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PubMed1994

Modulation of cardiac myocyte phenotype in vitro by the composition and orientation of the extracellular matrix.

Cellular phenotype is the result of a dynamic interaction between a cell's intrinsic genetic program and the morphogenetic signals that serve to modulate the extent to which that program is expressed. In the present study we have examined how morphogenetic information might be stored in the extracellular matrix (ECM) and communicated to the neonatal heart cell (NHC) by the cardiac alpha 1 beta 1 integrin molecule. A thin film of type I collagen (T1C) was prepared with a defined orientation. This was achieved by applying T1C to the peripheral edge of a 100 mm culture dish. The T1C was then drawn across the surface of the dish in a continuous stroke with a sterile cell scraper and allowed to polymerize. When NHCs were cultured on this substrate, they spread, as a population, along a common axis in parallel with the gel lattice and expressed an in vivo-like phenotype. Individual NHCs displayed an elongated, rod-like shape and disclosed parallel arrays of myofibrils. These phenotypic characteristics were maintained for at least 4 weeks in primary culture. The evolution of this tissue-like organizational pattern was dependent upon specific interactions between the NHCs and the collagen-based matrix that were mediated by the cardiac alpha 1 beta 1 integrin complex. This conclusion was supported by a variety of experimental results. Altering the tertiary structure of the matrix or blocking the extracellular domains of either the cardiac alpha 1 or beta 1 integrin chain inhibited the expression of the tissue-like pattern of organization. Neither cell-to-cell contact or contractile function were necessary to induce the formation of the rod-like cell shape. However, beating activity was necessary for the assembly of a well-differentiated myofibrillar apparatus. These data suggest that the cardiac alpha 1 beta 1 integrin complex serves to detect and transduce phenotypic information stored within the tertiary structure of the surrounding matrix.

Animals↗
PubMed1995

Mechanisms involved in platelet vessel wall interaction.

The molecular mechanisms underlying formation of platelet thrombi constitute one of the central problems in vascular biology and medicine. Fibrinogen binding to its platelet integrin receptor alpha IIb beta 3 (glycoproteins IIb-IIIa complex) plays a pivotal role in formation of platelet thrombi by providing molecular bridges spanning platelets and by contributing to its receptor-mediated outside-in signaling. Conversely, fibrinogen binding to integrin alpha IIb beta 3 requires inside-out signaling mediated by intraplatelet signal transducers activated in response to external signals generated at the site of vascular injury. This tightly regulated fibrinogen-integrin alpha IIb beta 3 interaction constitutes a fundamental platelet mechanism of response to vascular injuries such as accidental and surgical wounds, rupture of atherosclerotic plaques in coronary and cerebral atherosclerosis and microvascular endothelial desquamation in septic shock. After mapping the fibrinogen site on the gamma chain responsible for recognition of platelet integrin alpha IIb beta 3 and the development of synthetic peptide inhibitors, we solved the 3D structure of the carboxy-terminal segment of the human fibrinogen gamma chain using our new technology of carrier protein-driven crystallization. Fundamental knowledge concerning a molecular 3D model of fibrinogen-integrin alpha IIb beta 3 interaction, coupled to the mechanism of its inside-out and outside-in regulation, will lead to development of a new generation of platelet-selective antithrombotic drugs.

Amino Acid Sequence↗
PubMed2002

alpha 11beta 1 integrin recognizes the GFOGER sequence in interstitial collagens.

