Tissue plasminogen activator is a serine protease that activates the proenzyme plasminogen to plasmin, which
in turn is responsible for fibrinolytic activity. TPA is synthesized in vascular endothelial cells as a
single polypeptide chain. Proteolytic cleavage of the single chain protein at a centrally located arginine-isoleucine bond
by plasmin gives rise to a 2-chain disulfide-linked form, composed of the N-terminally derived heavy chain and the
C-terminal light chain.
NCBI Summary:
This gene encodes tissue-type plasminogen activator, a secreted serine protease that converts the proenzyme plasminogen to plasmin, a fibrinolytic enzyme. The encoded preproprotein is proteolytically processed by plasmin or trypsin to generate heavy and light chains. These chains associate via disulfide linkages to form the heterodimeric enzyme. This enzyme plays a role in cell migration and tissue remodeling. Increased enzymatic activity causes hyperfibrinolysis, which manifests as excessive bleeding, while decreased activity leads to hypofibrinolysis, which can result in thrombosis or embolism. Alternative splicing of this gene results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]
General function
Enzyme, Hydrolase, Peptidase/Protease
Comment
Cellular localization
Secreted
Comment
A specific elevation in tissue plasminogen activator antigen in women with polycystic ovarian syndrome. Kelly CJ et al. (2002) There is increasing evidence that elevated plasma levels of hemostatic factors [fibrinogen, factor VII, von Willebrand factor, fibrin D-dimer, and tissue plasminogen activator (t-PA) antigen] are independently linked to risk for coronary heart disease (CHD). Women with polycystic ovary syndrome (PCOS) are insulin-resistant and have increased risk for CHD and type 2 diabetes, but there are few data on hemostatic markers in women with PCOS. Seventeen women with PCOS (defined on the basis of elevated testosterone and oligomenorrhea) and 15 healthy women matched as a group for body mass index (BMI) were recruited. Insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique. Factor VIIc was determined by a clotting assay; fibrinogen was determined by nephelometry; and t-PA, D-dimer, and von Willebrand factor antigens were measured by ELISA techniques. Of these hemostatic markers, only t-PA concentration was significantly (P = 0.013) elevated in women with PCOS relative to controls. t-PA correlated with BMI in both PCOS and controls (r = 0.428, P < 0.1; and r = 0.686, P < 0.01) and inversely with the insulin sensitivity index (r = -0.590, P < 0.05; and r = -0.620, P < 0.05, respectively). After further adjustment for BMI and insulin sensitivity, there remained a significant difference in t-PA between cases and controls (P = 0.017). Together, age and insulin sensitivity explained 39% of the variance in t-PA in women with PCOS (P < 0.05). Total testosterone did not correlate significantly with t-PA in either group. We conclude that women with PCOS have significantly increased t-PA concentrations relative to women with normal menstrual rhythm and normal androgens. We suggest that elevated t-PA and dysfibrinolysis may be a factor in the increased cardiovascular morbidity seen in PCOS.//////////////////
Plasminogen activator, tissue type regulates germinal vesicle breakdown and cumulus expansion of bovine cumulus-oocyte complex in vitro†. Yu BY et al. (2019) Plasminogen activator, tissue type (PLAT) and its inhibitor serpin family E member 1 (SERPINE1) cooperatively regulate PLAT activity in various reproductive processes. However, it is unknown whether this includes bovine oocyte maturation. We addressed this question in the present study by evaluating PLAT and SERPINE1 protein localization in immature cumulus-oocyte complexes (COCs), as well as PLAT mRNA and protein expression in cultured COCs after 0, 8, 16, and 24 h of in vitro maturation (IVM). We also examined the effects of PLAT and SERPINE1 on germinal vesicle breakdown (GVBD) and oocyte cyclic 3' 5' adenosine monophosphate (cAMP) levels, cumulus expansion index, and expansion-related gene expression in oocytes derived from bovine COCs cultured for 4, 8, and 12 h and in COCs cultured for 16 h. PLAT and SERPINE1 both localized in cumulus cells but only the latter was detected in oocytes. PLAT and SERPINE1 transcript levels increased during IVM; however, from 8 to 16 h, the levels of PLAT remained stable whereas those of SERPINE1 increased, resulting in a decline in PLAT concentration. Additionally, PLAT delayed GVBD, increased oocyte cAMP levels, and blocked cumulus expansion and associated gene expression, which was reversed by SERPINE1 supplemented. Thus, PLAT delays bovine oocyte GVBD by enhancing oocyte cAMP levels during the first 8 h of IVM; suppression of PLAT activity via accumulation of SERPINE1 in COCs results in cumulus expansion from 8 to 16 h of IVM. These findings provide novel insights into the molecular mechanisms underlying in vitro bovine oocyte maturation.//////////////////
Cajander et al 1989 reported the immunohistochemical localization of tissue-type plasminogen activator in ovaries
before and after induced and spontaneous ovulation in the rat.
