Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Integrin alpha Chains”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 739 records · Page 41Linked to original sources
PubMed1995

The glomerular mesangium: studies of its developmental origin and markers in vivo and in vitro.

Cultured mesangial cells are widely used to explore their role in kidney glomerular functions, but methods to reliably identify these cells in vivo and in vitro are lacking. Furthermore, the proposed relationship of mesangial cells to e.g. fibroblasts and smooth muscle cells has not been systematically studied. Here we wanted to search for markers of practical use also in identifying cultured mesangial cells, and to apply these markers in a study of the origin of glomerular mesangium. No epitopes specific for only mesangial cells could be identified, and no evidence of their true relationship with neural or lymphocytic lineages could be found. Findings with the variety of markers used suggest that mesangial cells may be indistinguishable from smooth muscle cells and fibroblasts. A panel of antibodies, including those against Thy1.1, smooth muscle actin, desmin, cellular fibronectin and beta 1 integrin alpha 1 and alpha 5 chains, and Wistaria floribunda (WFA) and Ricinus communis (RCA I) lectins, were found useful for mesangial cell detection in vivo and in vitro. The origin of glomerular mesangial cells could not be conclusively determined, although the results indirectly suggest that mesangial cells together with endothelial cells migrate to the glomerulus from the outside.

Animals↗
PubMed1993

Modulation of alpha 1 beta 1, alpha 2 beta 1 and alpha 3 beta 1 integrin heterodimers during human neuroblastoma cell differentiation.

Two human neuroblastoma cell lines, LAN-5 and GI-CA-N, have been analyzed for their capability to adhere to different extracellular matrix (ECM) components. The GI-CA-N cells adhered to all the tested substrates: laminin (LN), type I and type IV collagen (Coll I, Coll IV), vitronectin (VN), and fibronectin (FN). Conversely LAN-5 cells weakly attached to FN and VN, whilst adhesion on LN and Coll I and IV was strong and induced a rapid elongation of cell processes. By means of RT-PCR and immunoprecipitation we showed that the integrin pattern of these two lines was different and could explain their diversity in adhesion capability. Both cell lines express a large amount of the beta 1 integrin subunit, associated with different alpha chains, probably responsible for their adhesion to some ECM proteins. After treatment of LAN-5 cells with biological differentiating agents, such as gamma-interferon, alone or in combination with tumour necrosis factor-alpha (TNF-alpha), or retinoic acid, the levels of alpha 1 beta 1, alpha 2 beta 1, and alpha 3 beta 1 integrin expression were enhanced, while the amount of alpha v remained constant. In contrast, treatment of LAN-5 cells with TNF-alpha, that did not induce any maturation, or starvation in 2% foetal calf serum, that inhibited cell proliferation without affecting neural differentiation, did not induce any change in the integrin assessment. Messenger-RNAs for the two alpha 6 isoforms, A and B, were present in both cell lines. However, in LAN-5 cells, the protein product was neither detectable nor inducible by differentiation. Our results confirm the specific modulation of the alpha 1 beta 1 integrin expression in human neuronal development, and show, for the first time, the involvement of alpha 2 beta 1 and alpha 3 beta 1 heterodimers in this maturational process.

Cell Adhesion↗
PubMed1997

Expression of three cell adhesion molecules in bladder carcinomas: correlation with pathological features.

Recently, independent studies have shown that the expression of two integrin chains, beta 4 and alpha 2, plus the epithelial cadherin are related to tumour progression in human bladder carcinomas. For the first time, we compare the expression of these three cell adhesion molecules using immunohistochemical analysis of consecutive cryosections from a series of 50 bladder tumors. E-cadherin, beta 4, and alpha 2 were strongly expressed in normal urothelium. A majority of non-invasive bladder cancers stained positively for E-cadherin (62%), whereas only 29% expressed normal positivity for alpha 2, and only 35% for beta 4. However, most invasive tumours presented an aberrant expression of alpha 2 (81%), beta 4 (100%), and E-cadherin (75%). We studied the correlation of immunoreactivity with histological grade and stage. The alpha 2 pattern was not correlated with stage and grade. In contrast, loss of normal beta 4 expression was significantly related to increasing tumour grade and deep invasion with a higher correlation for grade. Finally, E-cadherin expression was highly correlated with stage, but not with grade. Thus our results indicate that, although many invasive bladder tumours presented a disorder in expression of the two integrins alpha 2 and beta 4, E-cadherin appeared to be a better market of invasiveness in bladder carcinomas.