The integrins alpha(1)beta(1), alpha(2)beta(1), alpha(10)beta(1), and alpha(11)beta(1) are referred to as a collagen receptor subgroup of the integrin family. Recently, both alpha(1)beta(1) and alpha(2)beta(1) integrins have been shown to recognize triple-helical GFOGER (where single letter amino acid nomenclature is used, O = hydroxyproline) or GFOGER-like motifs found in collagens, despite their distinct binding specificity for various collagen subtypes. In the present study we have investigated the mechanism whereby the latest member in the integrin family, alpha(11)beta(1), recognizes collagens using C2C12 cells transfected with alpha(11) cDNA and the bacterially expressed recombinant alpha(11) I domain. The ligand binding properties of alpha(11)beta(1) were compared with those of alpha(2)beta(1). Mg(2+)-dependent alpha(11)beta(1) binding to type I collagen required micromolar Ca(2+) but was inhibited by 1 mm Ca(2+), whereas alpha(2)beta(1)-mediated binding was refractory to millimolar concentrations of Ca(2+). The bacterially expressed recombinant alpha(11) I domain preference for fibrillar collagens over collagens IV and VI was the same as the alpha(2) I domain. Despite the difference in Ca(2+) sensitivity, alpha(11)beta(1)-expressing cells and the alpha(11) I domain bound to helical GFOGER sequences in a manner similar to alpha(2)beta(1)-expressing cells and the alpha(2) I domain. Modeling of the alpha I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar collagens is a common recognition motif used by alpha(1)beta(1), alpha(2)beta(1), and also alpha(11)beta(1) integrins. Although alpha(10) and alpha(11) chains show the highest sequence identity, alpha(2) and alpha(11) are more similar with regard to collagen specificity. Future studies will reveal whether alpha(2)beta(1) and alpha(11)beta(1) integrins also show overlapping biological functions.

Amino Acid Motifs↗
PubMed1991

Asn-linked oligosaccharide-dependent interaction between laminin and gp120/140. An alpha 6/beta 1 integrin.

Receptor-mediated recognition and adhesion to laminin, a specific glycoprotein from basement membranes, exert an important role in many biological phenomena. Studying cell surface proteins of B16-F10, a metastatic murine melanoma cell line, we identified a 120-140 kDa glycoprotein (gp120/140) that binds laminin. This glycoprotein was recognized by a polyclonal antibody raised against the human fibronectin receptor beta 1-integrin chain, as well as immunoprecipitated by an anti-alpha 6 chain (monoclonal antibody GoH3), characterizing it as an alpha 6/beta 1-integrin. Its binding to laminin was specific and displayed moderate affinity, as its apparent dissociation constant was 18 nM. To characterize the influence of carbohydrate moieties on the laminin-gp120/140 interaction, metaperiodate oxidation, metabolic inhibition of glycosylation, and enzymatic deglycosylation studies were performed. Our results indicate that gp120/140 Asn-linked oligosaccharides play a part in this interaction. Reciprocally, both metaperiodate and N-glycanase treatment of native laminin reduced its binding to gp120/140, characterizing the latter as a lectin-like molecule. These results point to glycosylation processes as a possible mechanism for variable binding specificity profiles among integrins.

Animals↗
PubMed1991

Integrin alpha 2 beta 1 is upregulated in fibroblasts and highly aggressive melanoma cells in three-dimensional collagen lattices and mediates the reorganization of collagen I fibrils.

The ability of cultured human fibroblasts to reorganize and contract three dimensional collagen I gels is regarded as an in vitro model for the reorganization of connective tissue during wound healing. We investigated whether adhesion receptors of the integrin family are involved. It was found that synthesis and transcription of the alpha 2 beta 1 integrin (but not of alpha 1 beta 1 or alpha 3 beta 1) is selectively upregulated when fibroblasts are seeded into type I collagen gels. Time course experiments revealed that high synthetic levels of alpha 2 beta 1 parallel the gel contraction process and return to "baseline" levels after the contraction has subsided. Furthermore, function-blocking mAbs directed to the alpha 2 and beta 1 chain of integrins inhibited gel contraction. Remodelling of connective tissue can be important for tumor cells during invasion and formation of metastases. Therefore, we tested human melanoma cell lines for this function. Five out of nine melanoma lines contracted collagen gels in vitro. Among these, two highly aggressive melanoma cell lines (MV3 and BLM) most efficiently contracted gels almost reaching the rate of normal adult fibroblasts. In these cells, synthesis of alpha 2 beta 1 was also significantly upregulated when seeded into collagen I gels. Moreover, function blocking anti-alpha 2 in conjunction with anti-beta 1 chain mAbs completely inhibited gel contraction for several days. Other melanoma cells (530) with lower metastatic potential which were not able to contract gels, showed no induction of alpha 2 beta 1 synthesis in gel culture. Our results suggest an important role of integrin alpha 2 beta 1 in the contraction of collagen I by normal diploid fibroblasts during wound healing and in the reorganization of collagen matrices by highly aggressive human melanoma cells.

