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PubMed2004

Correlation between the polymorphism of glycoprotein Ia gene and acute coronary syndrome.

OBJECTIVE: The platelet membrane glycoprotein (GP) Ia/IIa plays a major part as a primary collagen receptor in platelet function. Previous studies indicated that variations of GPIa/IIa density and function are associated with the 807 C/T polymorphism of GPIa gene in American and Spanish Caucasian populations. This study investigated the correlation between acute coronary syndrome (ACS) and 807 C/T dimorphism of GPIa gene in Chinese of Han ethnicity. METHODS: A case-control study was carried out, including 75 patients with either acute myocardial infarction (AMI) or unstable angina pectoris (UAP), and 65 controls with no history of coronary heart disease, thrombogenic and hemorrhagenic diseases. Genotypes of GPIa were checked by polymerase chain reaction-sequence specific primers (PCR-SSP) technique. RESULTS: The frequencies of both homozygotes and heterozygotes for T807 allele (TT+TC) were significantly higher in patients with AMI than in controls (62.16% vs 33.85%, P<0.01; odds ratio 3.21). The prevalence of (TT+TC) genotypes was also markedly higher in patients with UAP than in controls (65.79% vs 33.85%, P < 0.005; odds ratio 3.76). There was significant difference in the distribution of (TT+TC) genotypes not only between all patients and controls (64.00% vs 33.85%, P<0.005; odds ratio 3.47) but also between the two subgroups aged <60 years (70.00% vs 38.24%, P<0.005; odds ratio 3.77). However, there was no significant difference in the distribution of (TT+TC) genotypes between patients with AMI and with UAP. Platelet GPIa T807 allele remained significantly associated with AMI and UAP by multiple logistic regression (odds ratio 4.94). CONCLUSION: This study suggests a strong association between presence of GPIa T807 allele and ACS. T807 allele can be a marker of genetic susceptibility to ACS.

Aged↗
PubMed2005

Expression of cell adhesion molecules and chemokine receptors: angioinvasiveness in nasal NK/T-cell lymphoma.

Sinonasal natural killer (NK)/T-cell lymphoma (NKTCL) is closely associated with Epstein-Barr virus (EBV) infection and expresses latent membrane protein (LMP)-1 and EB nuclear antigen (EBNA)-1, i.e., latency II of EBV infection. Angioinvasion by neoplastic cells is a characteristic feature of NKTCL, but its mechanism is unknown. To elucidate the molecular mechanism of angio-invasiveness in NKTCL, expression of cell adhesion molecules and chemokine receptors at mRNA and protein levels was examined using real-time PCR and immunohistochemistry in 17 NKTCL together with 10 diffuse large B-cell lymphoma (DLBL) and 9 non-neoplastic nasal mucosa as controls. EBV DNA was detected in 14 of 16 NKTCL examined, and 7 of these 14 expressed LMP-1. mRNA expression levels of integrin subunits alpha4, alpha L, alpha M, and beta2 were significantly higher in NKTCL than non-neoplastic controls. Integrin subunits alpha2 and alpha M were expressed at a significantly higher level in NKTCL with angioinvasion than those without. Expression level of alpha M was significantly higher in 7 cases of NKTCL with LMP-1 expression than 7 without. Immunohistochemistry showed expression of these molecules in NKTCL cells. These findings suggest that EBV infection might be involved in the pathogenesis of angioinvasion of NKTCL through up-regulation of alpha M by LMP-1.

Adult↗
PubMed2005

The prevalence of C807T mutation of glycoprotein Ia gene among young male survivors of myocardial infarction: a relation with coronary angiography results.