Adult↗
PubMed1994

Thalidomide and the immune system. 3. Simultaneous up- and down-regulation of different integrin receptors on human white blood cells.

Time-dependent changes in the surface receptor expression of various maturational and integrin receptors on peripheral blood cells were studied in two healthy human volunteers following oral applications of thalidomide (Thd). In each measurement the receptor density was quantified by prior calibration of the flow cytometer with latex beads bearing a determined number of fluorescence molecules. The effects observed in the course of the Thd-treatment were practically identical or at least very similar in both the volunteers during four different trials, and were in accord with previous results obtained in large-scale studies (68 treated animals) with non-human primates. It should be stressed that no clear-cut changes were observed in the percentage or absolute numbers of primary lymphocyte subsets such as CD3, CD4 and CD20. After the first two doses of 7 mg Thd/kg body wt the CD18 (the common beta-chain of the beta 2-integrins) marker already decreased in surface density or was no longer detectable on granulocytes, monocytes and lymphocytes. This effect persisted throughout the treatment period and slowly subsided after discontinuation of treatment. With a few days lag phase, the surface density of CD54 (ICAM-1) on granulocytes increased and many cells previously not bearing this receptor newly acquired such surface markers. On monocytes however, the CD54 receptor was lost on many cells. Within the lymphocyte fraction a loss of the CD54 marker could be noted on CD4 cells but not on CD8 cells, where an increase of the receptor expression could be observed. Other markers, such as the alpha chains of the beta 1 integrins CD49b (VLA alpha 2) and CD49d (VLA alpha 4) showed contrasting reactions to the Thd-treatment. Whereas a pronounced loss of the receptor density of CD49d was observed and only few cells with high epitope density were left in the blood at the end of the complete dosing schedule, no such effect was observable on cells bearing the CD49b epitope. A distinct reduction of the number of receptors was also noticeable on L-selectin (Leu8) bearing cells. On CD4 positive lymphocytes, the majority of the described effects on the integrin and adhesion receptors was seen on cells bearing the CD45R0 maturational epitope. This functional receptor is strongly down-regulated and the pathway of CD45RA to CD45R0 maturation is apparently altered by Thd-treatment. These multiple changes we observed may explain the large variety of therapeutic effects experienced in the treatment with Thd.

Carrier Proteins↗
PubMed1993

Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1.

The mucosal vascular addressin, MAdCAM-1, is an immunoglobulin superfamily adhesion molecule for lymphocytes that is expressed by mucosal venules and helps direct lymphocyte traffic into Peyer's patches (PP) and the intestinal lamina propria. We demonstrate that the lymphocyte integrin alpha 4 beta 7, also implicated in homing to PP, is a receptor for MAdCAM-1. Certain antibodies to alpha 4 and beta 7 integrin chains but not to the beta 2 integrin LFA-1 inhibit lymphocyte binding to purified MAdCAM-1 and to MAdCAM-1 transfectants. Lymph node lymphocytes, alpha 4 beta 7+ TK1 lymphoma cells, and a beta 7-transfected variant of an alpha 4+ B cell line, 38C13, bind constitutively to MAdCAM-1. Binding is enhanced by Mn(++)-induced integrin activation. The related integrin alpha 4 beta 1 supports efficient binding to VCAM-1 but not to MAdCAM-1, even after integrin activation, indicating that MAdCAM-1 is a preferential ligand for alpha 4 beta 7. Alpha 4 beta 7 can also bind VCAM-1, but this requires greater integrin activation than binding to MAdCAM-1. The findings imply a selective role for the interaction of alpha 4 beta 7 and MAdCAM-1 lymphocyte in homing to mucosal sites.