Adult↗
PubMed1993

Regulation of in vitro capillary tube formation by anti-integrin antibodies.

Human endothelial cells are induced to form an anastomosing network of capillary tubes on a gel of collagen I in the presence of PMA. We show here that the addition of mAbs, AK7, or RMAC11 directed to the alpha chain of the major collagen receptor on endothelial cells, the integrin alpha 2 beta 1, enhance the number, length, and width of capillary tubes formed by endothelial cells derived from umbilical vein or neonatal foreskins. The anti-alpha 2 beta 1 antibodies maintained the endothelial cells in a rounded morphology and inhibited both their attachment to and proliferation on collagen but not on fibronectin, laminin, or gelatin matrices. Furthermore, RMAC11 promoted tube formation in collagen gels of increased density which in the absence of RMAC11 did not allow tube formation. Neither RMAC11 or AK7 enhanced capillary formation in the absence of PMA. Lumen structure and size were also altered by antibody RMAC11. In the absence of antibody the majority of lumina were formed intracellularly from single cells, but in the presence of RMAC11, multiple cells were involved and the lumen size was correspondingly increased. Endothelial cells were also induced to undergo capillary formation in fibrin gels after PMA stimulation. The addition of anti-alpha v beta 3 antibodies promoted tube formation in fibrin gels and inhibited EC adhesion to and proliferation on a fibrinogen matrix. The enhancement of capillary formation by the anti-integrin antibodies was matrix specific; that is, anti-alpha v beta 3 antibodies only enhanced tube formation on fibrin gels and not on collagen gels while anti-alpha v beta 1 antibodies only enhanced tubes on collagen and not on fibrin gels. Thus we postulate that changes in the adhesive nature of endothelial cells for their extracellular matrix can profoundly effect their function. Anti-integrin antibodies which inhibit cell-matrix interactions convert endothelial cells from a proliferative phenotype towards differentiation which results in enhanced capillary tube formation.

Animals↗
PubMed1991

The A9 antigen associated with aggressive human squamous carcinoma is structurally and functionally similar to the newly defined integrin alpha 6 beta 4.