Tsafriri et al 1989 reported the suppression of ovulation rate by antibodies to tissue-type plasminogen activator
and alpha 2-antiplasmin.
Deutinger et al 1988 reported that elevated tissue type plasminogen activator in human granulosa cells correlates
with fertilizing capacity.
Johnson et al 1997 reported the expression of avian urokinase and tissue-type plasminogen activator messenger
ribonucleic acid during follicle development and atresia.
Liu et al 1996 reported coordinated expression of tissue-type plasminogen activator and plasminogen
activator inhibitor type 1 during corpus luteum formation and luteolysis in the
adult pseudopregnant rat.
This gene is upregulated during oocyte maturation (Fig. 2) Wang et al 2004 .
Expression regulated by
FSH, LH, Steroids, Growth Factors/ cytokines
Comment
Galway et al 1990 reported that recombinant follicle-stimulating hormone induces ovulation and tissue
plasminogen activator expression in hypophysectomized rats.
LaPolt et al 1990 reported that basic fibroblast growth factor induction of granulosa cell tissue-type plasminogen
activator expression.
Galway et al 1989 reported that epidermal growth factor stimulates tissue plasminogen activator activity and
messenger ribonucleic acid levels in cultured rat granulosa cells: mediation by
pathways independent of protein kinases-A and -C.
Liu YX, et al 1998 reported the prolactin regulation of tissue type plasminogen activator and plasminogen
activator inhibitor type-I gene expression in eCG-primed rat granulosa cells in
culture.
Results in cultured rat granulosa cells suggest
that a dose- and time-dependent decrease in the gonadotropin-induced tPA
activity in the culture by the presence of PRL as a result of decreasing tPA
mRNA synthesis on one hand and to neutralization of the tPA activity by the
increased PAI-I activity on the other.
Ovarian localization
Oocyte, Cumulus, Granulosa, Theca, Luteal cells
Comment
Oocytes use the plasminogen-plasmin system to remove supernumerary spermatozoa. Coy P et al. BACKGROUNDThe role of the plasminogen-plasmin (PLG-PLA) system in fertilization is unknown, although its dysfunction has been associated with subfertility in humans. We have recently detected and quantified plasminogen in the oviductal fluid of two mammals and showed a reduction in sperm penetration during IVF when plasminogen is present. The objective of this study was to describe the mechanism by which PLG-PLA system regulates sperm entry into the oocyte.METHODS AND RESULTSBy combining biochemical, functional, electron microscopic, immunocytochemical and live cell imaging methods, we show here that (i) plasminogen is activated into the protease plasmin, by gamete interaction; (ii) urokinase-type and tissue-type plasminogen activators are present in oocytes, but they are not of cortical granule origin; (iii) sperm binding to oocytes triggers the releasing of plasminogen activators and (iv) the generated plasmin causes sperm detachment from the zona pellucida.CONCLUSIONSOur results describe a novel mechanism for the success or failure of fertilization in mammals, by which molecules present in the oviductal environment are activated by molecules originating within the gametes. We anticipate that therapeutic up- or down-regulation of this physiological mechanism may be used to help in conception or as a contraceptive tool. Since components of the PLG-PLA system are already available as drugs for heart attacks or cancer therapies, basic research on this novel function would be rapidly transferable for clinical application.
Politis et al 1990 reported changes in tissue-type plasminogen activator-like and plasminogen activator
inhibitor activities in granulosa and theca layers during ovarian follicle
development in the domestic hen.
Liu et al 1987 reported the identification and regulation of tissue plasminogen activator activity in rat
cumulus-oocyte complexes.
Follicle stages
Secondary, Antral, Preovulatory, Corpus luteum
Comment
Atiomo WU, et al reported the plasminogen activator system in women with polycystic
ovary syndrome.
Liu et al 1987 reported the gonadotropin regulation of tissue-type and urokinase-type plasminogen activators
in rat granulosa and theca-interstitial cells during the periovulatory period.
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Ny A, et al reported that studies on mice lacking plasminogen activator gene function suggest that plasmin
production prior to ovulation exceeds the amount needed for optimal ovulation
efficiency.
Hagglund et al 1996 reported coordinated and cell-specific induction of both physiological plasminogen
activators creates functionally redundant mechanisms for plasmin formation during
ovulation.
Leonardsson G et al 1995 reported that ovulation efficiency is reduced in mice that lack plasminogen activator gene
function: functional redundancy among physiological plasminogen activators.