Animals↗
PubMed1992

Immunotype findings in macrophages in aural cholesteatomas.

Since a heavy cellular infiltrate is seen in the stroma of most aural cholesteatomas, we attempted to characterize this cell population in more detail using monocyte/macrophage-specific monoclonal antibodies. KiM1 + (specific for CD11c antigen, the 150 kDa alpha-chain of a leukocyte integrin), and KiM6+ phagocytes were present in two- or fourfold higher numbers in the stroma of the six excised cholesteatomas than in the control tissues. Since the stroma of the cholesteatoma is devoid of microvessels, the typical perivascular localization of dermal macrophages was not seen in the cholesteatomas studied. The density of the macrophages in the normal ear skin was much higher in the upper dermis than in the lower dermis. In the cholesteatomatous specimens, the phagocytes were evenly scattered within the connective tissue and the cellular infiltrate. In contrast to diseased skin, no Mac 387+ macrophages were detected in the cholesteatomas. A great number of phagocytic cells closely resembling dermal macrophages was found in the stroma of the cholesteatomas and probably contributes to an active autoimmune process.

Antibodies, Monoclonal↗
PubMed1993

Maturation induced internalization of beta 1-integrin by Xenopus oocytes and formation of the maternal integrin pool.

A pool of beta 1-integrin, ready to be inserted into the cleavage membranes, is present in the cytoplasm of the Xenopus egg, while its plasma membrane is devoid of this membrane protein (Gawantka et al., 1992). The underlying mechanisms that lead to this specific pattern of beta 1-integrin distribution in the egg have been investigated. beta 1-Integrin is present on the oocyte membrane throughout oogenesis. During maturation the oocyte membrane is cleared of beta 1-integrin via internalization of the protein by the oocyte. Synthesis of beta 1-integrin precursor is stimulated moderately in the maturing oocyte. At the same time processing of the precursor into the mature form of beta 1-integrin and its complexing with a putative alpha-chain is greatly accelerated. This way a maternal integrin pool accumulates in the mature oocyte. It is localized in conspicuous yolk free patches which contain large amounts of endoplasmic reticulum, Golgi complexes and smooth vesicles. We suggest that membrane vesicles harbouring the beta 1-integrin are generated in these cytoplasmic regions and that this store of vesicles provides the material source for the rapid membrane formation during cleavage.

Animals↗
PubMed2001

Summary of workshop findings for porcine myelomonocytic markers.

About 65 monoclonal antibodies (mAb) including 17 internal controls were analyzed for their ability to recognize and bind to various cells of the myelomonocytic lineage. Flow cytometry (FCM) utilizing both single and double staining, and immunoprecipitation (IP) assays were used in the analysis. About 38 of the mAb were reactive with myelomonocytic cells, resulting in nine clusters of interest. Although the exact identity of many of the molecules on the cells bound by the mAb remains undetermined, information obtained about the mAb analyzed in this workshop should be helpful in further identifying various populations of myelomonocytic cells and their stages of differentiation. Out of 12 mAbs with potential CD11 specificity, seven were assigned to three different swine specific alpha chains of the CD11/CD18 integrin heterodimer, the assignment of the remaining four was tentative. One antibody had a binding specificity consistent with SWC3 and one with SWC8. CD14 expression on pig cells was characterized with a panel of CD14-positive antibodies, two of these antibodies were assigned to swine CD14. Two antibodies were assigned to CD163. Further work is required to determine the antigens recognized by many of the other mAb.

Animals↗
PubMed1997

Human fibroblast adhesion to fibrinogen.

Fibrinogen and fibrin mediate the adhesion of many cell types. In this report, the adhesion sites for human dermal fibroblasts on fibrinogen are identified and characterized. Fibroblasts showed a time- and dose-dependent adhesion to fibrinogen. Using a combination of synthetic peptide mimetics, monoclonal antibodies, and recombinant fibrinogens, two major classes of adhesive sites were identified. One class was RGD-dependent and involved the RGD sites in the alpha chain of fibrinogen. alpha V integrins present on fibroblasts appeared to mediate this adhesion. Inhibition studies showed that the RGD-independent site was blocked by an ICAM-1 antagonist peptide. Furthermore, the inhibition was additive with RGD peptide inhibition and accounted for essentially all of the fibroblast adhesion. Together, these results suggest that fibroblast adhesion to fibrinogen is mediated by both alpha V integrins and ICAM-1.