We previously reported that altered expression of the A9 antigen (defined by monoclonal antibody UM-A9) is a predictive marker of early recurrence and progression of squamous cell carcinoma (SCC). In normal squamous cells A9 expression is limited to the site of contact with the basement membrane in vivo and the culture surface in vitro, whereas aggressive SCCs exhibit loss of polarity and increased intensity of A9 expression. The potential relationship of the A9 antigen to structures known to be involved in cell adhesion was analyzed by immunobiochemical and cell adhesion assays. UM-A9 precipitates a complex of protein chains reminiscent of the alpha and beta heterodimer glycoproteins that characterize the integrin family of extracellular matrix receptors. Proteins were isolated from A9-positive cells using UM-A9 and well-defined antibodies specific for integrin alpha and beta chains. UM-A9, anti-alpha 6, and anti-beta 4 monoclonal antibodies (mAbs) all precipitated proteins with comparable electrophoretic mobilities. Furthermore, UM-A9 mAb precleared the SCC alpha 6 beta 4 integrin complex isolated with anti-alpha 6 or anti-beta 4 mAbs but not that isolated by anti-beta 1 mAb. The isoelectric points of the A9 complex chains were consistent with those reported for alpha 6 and beta 4. Three of the polypeptide chains (140, 175, and 205 kDa) precipitated by UM-A9 showed peptide homology to one another and to the beta 4 chain precipitated by mAb 439-9B. The A9/alpha 6 subunit is composed of 125- and 30-kDa chains and was distinguished from beta 4 and beta 1 chains by its peptide map and isoelectric point. UM-A9 binds to an epitope common to the beta 4 subunits since in pulse-chase analysis the beta 4 species are precipitated at an early time point, whereas detection of alpha-subunit synthesis is detected during assembly of the mature complex. Immunoprecipitation and preclearing experiments demonstrated that in SCC the alpha 6 subunit is associated primarily with the beta 4 species and not with the 130-kDa beta 1 subunit. In cell adhesion assays on extracellular matrix proteins, the alpha 6-specific GoH3 mAb inhibited binding of SCC to laminin, suggesting that alpha 6 beta 4 may function as a laminin receptor in SCC. These data and our prior observations showing an association between altered A9 expression and early recurrence in SCC provide the first evidence that altered expression of alpha 6 beta 4 integrin is associated with the clinical behavior of human squamous cell carcinomas.

Antigens, Neoplasm↗
PubMed1991

Human monoclonal autoantibody 2E7 is specific for a peptide sequence of platelet glycoprotein IIb. Localization of the epitope to IIb231-238 with an immunodominant Trp235.

2E7 is a human monoclonal IgM autoantibody that binds to a site on the heavy chain of the human platelet integrin alpha subunit glycoprotein IIb. The epitope recognized by 2E7 is stable to denaturation with sodium dodecyl sulfate and reduction of disulfide bonds but is destroyed by proteolysis with papain, chymotrypsin or elastase. By evaluating the reaction of 2E7 with a number of protein sequences from the IIb heavy chain, we have determined that the epitope is located in the octapeptide Phe-Asp-Gly-Tyr-Trp-Gly-Tyr-Ser (FDGYWGYS), corresponding to residues 231-238, and that substitution of the Trp at position 235 completely destroys the epitope. This represents the first precise localization of an epitope on the human platelet integrin IIb-IIIa or on any platelet membrane glycoprotein that is recognized by a human autoantibody.

Amino Acid Sequence↗
PubMed1997

Microglial production of TNF-alpha is induced by activated T lymphocytes. Involvement of VLA-4 and inhibition by interferonbeta-1b.

TNF-alpha is a proinflammatory cytokine involved in many inflammatory conditions such as Crohn's disease, rheumatoid arthritis, cachexia, AIDS, and multiple sclerosis (MS). TNF-alpha is produced mainly by cells of the macrophage lineage, which includes microglia in the central nervous system. Here, we describe a mechanism through which TNF-alpha is generated by microglia. We show that activated human T lymphocytes induce the microglial production of TNF-alpha, and that is attenuated by a functional blocking antibody to CD49d, the alpha chain of the VLA-4 integrin on T cells. We also report that interferonbeta-1b (IFNbeta-1b), a drug that alleviates symptoms in MS, downregulates the expression of CD49d and reduces TNF-alpha production, mechanisms which can help account for its efficacy in MS.

Cells, Cultured↗
PubMed2004

Pathophysiologic roles of the fibrinogen gamma chain.