INTRODUCTION: The glycoprotein complex Ia/IIa (GP Ia/IIa) is a major collagen receptor on platelets and other cell types. Recently, linked polymorphisms within the coding region of the GP Ia gene (C807T and G873A) related to GP Ia/IIa surface expression have been identified. The 807T/873A allele is associated with high expression, whereas the 807C/873G allele is associated with low surface expression of GP Ia/IIa. Subsequently, the 807T allele was found to be associated with coronary artery disease (CAD) and cerebral infarction in younger patients. Moreover, platelet thrombus formation is significantly influenced by genetic variations of the GPIb alpha and GPIa receptors and is dependent on the blood flow rate. AIM: 1. To determine the frequency of C807T polymorphism of the GPIa gene in young survivors of myocardial infarction (MI) and 2. to evaluate the relationship between the intensity of CAD in the coronary angiography examination and the 807C/T genetic status of the patients. METHODS: 102 young male survivors of MI (YSMI) -- mean age 43, range 29-49 years, mean age at the time of the first episode 37+/-3 years -- were studied. Obesity was found in 15%, diabetes in 14%, hyperlipidemia in 87%, hypertension in 22% and smoking history in 90% of cases. Familial CAD and/or MI were confirmed in 50% of patients. The control group consisted of 106 healthy volunteers with a negative family history of CAD, both medical staff members and blood donors (mean age 40, range 18-42 years). The genetic study was performed using genomic DNA obtained from peripheral blood leukocytes. The C807T polymorphism of platelet glycoprotein Ia (GPIa) was investigated using the PCR method introduced by Santoso et al. RESULTS: Coronary angiography (Siemens Bicor system) revealed single-artery disease in 34%, two-artery disease in 36% and three-artery disease in 26% of patients. In two patients there were no signs of CAD. The C807T polymorphism of GPIa was found in 73.5% of investigated patients (heterozygotes CT 59.8%, homozygotes TT 13.7%). The CC genotype was confirmed in 26.5% of patients. A similar analysis performed in the group of healthy men showed C807T polymorphism of the GPIa gene in 73.6% (CT in 58.5% and TT in 15.1% of persons, ns). CC genotype was found in 26.4% of persons. Interestingly, the T genotype frequency was similar in patients with three- or two-artery disease in comparison with patients with single-vessel or without CAD (49.3% vs. 50.7%, respectively, ns). In 75 YSMI carrying C807T polymorphism of the GPIa gene additional genetic abnormalities were confirmed in 21 patients - BclI polymorphism of b-chain fibrinogen gene, G4070A and G1691A (FV Leiden) mutation of factor V gene and C677T polymorphism of methylenetetrahydrofolate reductase gene. Partial occurrence of combined polymorphisms was found. This was confirmed independently of the number of coronary arteries involved. CONCLUSIONS: Our results may question the potential role of C807T the GPIa anomaly as a single genetic abnormality predisposing young men to coronary artery disease.

Adult↗
PubMed2006

Identification of a unique set of genes altered during cell-cell contact in an in vitro model of prostate cancer bone metastasis.

The interaction between prostate cancer cells and bone marrow stromal cells (BMSC) is critical for survival and proliferation of metastatic cancer cells in the bone microenvironment. In order to study molecular mechanisms of prostate cancer bone metastasis, we established a novel heterotypic co-culture system, in which the role of direct cell-cell contact between prostate cancer cells and BMSC in addition to soluble factors can be analyzed. Using both bi-compartmental (insert) system and heterotypic (contact) system, we identified gene expression profiles of interaction between prostate cancer and bone cells. Analysis of differential gene expressions in these two co-culture systems revealed three distinctive sets of genes: 1) genes that were modified only by soluble factors; 2) genes that were regulated by both soluble factors and physical contact; and 3) genes that were altered only by physical contact. The last group consisted of specific set of genes including collagen III, IV, X, XII, integrin alpha1, alpha2, MMP-2, MMP-9, uPA, biglycan, osteopontin and raf-1 in PC3, and collagen VIII, IX, BMP6, TGFbeta1, Smad6 and Twist in BMSC. Among genes that were modified by both soluble factors and physical contact, the gene expression was affected in the same direction (such as MKK4) or in the opposite direction (such as TGFbeta receptor 3). Overall, this suggests that heterotypic cell-cell contact may act as an independent factor affecting the progression of bone metastasis.

Animals↗
PubMed2006

Gene polymorphisms implicated in influencing susceptibility to venous and arterial thromboembolism: frequency distribution in a healthy German population.