Amino Acid Sequence↗
PubMed1991

Expression of the LFA-1 beta 2 integrin (CD11a/CD18) and ICAM-1 (CD54) in normal and coeliac small bowel mucosa.

The leucocyte adhesion molecules (beta 2 integrins) comprise CD11 alpha-chains and a common beta-chain (CD18). CD11a (leucocyte function-associated antigen 1, LFA-1) is expressed by most T cells, and is involved in antigen presentation by macrophages via its counter-receptor, intercellular adhesion molecule (ICAM-1, CD54). By criteria of double-label immunofluorescence of cryostat tissue sections, virtually all lamina propria T cells of the normal small bowel were found to express LFA-1 strongly. By contrast, only 30-60% of intra-epithelial lymphocytes (IEL) expressed detectable LFA-1, most of which were LFA-1 weak and CD18-. ICAM-1 was expressed strongly only by vascular endothelium. In coeliac disease, there was a modest increase of diffuse ICAM-1 expression in the lamina propria, mainly in the subepithelial zone, where ICAM-1+ macrophages were occasionally seen. There was also a slight overall increase in CD11a expression by IEL, seen predominantly in surface epithelium and mainly by the CD4+ minority subset, but not by CD4-CD8- (TcR gamma delta +) cells. These data suggest that the LFA-1/ICAM-1-dependent antigen presentation pathway is of minor importance to IEL in the normal small bowel, and does not assume a major role in coeliac disease.

Antigens, CD↗
PubMedDate not supplied

Leukocyte adhesion deficiency disorder in an infant.

Leukocyte adhesion defect (LAD) is an inherited disorder of phagocytic function. The three different alpha-chains of the leukocyte integrin family (CD 11a, 11b, 11c) are all dependent on the common beta chain (CD18) for proper insertion into the cell membrane. Deficiency of CD 18 thus causes an inability to express any of these proteins and results in the syndrome of LAD type 1. Clinical features include delayed separation of the umbilical cord, persistent leukocytosis and recurrent infection. A case of severe LAD occurred in a 1 month-old infant. The immunological pattern of the baby showed pathological values of CD11b and CD18 (1.3% and 0.2% respectively) when compared with normal values (50-70%) and lack of random (1.0 nm vs normal of 10±5) and casein-induced (22.0 nm vs normal of 60-120nm) chemotaxis. The baby is now waiting for bone marrow transplantation. Although LAD is a rare form of congenital immune deficiency this disease should be considered when delayed wound healing and recurrent bacterial skin infections are present in a newborn.

Journal Article↗
PubMed1998

Distinct homing pathways direct T lymphocytes to the genital and intestinal mucosae in Chlamydia-infected mice.

Immunity to genital tract infection with Chlamydia trachomatis is mediated by type 1 CD4+ T lymphocytes. To define the signals that govern lymphocyte trafficking to the genital mucosa, integrins expressed by infiltrating T cells and endothelial addressins displayed on local vasculature were characterized during the course of infection. All T cells expressed the alphaLbeta2 heterodimer that binds vascular ICAM-1, and most displayed enhanced levels of the alpha4beta1 integrin that interacts with VCAM-1. AlphaE and beta7(low) integrin chains were detected on approximately 15 and 30% of infiltrating T cells, respectively. Lymphocytes derived from the spleen or draining lymph nodes expressed this same integrin profile, suggesting that cells are recruited to the genital mucosa from the systemic circulation without significant selection pressure for these markers. Immunofluorescent staining for the corresponding vascular addressins revealed intense expression of VCAM-1 on small vessels within Chlamydia-infected genital tracts and up-regulation of ICAM-1 on endothelial, stromal, and epithelial cells. Mucosal addressin cell adhesion molecule-1 was not detected within genital tissues. These results indicate that T lymphocyte homing to the genital mucosa requires the interaction of alphaLbeta2 and alpha4beta1 with endothelial ICAM-1 and VCAM-1, respectively, which is the same pathway that directs lymphocytes to systemic sites of inflammation. Homing pathways defined for the intestinal mucosa and assumed to be relevant to all mucosal sites are not well represented in the genital tract. The identification of T lymphocyte trafficking pathways shared between systemic and mucosal tissues should facilitate vaccine strategies aimed at maximizing immune responses against Chlamydia and other pathogens of the urogenital tract.