PURPOSE OF REVIEW: Fibrinogen binds through its gamma chains to cell surface receptors, growth factors, and coagulation factors to perform its key roles in fibrin clot formation, platelet aggregation, and wound healing. However, these binding interactions can also contribute to pathophysiologic processes, including inflammation and thrombosis. This review summarizes the latest findings on the role of the fibrinogen gamma chain in these processes, and illustrates the potential for therapeutic intervention. RECENT FINDINGS: Novel gamma chain epitopes that bind platelet integrin alpha IIbbeta3 and leukocyte integrin alphaMbeta2 have been characterized, leading to the revision of former dogma regarding the processes of platelet aggregation, clot retraction, inflammation, and thrombosis. A series of studies has shown that the gamma chain serves as a depot for fibroblast growth factor-2 (FGF-2), which is likely to play an important role in wound healing. Inhibition of gamma chain function with the monoclonal antibody 7E9 has been shown to interfere with multiple fibrinogen activities, including factor XIIIa crosslinking, platelet adhesion, and platelet-mediated clot retraction. The role of the enigmatic variant fibrinogen gamma chain has also become clearer. Studies have shown that gamma chain binding to thrombin and factor XIII results in clots that are mechanically stiffer and resistant to fibrinolysis, which may explain the association between gammaA/gamma' fibrinogen levels and cardiovascular disease. SUMMARY: The identification of new interactions with gamma chains has revealed novel targets for the treatment of inflammation and thrombosis. In addition, several exciting studies have shown new functions for the variant gamma chain that may contribute to cardiovascular disease.

Animals↗
PubMed1998

Neural precursor cell chain migration and division are regulated through different beta1 integrins.

Proliferation and tangential migration of neural precursor cells are essential determinants of CNS development. We have established cell culture models of both these processes using neural precursor cells grown as neurospheres. The pattern of migration that we observe in these cells is homotypic and occurs in the absence of a glial or neuronal scaffold, and is therefore equivalent to that previously described as chain migration. To determine the role of integrins in proliferation and migration, we have analysed the expression pattern of integrins on neurosphere cells and then performed blocking peptide and antibody experiments. Neurosphere cells express five major integrins, alpha5 beta1, alpha 6Abeta1, alphav beta1, alphav beta5 and alpha vbeta8 and, in addition, express low levels of alpha 6Bbeta1. Chain migration is inhibited by blocking the alpha 6beta1 integrin. Proliferation, by contrast, is inhibited by blocking the other beta1 integrins, alphav beta1 and alpha5 beta1. These results show that integrins are important regulators of neural precursor cell behaviour, with distinct beta1 integrins regulating proliferation and migration. They also demonstrate a novel role for the alpha6 beta1 integrin in the cell-cell interactions underlying homotypic chain migration.

Animals↗
PubMedDate not supplied

Localization of the alpha 3 beta 1 integrin in some common epithelial tumors of the ovary and in normal equivalents.

Monoclonal antibodies (mAbs) against cultured human ovary carcinoma cells were produced. We obtained 7 mAbs which reacted diffusely with carcinoma of the ovary but only weakly with vessels and the surface epithelial layer of normal ovary. Biochemical characterization of these mAbs indicated that 3 out of 7 were specific for the alpha 3 chain of the Vla-3 integrin, a receptor for fibronectin, collagen and laminin. Using one of these mAbs, we have studied, by immunohistochemical methods, the distribution of alpha 3 beta 1 integrin in mucinous, serous and endometrioid cystoadenocarcinoma of the ovary and in their normal equivalent: endocervical, tubal and endometrial epithelia. The results show that alpha 3 beta 1 is present in cell-cell contact areas and more abundantly at the junction between epithelial cells and basement membrane in endocervical, tubal epithelia, in epithelium lining the cavity of the uterus and in surface epithelium of the ovary. However, endometrial glands showed only weak and fragmented positivity at the basal pole of the cells. 26 out of 31 ovarian cancers studied, expressed the alpha 3 beta 1 integrin. However, basal localization, typical of normal epithelia, is not prominent or disappears in tumors and is replaced by a more diffuse reaction with variable immunohistochemical staining of the neoplastic cells. Furthermore, a comparative analysis of the expression of alpha 3 beta 1 and its ligands, laminin (LM), fibronectin (FN) and collagen IV (Coll IV), demonstrated that basal polarization of Vla-3 was always correlated with the presence of laminin and Coll IV, intrinsic components of the basement membranes.