Evolvement and progression of cardiovascular diseases affecting the venous and arterial system are influenced by a multitude of environmental and hereditary factors. Many of these hereditary factors consist of defined gene polymorphisms, such as single nucleotide polymorphisms (SNPs) or insertion-deletion polymorphisms, which directly or indirectly affect the hemostatic system. The frequencies of individual hemostatic gene polymorphisms in different normal populations are well defined. However, descriptions of patterns of genetic variability of a larger extent of different factors of hereditary hypercoagulability in single populations are scarce. The aim of this study was i) to give a detailed description of the frequencies of factors of hereditary thrombophilia and their combinations in a German population (n = 282) and ii) to compare their distributions with those reported for other regions. Variants of coagulation factors [factor V 1691G>A (factor V Leiden), factor V 4070A>G (factor V HR2 haplotype), factor VII Arg353Gln, factor XIII Val34Leu, beta-fibrinogen -455G>A, prothrombin 20210G>A], coagulation inhibitors [tissue factor pathway inhibitor 536C>T, thrombomodulin 127G>A], fibrinolytic factors [angiotensin converting enzyme intron 16 insertion/deletion, factor VII-activating protease 1601G>A (FSAP Marburg I), plasminogen activator inhibitor 1-675 insertion/deletion (5G/4G), tissue plasminogen activator intron h deletion/insertion], and other factors implicated in influencing susceptibility to thromboembolic diseases [apolipoprotein E2/E3/E4, glycoprotein Ia 807C>T, methylenetetrahydrofolate reductase 677C>T] were included. The distribution of glycoprotein Ia 807C>T deviated significantly from the Hardy-Weinberg equilibrium, and a comparison with previously published data indicates marked region and ethnicity dependent differences in the genotype distributions of some other factors.

Arterial Occlusive Diseases↗
PubMed1990

Identification of an abnormal gene for the GPIIIa subunit of the platelet fibrinogen receptor resulting in Glanzmann's thrombasthenia.

The platelet fibrinogen receptor, which is composed of glycoproteins IIb (GPIIb) and IIIa (GPIIIa), belongs to a large family of receptors that participate in a multitude of biologically important adhesive interactions. Platelets from most patients with the autosomal recessive bleeding disorder, Glanzmann's thrombasthenia, are deficient in GPIIb and GPIIIa. We have used cDNA probes to analyze the GPIIb and GPIIIa genes in four patients from three kindreds with Glanzmann's thrombasthenia. Southern analysis of their DNA was identical to that observed in normals when probed with a full-length GPIIb cDNA or a 3' GPIIIa cDNA. However, in one family, a 5' 2.0 kb GPIIIa cDNA identified abnormal DNA fragments in the father and two affected siblings' genes. A series of restriction digests resulting in small genomic fragments were probed with portions of the 5' 2.0 kb GPIIIa cDNA and indicated that the abnormal sequences are flanked by normal fragments of the GPIIIa gene. To analyze further the genetic defect in this family, RNA was prepared from their platelets. Northern analysis revealed normal levels of GPIIb mRNA compared to control platelets. We were unable to identify GPIIIa mRNA of any size in the clinically affected family members. We also identified an EcoRI restriction fragment length polymorphism (RFLP) that permitted carrier status determination in the clinically unaffected siblings. These studies indicate that Glanzmann's thrombasthenia can be caused by heterogeneous defects in the GPIIIa gene. Furthermore, we have shown that platelets can be used to characterize normal and abnormal GPIIIa and GPIIb mRNA, and RFLPs may be used to determine the carrier status in some families with Glanzmann's thrombasthenia. The specific gene abnormality in this family appears to represent an example of an insertional mutation resulting in a human disease.

Blood Platelet Disorders↗
PubMed1990

von Willebrand factor competes with fibrin for occupancy of GPIIb:IIIa on thrombin-stimulated platelets.

We have investigated two major questions related to the molecular basis of interactions between the three-dimensional fibrin network and thrombin-stimulated human platelets. First, what are the roles played by glycoproteins (GP) Ib and IIb:IIIa in linking the fibrin clot tightly to the platelet surface? Second, does von Willebrand factor (vWF) modulate the extent of platelet-fibrin interactions? Quantitative fluorescence microscopy (microfluorimetry) has been used to determine the quantity of fluorescein-labeled fibrin bound to the surface of thrombin-stimulated, gel-filtered platelets (the supernatants of which contained small quantities of vWF) in the presence/absence of receptor-specific and vWF-specific monoclonal antibodies (MoAbs), as well as exogenous vWF. A MoAb specific for the GPIIb:IIIa complex exhibited a concentration-dependent inhibition of fibrin binding, whereas a MoAb specific for GPIb was ineffective in this regard. Similarly, a MoAb that recognizes the N-terminal region of vWF involved in GPIb binding did not influence fibrin binding. In contrast, a MoAb that binds to a C-terminal region of vWF involved in GPIIb:IIIa recognition caused a specific, concentration-dependent increase in the quantity of platelet-bound fibrin. We also found that exogenous vWF caused a concentration-dependent decrease in fibrin binding. These results support the hypothesis that vWF and fibrin, both of which are multimeric adhesive ligands, compete for occupancy of the GPIIb:IIIa complex on thrombin-stimulated platelets.