Animals↗
PubMed1993

Human acute myeloid leukaemia cells express adhesion proteins and bind to bone marrow fibroblast monolayers and extracellular matrix proteins.

Adhesion protein expression by acute myeloid leukaemia (AML) cells may affect bone marrow stromal localization and determine exposure of leukaemic cells to stromal derived myeloid growth factors. We have analysed the surface expression by myeloid leukaemic cells of proteins with known adhesive function and the ability of AML cells to adhere to bone marrow fibroblasts and the extracellular matrix proteins fibronectin and laminin. Cells from all six patients tested adhered to bone marrow fibroblast monolayers (mean binding 28.8 +/- 12.8%) and to purified fibronectin in five cases studied (mean binding 33.8 +/- 15.3%). Cells from four patients with AML also adhered to laminin (mean binding 20.9 +/- 4.0%). AML cells from the majority of patients with leukaemia at diagnosis or relapse expressed the ligand pair LFA-1 and ICAM-1, the CD2 ligand LFA-3, alpha and beta chains of the integrins VLA-4, VLA-5 and VLA-6, and the hyaluronate receptor CD44. Antibodies to CD11a, CD18, VLA-4 alpha, and VLA-5 alpha failed to inhibit binding of AML cells to bone marrow fibroblasts but anti-VLA-5 alpha antibodies inhibited AML cell binding to fibronectin by approximately 50%. The ability of AML cells to adhere to bone marrow fibroblasts and extracellular matrix proteins such as fibronectin and laminin may to help explain the capacity of AML cells to persist in the marrow during periods of apparent complete remission and to subsequently proliferate under the influence of locally secreted myeloid growth factors.

Bone Marrow Cells↗
PubMed1994

Conformation-dependent platelet adhesion to collagen involving integrin alpha 2 beta 1-mediated and other mechanisms: multiple alpha 2 beta 1-recognition sites in collagen type I.

Platelet adhesion has been measured to type-I monomeric collagen, collagen fibres, alpha 1(I) and alpha 2(I) chains and the chain fragments alpha 1(I)CB3, alpha 1(I)CB6, alpha 1(I)CB7 and alpha 1(I)CB8, and alpha 2(I)CB3,5 and alpha 2(I)CB4. Little if any adhesion occurred to any denatured species at 37 degrees C, demonstrating the importance of the collagen helix. However, on coating at 4 degrees C to promote helix formation, and assaying at room temperature to avoid denaturation, adhesion was observed to both alpha-chain types and all fragments, the exact level of which depended on the identity of the species in question. Adhesion was strongly Mg(2+)-dependent. Antibodies against the integrin alpha 2 beta 1 partially inhibited adhesion to alpha-chains and all fragments except alpha 1(I)CB6, indicating a wide distribution of alpha 2 beta 1-binding sites in the collagen molecule. 'Activation-dependent' adhesion to monomeric collagen, totally secondary to alpha 2 beta 1-mediated adhesion, involved at least two mechanisms, one mediated by integrin alpha IIb beta 3 and insensitive to prostaglandin E1, the other inhibitable by prostaglandin E1 but independent of integrin alpha IIb beta 3. alpha IIb beta 3-mediated adhesion to fragments was, at least in part, independent of the alpha 2 beta 1-mediated adhesion. Adhesion to fibres was largely bivalent-cation-independent with only minor involvement of integrin alpha 2 beta 1. Some alpha IIb beta 3-mediated adhesion occurred but was independent of any alpha 2 beta 1-initiated adhesion. Total 'activation-dependent' adhesion to fibres was less than to monomeric collagen. Affinity chromatography revealed bivalent-cation-independent binding to fibres of three main platelet surface proteins, 90, 150 and 190 kDa in size.

