostate-specific antigen: activation by trypsin
and by human glandular kallikrein.
J Biol Chem.
1997;
272
21582-21588
- 41
Frenette G, Deperthes D, Tremblay R R, Lazure C, Dube J Y.
Purification of enzymatically active kallikrein hK2 from human seminal plasma.
Biochim Biophys Acta.
1997;
1334
109-115
- 42
Ecke S, Geiger M, Resch I et al..
Inhibition of tissue kallikrein by protein C inhibitor: evidence for identity of protein
C inhibitor with the kallikrein binding protein.
J Biol Chem.
1992;
267
7048-7052
- 43
Geiger M, Zechmeister-Machhart M, Uhrin P et al..
Protein C inhibitor (PCI).
Immunopharmacology.
1996;
32
53-56
- 44
Rao L VM, Pendurthi U R.
Tissue factor-factor VIIa signaling.
Arterioscler Thromb Vasc Biol.
2005;
25
47-56
- 45
Mackman N.
Role of tissue factor in hemostasis, thrombosis, and vascular development.
Arterioscler Thromb Vasc Biol.
2004;
24
1015-1022
- 46
Chu A J.
Role of tissue factor in thrombosis. Coagulation-inflammation-thrombosis circuit.
Front Biosci.
2006;
11
256-271
- 47
Lwaleed B A, Greenfield R S, Birch B R, Cooper A J.
Does human semen contain a functional haemostatic system? A possible role for tissue
factor pathway inhibitor in fertility through semen liquefaction.
Thromb Haemost.
2005;
93
847-852
- 48
Ohta S, Wada H, Gabazza E C, Nobori T, Fuse H.
Evaluation of tissue factor antigen level in human seminal plasma.
Urol Res.
2002;
30
317-320
- 49
Belting M, Ahamed J, Ruf W.
Signaling of the tissue factor coagulation pathway in angiogenesis and cancer.
Arterioscler Thromb Vasc Biol.
2005;
25
1545-1550
- 50 Babiker A A. Prostasome Modulation of Blood Cascade System and Phosphoprotein Reactions
with Focus on Prostate Cancer [dissertation 1-65]. Uppsala, Sweden, Uppsala University
2005
- 51
Fan Z Q, Larson P J, Bognacki J et al..
Tissue factor regulates plasminogen binding and activation.
Blood.
1998;
91
1987-1998
- 52
Gonzalez-Gronow M, Gawdi G, Pizzo S V.
Tissue factor is the receptor for plasminogen type 1 on 1-LN human prostate cancer
cells.
Blood.
2002;
99
4562-4567
- 53
Riewald M, Huang H Y, Ott I et al..
Tissue factor-mediated cell adhesion and signaling is dependent on actin binding protein
280 (filamin-1).
Blood.
1998;
92
474 (Abst)
- 54
Fischer E G, Riewald M, Huang H Y et al..
Tumor cell adhesion and migration supported by interaction of a receptor-protease
complex with its inhibitor.
J Clin Invest.
1999;
104
1213-1221
- 55
Kobayashi T, Matsuda Y, Park J Y et al..
Trypsin-like arginine amidases including plasminogen and plasmin in human seminal
plasma by affinity adsorption and elution.
Arch Androl.
1992;
28
165-170
- 56
Smokovitis A, Kokolis N, Taitzoglou I, Rekkas C.
Plasminogen activator: the identification of an additional proteinase at the outer
acrosomal membrane of human and boar spermatozoa.
Int J Fertil.
1992;
37
308-314
- 57
Llanos M N, Lui C W, Meizel S.
Studies of phospholipase-A2 related to the hamster sperm acrosome reaction.
J Exp Zool.
1982;
221
107-117
- 58
Taitzoglou L A, Chapman D A, Zervos I A, Killian G J.
Effect of plasmin on movement characteristics of ejaculated bull spermatozoa.
Theriogenology.
2004;
62
553-561
- 59
Ronquist G, Nilsson B O.
The Janus-faced nature of prostasomes: their pluripotency favours the normal reproductive
process and malignant prostate growth.
Prostate Cancer Prostatic Dis.
2004;
7
21-31
- 60
Arienti G, Carlini E, Saccardi C, Palmerini C A.
Role of human prostasomes in the activation of spermatozoa.
J Cell Mol Med.
2004;
8
77-84
- 61
Palmerini C A, Saccardi C, Carlini E, Fabiani R, Arienti G.
Fusion of prostasomes to human spermatozoa stimulates the acrosome reaction.
Fertil Steril.
2003;
80
1181-1184
- 62
Kravets F G, Lee J, Singh B et al..
Prostasomes: current concepts.
Prostate.
2000;
43
169-174
José A FernándezM.D. Ph.D.
Scientific Associate, Department of Molecular and Experimental Medicine, The Scripps
Research Institute
10550 North Torrey Pines Rd., MEM-180, La Jolla, CA 92037
Email: jfernand@scripps.edu