Antibodies, Monoclonal↗
PubMed1990

Gova/b alloantigen system on human platelets.

In this report we describe a platelet alloantigen system that is carried on a novel platelet protein of 175 Kd. Antisera against the two alleles (Gova/Govb) were found in two patients who had received large numbers of platelet transfusions. The anti-Gov alloantibodies could not be detected using a whole platelet solid phase enzyme immunoassay, or by a platelet glycoprotein capture enzyme immunoassay using monoclonal antibodies against glycoproteins Ib/IX, Ia/IIa, and IIb/IIIa. Using radioimmunoprecipitation techniques, a protein was precipitated that migrated at 175 Kd (reduced). Under nonreduced conditions, a 150-Kd protein was detected with a minor component at 175Kd. The detection of the alloantigens was not activation-dependent. Using immunodepletion studies, we demonstrated that each alloantiserum recognized an epitope on a discrete population of the 175-Kd platelet protein. Family studies demonstrated that the alloantigens designated as Gova and Govb were inherited in an autosomal codominant fashion. The phenotypic frequencies were Gova/Gova, 26%; Gova/Govb, 55%; Govb/Govb, 19%; giving gene frequencies of 0.532 and 0.468 for Gova and Govb, respectively (n = 33).

Alleles↗
PubMed1989

[Microcytofluorometrical measurement of DNA content in immunologically identified micromegakaryocytes of human bone marrow].

We have developed a method to microfluorometrically determine the amount of DNA in immunologically identified micromegakaryocytes on bone marrow smears. Bone marrow smears were fixed with acetone-formalin buffer and immunostained with a monoclonal anti-GPIIb/IIIa antibody, followed by FITC conjugated anti-mouse IgG. After the smears were re-fixed with methanol, DAPI (4', 6-diamidino-2-phenylindole) staining was performed. Using an automatic Digital-Microfluorometer (Olympus MMSP-FR-II), megakaryocytes on the smears were identifies by the GPIIb/IIIa immunofluorescence and, after changing the barrier filters, their nuclear DNA content was measured by the intensity of DAPI fluorescence, which is proportional to the amount of DNA. Using this method, we found that the DNA histogram of the megakaryocytes from a patient with myelodysplastic syndrome showed a shift to small ploidy compared with normal controls. This method may be valuable in the measurement of the megakaryocyte DNA content.

Adult↗
PubMed1995

Expression of fibrinogen receptors and GPIIb molecules on uraemic platelets: effect of recombinant human erythropoietin therapy.

In 14 chronic uraemic patients on regular haemodialysis treatment mean numbers of fibrinogen (Fg) receptors and glycoprotein IIb (GPIIb) molecules on one blood platelet were 8370 +/- 1282 and 15,694 +/- 2102 respectively, and they were significantly lowered in comparison with those found in 14 healthy persons (37,826 +/- 966 and 57,994 +/- 6824 respectively). A high positive correlation was found between numbers of GPIIb molecules and those of Fg receptors both in chronic uraemic patients and healthy subjects. Four-month treatment of haemodialysis patients with recombinant human erythropoietin (rHuEpo) induced significant rises in haematocrit from 22.3 +/- 1.2 to 31.2 +/- 1.7%, blood platelet count from 164,000 +/- 27,000/microliters to 206,000 +/- 16,000/microliters and mean platelet volume from 7.08 +/- 0.29 fl to 8.26 +/- 0.22 fl. However, in haemodialysis patients numbers of the investigated surface platelet receptors, measured at 8 and 16 week of rHuEpo treatment, remained unchanged.

Adenosine Diphosphate↗
PubMed1993

Characterization of glycoprotein II from bovine adrenal medullary chromaffin granules. Identification of components representing the secretory vesicle counterparts of the lysosomal-associated membrane glycoproteins (lamp-1 and lamp-2).