Amino Acid Sequence↗
PubMed1994

Composition of extracellular matrix and distribution of cell adhesion molecules in renal cell tumors.

BACKGROUND: Cell to cell and cell to matrix interactions play a major role in tumor growth and invasion. Therefore, we studied the composition of extracellular matrices and the distribution of cell adhesion molecules in 50 renal cell tumors of various types and various grades of malignancy as compared with nontumoral kidney. EXPERIMENTAL DESIGN: In the present study, we used immunolabeling with specific antibodies directed against the alpha 1, alpha 2, and alpha 3 chains of collagen type IV; laminin; heparan sulfate proteoglycan; fibronectin; collagen I; collagen III; the alpha 1, alpha 2, alpha 3, alpha 5, alpha 6, alpha v, beta 1, and beta 3 subunits of integrins; and ICAM-1, VCAM-1, and ELAM-1 molecules. RESULTS: In clear cell type carcinomas (24 cases) the basal laminae surrounding the tumor islets contained the alpha 1 and alpha 2 chains of collagen type IV and heparan sulfate proteoglycan in all cases, and laminin in 96% of the cases. The alpha 3 chain of collagen IV was present in only one case, whereas fibronectin, collagen I, and collagen III were detected in nearly 50% of the cases. The tumor cells expressed alpha 3, alpha 6, and beta 1 integrin subunits in all cases, alpha 5 in 25%, alpha v beta 3 in 54%, and alpha 2 in none. ICAM-1 was detected in all cases, and VCAM-1 in 58%. The expression of the alpha 6 subunit was weak in 2 tumors of high grade, whereas the alpha v subunit was expressed in 7 of 14 low grade and in 7 of 10 intermediate and high grade tumors. In tubulopapillary carcinomas with chromophilic cells (12 cases), the most prominent findings were the presence of the alpha 3 chain of collagen IV in tumor basal laminae in 66% and the expression of the alpha 2 integrin subunit by the tumor cells in 58% of the cases, both features characterizing distal renal tubules. In chromophobic carcinomas (4 cases), the tumor basement membranes were tenuous and contained no fibronectin or interstitial collagens. The tumor cells expressed the alpha 6, alpha 2, alpha 3, beta 1, and alpha nu beta 3 integrin subunits but neither ICAM-1 nor VCAM-1 molecules. In oncocytomas (10 cases), the tumor basement membranes contained the alpha 1, alpha 2, and alpha 3 chains of collagen IV, laminin, and heparan sulfate proteoglycan. Fibronectin was not detected, whereas interstitial collagens were present in half of the cases. In all tumors, cells expressed the alpha 6 and beta 1 integrin subunits, whereas alpha 2, alpha 3, and alpha nu beta 3 were present in 30%, 60%, and 90% of the cases, respectively. ICAM-1 and VCAM-1 were not detected. The vascular endothelial cells of the stroma expressed the alpha 1, alpha 5, alpha 6, and beta 1 integrin subunits in all 50 of the studied tumors. In addition, ICAM-1 was detected in 84%, VCAM-1 in 50%, and ELAM-1 in 34% irrespective of tumor cell type, growth, or nuclear grade. CONCLUSIONS: These results suggest that each type of renal cell tumor produces particular extracellular matrix components and expresses a characteristic repertoire of cell adhesion molecules, which could provide better understanding of the origin of these tumors. The expression of the alpha nu beta 3 integrin subunit was demonstrated in all types of renal cell tumors and was not found to be related to high grade tumors. Stromal vascular endothelial cells expressed activation molecules VCAM-1 and ELAM-1 in a significant number of cases in both benign and malignant tumors.

Adenocarcinoma, Clear Cell↗
PubMed2003

Engineering integrin-specific surfaces with a triple-helical collagen-mimetic peptide.