Amino Acid Sequence↗
PubMed2003

CXCR4 enhances adhesion of B16 tumor cells to endothelial cells in vitro and in vivo via beta(1) integrin.

The chemokine receptor, CXCR4, is expressed by human melanomas, and its ligand, CXCL12, is frequently produced at sites of melanoma metastasis. Herein, we examine CXCR4-enhanced binding of B16 murine melanoma cells to endothelial cells (ECs) and recombinant adhesion molecules in vitro to determine the role of tumor- and EC-derived adhesion molecules in tumor metastasis. By flow cytometry, unstimulated primary lung ECs showed constitutive expression of vascular cellular adhesion molecule 1 (VCAM-1), whereas skin-derived ECs did not. All B16 cell lines tested showed constitutive expression of alpha(4) and beta(1) integrin chains but showed no expression of beta(2) integrins. CXCR4-B16 arrest on VCAM-1/immunoglobulin-coated plates and tumor necrosis factor alpha-stimulated ECs under physiological shear stress conditions (1.5 dynes/cm(2)) was rapid, resistant to shear stress of 10 dynes/cm(2), and showed no evidence of rolling before arrest. In vitro, CXCR4-B16 cell binding to ECs was blocked by anti-beta(1) and anti-CXCL12 monoclonal antibodies. In vivo, metastasis of CXCR4-B16 cells to murine lungs was strongly inhibited by anti-CXCL12 and two different anti-beta(1) monoclonal antibodies. Finally, CXCR4-B16 exposed to CXCL12 rapidly increased binding affinity for soluble VCAM-1/immunoglobulin as detected by a flow cytometric assay. Thus, beta(1) integrins play a critical role in CXCR4-mediated B16 tumor cell metastasis in vivo and may be a potential target for inhibition of tumor metastasis, particularly to the lung.

Animals↗
PubMed1997

Bone marrow fibroblast exposure to the inflammatory cytokines tumor necrosis factor-alpha and interferon-gamma increases adhesion of acute myeloid leukemia cells and alters the adhesive mechanism.

Human acute myeloid leukemia (AML) cells adhere to bone marrow fibroblasts (BMF) and extracellular matrix proteins including fibronectin. Adhesion is increased when fibroblast monolayers are exposed to tumor necrosis factor-alpha (TNF) alone and in combination with interferon-gamma (IFN) or interleukin-4 (IL-4). The combination of TNF and IFN caused enhanced AML cell adhesion to treated BMFs, from a mean of 25.0 +/- 4.1% to 36.3 +/- 5.4% (p = 0.0007). Enhanced binding was partially a result of upregulated vascular cell adhesion molecule-1 expression on BMFs. Intercellular adhesion molecule-1 was also upregulated, but did not appear to play a role in the increased binding to cytokine-stimulated BMFs. In contrast to observed adhesion to resting BMFs, AML cells binding to TNF/IFN-stimulated BMFs rely more heavily on the VLA-4 alpha chain (CD49d). In some cases, alpha4 integrin chain antibody was more effective than beta1 antibody in blocking binding, suggesting that a non-beta1 alpha4 integrin, possibly alpha4 beta7, on AML cells may act as a stromal ligand. The addition of alpha4 antibody to beta1 and beta2 antibodies significantly increased the inhibition of AML cells to stimulated BMFs. The myeloid cytokines granulocyte colony stimulating factor, granulocyte-monocyte colony stimulating factor, interleukin-3 and stem cell factor enhanced the adhesion of AML blast cells to BMFs in some cases. The phorbol ester PMA, however, consistently upregulated AML cell-binding to BMFs, the increase being mediated entirely via beta1 and beta2 integrins without altering AML cell integrin expression. Binding of AML cells to marrow stroma can be enhanced by influences on leukemic cell or stroma. Enhanced binding under these conditions occurs via different pathways, illustrating the heterogeneity of mechanisms underlying leukemic cell retention within the bone marrow stroma.

Acute Disease↗
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↗