Glycoprotein II (GpII) is a heterogenous glycoprotein isolated from the membranes of bovine chromaffin granules in the adrenal medulla. When viewed by two-dimensional electrophoresis this glycoprotein consists of two components, upper (GpIIa) and lower (GpIIb), with a molecular mass of 80,000-100,000 daltons and a pI of 4.2-4.7. NH2-terminal sequence analysis of GpIIa and GpIIb revealed sequence similarity with lysosomal membrane glycoproteins (lamp-1 and lamp-2), which was supported by sequence data of peptides from trypsin and cyanogen bromide digestions. An oligonucleotide probe was used to isolate a cDNA clone encoding the nucleotide sequence of GpIIa. The predicted amino acid sequence of GpIIa shares a 72% identity with the human lamp-1 type protein, which belongs to a highly conserved group of lysosomal-associated membrane glycoproteins (lamp proteins), whose function is still unknown. The COOH-terminal region of GpIIa was identical to the COOH-terminal region of lamp proteins. This COOH-terminal determinant has been demonstrated to be essential for the intracellular targeting of lamp proteins to lysosomes. A synthetic peptide antisera to the COOH-terminal region of GpIIa was used to show that this region is present on purified chromaffin granules and not proteolytically processed. The sequence analysis of GpIIa and immunological data confirm GpII as the secretory granule counterpart of lamp proteins and raise some questions regarding intracellular targeting between lysosomes and secretory granules within the chromaffin cell.

Adrenal Medulla↗
PubMed1996

Increased expression of the ETS-related transcription factor FLI-1/ERGB correlates with and can induce the megakaryocytic phenotype.

The human leukemia cell line K562 can be induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) to differentiate along the megakaryocytic pathway, generating morphological changes and increased expression of lineage-specific surface markers. We report that TPA-treated K562 cells also express higher levels of FLI-1/ERGB, a member of the ETS family of transcription factors. Furthermore, introduction of a retroviral construct expressing human FLI-1/ERGB into K562 cells induces changes similar to those seen following TPA treatment, including increased adherence to the surface of the culture vessel and altered size and morphology. Infected cells exhibit higher levels of the megakaryocyte marker CD41a and, to a lesser extent, CD49b. These markers, as well as virally encoded FLI-1/ERGB-specific RNA and protein, are expressed at the highest levels in the attached cell population, while the growth rate of adherent cells is reduced, and the fraction of cells in G0-G1 is increased. FLI-1/ERGB virus-infected cells also exhibit increased expression of hemoglobin, a marker of erythroid differentiation. Our results suggest FLI-1/ERGB plays a role in controlling differentiation and gene expression along the megakaryocyte/platelet pathway, and further implicate ETS-related genes in the control of multiple developmentally regulated hematopoietic genes.

Animals↗
PubMed1998

[Antagonists of glycoprotein IIb/IIIa as new antiplatelet agents].

Blood platelets play an essential role in arterial thrombosis. Platelets activation starts from their binding to membrane receptors what results in consecutive biochemical reactions. Glycoprotein IIb/IIIa receptor of fibrinogen plays a key role in platelet aggregation. Inhibition of activity of glycoprotein IIb/IIIa-fibrinogen receptor complex could prevent thrombus formation by blood platelets. Antagonists of GPIIb/IIIa are synthetic peptides, integrelin, specific monoclonal antibodies and some nonpeptide substances.

Animals↗
PubMed2006

Extraocular muscle is spared upon complete laminin alpha2 chain deficiency: comparative expression of laminin and integrin isoforms.

Mutations in the gene encoding laminin (LM) alpha2 chain cause congenital muscular dystrophy. Here, we show that extraocular muscle (EOM) is spared upon complete LMalpha2 chain absence. The major LM chains in limb muscle basement membranes are alpha2, beta1, beta2 and gamma1 whereas alpha2, alpha4, beta1, beta2 and gamma1 chains are expressed in EOM. Expression of LMalpha4 chain mRNA is further increased in LMalpha2 chain deficient EOM. Mainly integrin alpha7X1 subunit, which binds to laminin-411, is expressed in EOM and in contrast to dystrophic limb muscle, sustained integrin alpha7B expression is seen in LMalpha2 chain deficient EOM. We propose that LMalpha4 chain, possibly by binding to integrin alpha7BX1beta1D, protects EOM in LMalpha2 chain deficient muscular dystrophy.

Animals↗
PubMed1997

Effects of neuroblastoma tumor gangliosides on platelet adhesion to collagen.