Integrin-mediated cell adhesion to extracellular matrix proteins anchors cells and triggers signals that direct cell function. The integrin alpha(2)beta(1) recognizes the glycine-phenylalanine-hydroxyproline-glycine-glutamate-arginine (GFOGER) motif in residues 502-507 of the alpha(1)(I) chain of type I collagen. Integrin recognition is entirely dependent on the triple-helical conformation of the ligand similar to that of native collagen. This study focuses on engineering alpha(2)beta(1)-specific bioadhesive surfaces by immobilizing a triple-helical collagen-mimetic peptide incorporating the GFOGER binding sequence onto model nonadhesive substrates. Circular dichroism spectroscopy verified that this peptide adopts a stable triple-helical conformation in solution. Passively adsorbed GFOGER-peptide exhibited dose-dependent HT1080 cell adhesion and spreading comparable to that observed on type I collagen. Subsequent antibody blocking conditions verified the involvement of integrin alpha(2)beta(1) in these adhesion events. Focal adhesion formation was observed by immunofluorescent staining for alpha(2)beta(1) and vinculin on MC3T3-E1 cells. Model functionalized surfaces then were engineered using three complementary peptide-tethering schemes. These peptide-functionalized substrates supported alpha(2)beta(1)-mediated cell adhesion and focal adhesion assembly. Our results suggest that this peptide is active in an immobilized conformation and may be applied as a surface modification agent to promote alpha(2)beta(1)-specific cell adhesion. Engineering surfaces that specifically target certain integrin-ligand interactions and signaling cascades provides a biomolecular strategy for optimizing cellular responses in biomaterials and tissue engineering applications.

3T3 Cells↗
PubMedDate not supplied

The relationship between bone metastasis from human breast cancer and integrin alpha(v)beta3 expression.

BACKGROUND: Osteoclast activation plays an essential role in the development of bone metastasis (BM). Integrin alpha(v)beta3 mediates the attachment of osteoclasts to bone matrix, and it is overexpressed in bone-residing breast cancer cells. We studied BM from breast cancer in relation to its Integrin alpha(v)beta3 expression. MATERIALS AND METHODS: Integrin alpha(v)beta3 expression in 4 human breast cancer cell lines (MDA-MB-231, MDA-MB-435, MKL-4 and T-47D) was determined by immunohistochemistry, flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Integrin alpha(v)beta3 was expressed in MDA-MB-231 and MDA-MB-435, but not in MKL-4 or T-47D, using both immunohistochemistry and flow cytometry. By RT-PCR, positive bands for both alpha(v) and beta3 subunits were identified in MDA-MB-231 and 435, while only the alpha(v) subunit mRNA was present in MKL-4 and T-47D. BM was common in vivo following inoculation with MDA-MB-231 or 435, but not with MKL-4. CONCLUSION: Integrin alpha(v)beta3 expression appears to play a key role in the development of BM from breast cancer.

Animals↗
PubMed1997

[Adhesion molecules in squamous cell carcinoma of the larynx: possible indication of prognosis].

Thirty patients with laryngeal tumors were divided into two groups on the basis of whether clinical and pathological features indicated good or bad prognosis. Samples of each tumor group were selected and examined by immunohistochemistry using mAbs, raised against integrin chains (beta 1, beta 4, alpha 2, alpha 3, alpha 6) and their ligands laminin 1 and 5, collagen type IV, two fibronectin isoforms (ED-A and ED-B) and two isoforms of tenascin known to be associated with neoplasm. Controls were provided by samples of tumor-free laryngeal mucosa removed during the surgical procedure. The normal topographical integrin pattern and the continuity of the basement membrane components was altered in both groups but the extent of these changes was significantly greater in those tumors with poor prognosis. Therefore, the groups could easily and reliably be distinguished by simply observing their immunohistochemical features. It is suggested that performing immunohistochemical analysis on biopsies may aid in early diagnosis as well as in adopting the proper therapeutic strategy to follow for these tumors. The above molecules may become one of the diagnostic tools available for head and neck surgical pathologists.

Adult↗
PubMed1992

A peptide corresponding to GPIIb alpha 300-312, a presumptive fibrinogen gamma-chain binding site on the platelet integrin GPIIb/IIIa, inhibits the adhesion of platelets to at least four adhesive ligands.

The platelet fibrinogen (Fg) receptor (GPIIb/IIIa) is an integrin which plays a critical role in hemostasis by recognizing at least the four adhesive ligands: Fg, fibronectin (Fn), vitronectin (Vn), and von Willebrand factor (vWf). We reported that residues 309-312 of GPIIb alpha appear to comprise at least part of a Fg binding site on the Fg receptor (Gartner, T. K., and Taylor, D. B. (1990) Thromb. Res. 60, 291-309). Here we report that the peptide GPIIb alpha 300-312 (G13) inhibits platelet aggregation and binds Fg and Vn. Significantly, this peptide inhibits the adhesion of stimulated platelets to Fg, Fn, Vn, and vWf, but not the adhesion of resting platelets to Fn. Thus, GPIIb 300-312 may constitute a specific but common recognition site on GPIIb/IIIa for both LGGAKQAGDV- and RGD-containing ligands.

Amino Acid Sequence↗
PubMed1996

A novel monoclonal antibody mNI-58A against the alpha-chain of leukocyte function-associated antigen-1 (LFA-1) blocks the homotypic cell aggregation and actively regulates morphological changes in the phorbol myristate acetate (PMA)-activated human monocyte-like cell line, U937.

A monoclonal antibody (mAb), designated mNI-58A, was produced by immunizing mice with the lipopolysaccharide (LPS)-stimulated monocyte-like cell line, U937. The antigen defined by mNI-58A was widely expressed on various lymphoid cells and all cell lines examined except the erythroid cell line, K562. When the reactive patterns between mNI-58A and the mAbs to various human differentiation antigens (CD11a, CD11b, CD11c, CD14, CD16, CD18, CD23, CD28, CD29, CD31, CD43, CD44, CD45RA, CD50, CD54, CD58, CD80, CD102, CD106, HLA-class I and-class II antigen) were compared, that of mNI-58A was found to be similar to those of the leukocyte function-associated antigen-1 (LFA-1) mAbs. Using a competitive immunofluorescence binding assay it was found that the preincubation with one of the CD11a mAbs, 2F12 completely blocked the subsequent binding of mNI-58A. mNI-58A prevented the homotypic cell aggregation of the phorbol myristate acetate (PMA)-activated U937 cells (referred to as PMA-U937) and PMA-activated Epstein-Barr virus (EBV)-transformed B cell lines, B-85 and Mann. mNI-58A markedly induced the spread formation of the PMA-U937 cells following this blocking of the homotypic cell aggregation, whereas 2F12 did not under the same condition. The spread formation induced by mNI-58A was completely blocked by cytochalasin B (CyB), cytochalasin D (CyD), cycloheximide (CHX) or protein kinase C inhibitors, sphingosine and H-7. The U937 cells markedly adhered to the tumor necrosis factor-alpha (TNF-alpha)-stimulated human umbilical vein endothelial cells (HUVECs) and also to the extracellular matrix protein, fibronectin, but mNI-58A did not enhance or block these adhesion process. mNI-58A precipitated two glycoproteins with molecular weight 180 kDa and 95 kDa as determined by SDS-PAGE analysis, which were identical to the LFA-alpha (CD11a) and beta (CD18) chains of leukocyte integrin precipitated by the CD11a mAbs, respectively. Sequential immunoprecipitation studies using the CD11a mAb (2F12) also indicate that mNI-58A recognizes an epitope on the alpha-chain of the LFA-1 molecule. The ability of mNI-58A to block the PMA-U937 cells and to induce the spread formation of these cells suggests that mNI-58A is a novel mAb reacting with an epitope on the alpha-chain of LFA-1 different from those recognized with the existing CD11a mAbs.

Antibodies, Blocking↗