Gangliosides, sialic acid-containing glycosphingolipids, enhance tumor formation in experimental animals and are associated with tumor progression and metastasis in humans. The mechanism(s) for this activity is (are) unknown. One possibility is enhanced platelet activation, since the interaction of platelets with tumor cells contributes to tumor cell arrest in the vascular compartment. We have previously shown that neuroblastoma tumor gangliosides (NBTG) enhance platelet adenosine triphosphate (ATP) secretion, aggregation, and adhesion. We determined that these NBTG effects are specific for collagen and are mediated through an alpha2 beta1 integrin-dependent mechanism. This report describes the effects of NBTG on a physiologically relevant model of collagen-alpha2 betal interaction. Platelet adhesion to immobilized native collagen fibers similar to those found in the extracellular matrix of blood vessels was determined. Platelet adhesion is enhanced by NBTG in a concentration-dependent manner. Incubation with concentrations of 1 and 10 microM NBTG increased platelet adhesion by 9% and 52%, respectively, compared to less than 1% in controls not incubated with gangliosides (P = 0.001 and P < 0.0001, respectively). In addition to increasing the number of adherent platelets, NBTG promoted more rapid attachment. In NBTG-incubated platelets, platelet adhesion began after a 5-min lag phase and was maximal at 30 min compared to a 20-min lag phase and maximal adhesion at 60 min for control platelets. At 30 min this difference was significant (P = 0.017); however, by 120 min there was no difference between NBTG and controls (P = 0.259). NBTG also induces platelet adhesion at collagen concentrations (0.1 microg) that failed to support adhesion of control platelets. These effects of NBTG require Mg2+ or Mn2+ ions but are not supported by Zn2+ or Ca2+ ions. Furthermore, preincubation of platelets with a blocking antibody (6F1) to the integrin collagen receptor alpha2 beta1 abrogates all of the effects of NBTG. These results indicate that tumor gangliosides enhance platelet adhesion to extracellular matrix collagen and promote rapid stabilization of the collagen-alpha2 beta1 interaction, the initial steps in platelet activation.

Adenosine Triphosphate↗
PubMed2002

Aberrant expression of integrin and erbB subunits in breast cancer cell lines.

Integrin and growth factor receptors play an important role in cell functions and their aberrant expressions are implicated in breast cancer malignancy. Recent studies have shown that integrins physically and functionally associate with growth factor receptors suggesting the cooperative regulation of these two signals. We studied the expression of integrin and erbB subunits by flow cytometer in human normal mammary epithelial (HME) cell, non-metastatic (MCF-7, ZR-75-1, MDA-MB453) and metastatic tumor cell lines (MDA-MB231, MDA-MB435). Compared with HME cells, all of non-metastatic and metastatic cell lines showed decreased expressions of alpha2 and beta4 integrin subunits. Two metastatic cell lines, but not three non-metastatic tumor cell lines, expressed alpha5 and alpha6 comparable to HME cells. There was no correlation of erbB2 expression with integrin expressions. We isolated MDA-MB435 subpopulations expressing lower amount of alpha6 integrin and found that alpha5, but not alpha2 and alphav integrins, was concomitantly decreased while erbB family was not affected. Then we transfected erbB2 gene into MDA-MB435 and found the induction of erbB3 expression but not erbB1 and erbB4. However, erbB2 transfection had no effect on the expression of alpha6 and beta4 integrin subunits. These data suggest that the expression of alpha5 and alpha6 integrins may contribute to metastasis, and that the regulation of erbB2 and alpha6 integrin expressions is independent in breast cancer cells.

Breast Neoplasms↗
PubMed2004

Extracellular alpha 6 integrin cleavage by urokinase-type plasminogen activator in human prostate cancer.

During human prostate cancer progression, the integrin alpha6beta1 (laminin receptor) is expressed on the cancer cell surface during invasion and in lymph node metastases. We previously identified a novel structural variant of the alpha6 integrin called alpha6p. This variant was produced on the cell surface and was missing the beta-barrel extracellular domain. Using several different concentrations of amiloride, aminobenzamidine and PAI-1 and the urokinase-type plasminogen activator (uPA) function-blocking antibody (3689), we showed that uPA, acting as a protease, is responsible for production of alpha6p. We also showed that addition of uPA in the culture media of cells that do not produce alpha6p, resulted in a dose-dependent alpha6p production. In contrast, the addition of uPA did not result in the cleavage of other integrins. Using alpha2-antiplasmin and plasmin depleted media, we observed that uPA cleaves the alpha6 integrin directly. Further, 12-o-tetradecanoyl-phorbol-13-acetate (TPA) induced the production of alpha6p, and this induction was abolished by PAI-1 but not alpha2-antiplasmin. Finally, the alpha6p integrin variant was detected in invasive human prostate carcinoma tissue indicating that this is not a tissue culture phenomenon. These data, taken together, suggest that this is a novel function of uPA, that is, to remove the beta-barrel ligand-binding domain of the integrin while preserving its heterodimer association.

Antibodies↗