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PubMed1994

Differential expression of beta 1, beta 3, and beta 4 integrin subunits in nonneoplastic neural cells of the peripheral and autonomic nervous system and in tumors derived from these cells.

BACKGROUND: Extracellular matrix proteins and their receptors take part in physiologic neural development and organization and also in abnormal neoplastic growth and spread. There is increasing evidence for the implication of integrins in these processes. EXPERIMENTAL DESIGN: Human tissues containing nonneoplastic neural cells of the peripheral and autonomic nervous system and a comprehensive series of neural tumors were examined for the in situ expression of beta 1, beta 3, and beta 4 integrins. Serial frozen sections of each tissue sample were immunostained using an indirect streptavidin/biotin-peroxidase method and monoclonal antibodies against beta 1, alpha 1 to alpha 6, beta 3, alpha v, and beta 4 subunits. RESULTS: Both small- and large-diameter nerve fibers of normal peripheral nerve trunks were consistently beta 1+, alpha 6+, and beta 4+ in the absence of alpha 3, alpha 4, alpha 5, and beta 3. Small-diameter nerve fibers further expressed alpha 1, alpha 2, and alpha v. Meissner's corpuscles and inner cores of Pacinian corpuscles shared the integrin repertoire of small-diameter nerve fibers with additional expression of alpha 3; outer cores of Pacinian corpuscles were beta 1+, alpha 3+, alpha 6+, and beta 4+. Regenerating nerve fibers paralleled the integrin profile of normal peripheral nerves. By contrast, malignant schwannomas showed considerable changes in integrin expression. These alterations consisted mainly in a neoexpression of alpha 3, alpha 4, and alpha 5 and in an abnormal loss of alpha 6 and beta 4. Expression of alpha 1, alpha 2, and alpha v was variable; absence of beta 3 was generally conserved. In ganglion cells, integrin expression was restricted to beta 1 and alpha 3 subunits, and chromaffine cells of the adrenal medulla even lacked any detectable beta 1, beta 3, and beta 4 integrin subunits. (Ganglio)-neuroblastomas, however, were beta 1+, alpha 1+, and alpha 3+, whereas primitive peripheral neuroectodermal tumors were beta 1+ and alpha 5+. CONCLUSIONS: Nonneoplastic human neural cells exhibit a complex and, at the same time, differential pattern of beta 1, beta 3, and beta 4 integrin subunit expression. Malignant transformation leads to considerable changes in this integrin profile. The observation of neoplasia-associated abnormalities underlines the important role of integrins in the orderly development and maintenance of human neural tissue. Some aspects of the emerging integrin subunit patterns are useful for the differential diagnosis of neural soft-tissue tumors.

Adrenal Glands↗

PubMed1993

Integrins in the wounded and unwounded stratified squamous epithelium of the cornea.

PURPOSE: The authors determined the synthesis, cell surface expression, and localization of integrins in the rat corneal epithelium to detect whether any changes in integrins occur during epithelial migration in response to simple debridement wounding. METHODS: Immunoprecipitation analysis of extracts from either metabolically or surface-labeled rat epithelia was done to assess the synthesis and cell surface expression of integrins in the normal cornea. The localization of integrins was determined by indirect immunofluorescence of frozen sections obtained from control corneas and from those after debridement wounding. Immunoblotting of extracts from time course experiments was done on organ cultures of rat corneas after debridement to determine if any changes in the amounts of integrins occurred. The cell adhesion function of integrins on control and migrating epithelial cells was evaluated by cell adhesion assays. RESULTS: The data indicated that the corneal epithelium has a variety of distinct integrin subunits including beta 1, beta 4, beta 5, alpha 2, alpha 3, alpha 5, alpha 6, and alpha v. Although beta 1, beta 5, alpha 2, alpha 3, and alpha v were localized to sites of apparent cell-cell contact, alpha 5, alpha 6, and beta 4 were localized specifically to the basal membrane of the basal cells. Little change occurred in the localization of integrins in the migrating epithelial sheets. At 3, 6, 9, 12, 18, and 24 hr after wounding, the amount of the beta 1, beta 4, alpha 3, alpha 5, and alpha 6 integrin subunits (as measured by immunoblots) was not altered relative to that of the control corneas. Adhesion assays also showed no differences in adhesion of stationary versus migrating corneal epithelial cells to fibronectin and laminin. CONCLUSIONS: Integrin localization, production, and cell adhesion function in the stratified squamous epithelium of the cornea are not dramatically altered during epithelial cell migration over simple debridement wounds. Integrins in the cell membrane at sites of cell-cell interaction and as components of the hemidesmosomes in stationary epithelia may be available for rapid recruitment as epithelial cell migration proceeds.

Animals↗

PubMed2003

Functional overlap and cooperativity among alphav and beta1 integrin subfamilies during skin angiogenesis.

Angiogenesis requires endothelial cell survival and proliferation, which depend upon cytokine stimulation together with integrin-mediated cell adhesion to extracellular matrix; however, the question of which specific integrins are the best targets for suppressing neovascularization is controversial and unresolved. Therefore, we designed experiments to compare contributions of individual integrins from both the alphav and beta1 integrin subfamilies. With immobilized antibodies, we determined that adhesion through integrins alpha1beta1, alpha2beta1, alphavbeta3, and alphavbeta5 each individually supported dermal microvascular endothelial cell survival. Also, substratum coated with collagen I (which binds alpha1beta1 and alpha2beta1) and vitronectin (which binds alphavbeta3 and alphavbeta5) each supported survival. Importantly, substratum coated with combinations of collagen I and vitronectin were most effective at promoting survival, and survival on three-dimensional collagen I gels was strongly enhanced by vitronectin. Vascular endothelial growth factor activation of the p44/p42 mitogen-activated protein kinase pathway, which is required for angiogenesis, was supported by adhesion through either alpha1beta1, alpha2beta1, alphavbeta3, or alphavbeta5, and pharmacologic inhibition of this pathway blocked proliferation and suppressed survival. Therefore, these studies establish that the alpha1beta1, alpha2beta1, alphavbeta3, and alphavbeta5 integrins each support dermal microvascular endothelial cell viability, and that each collaborate with vascular endothelial growth factor to support robust activation of the mitogen-activated protein kinase pathway which mediates both proliferation and survival. Moreover, survival is supported most significantly by extracellular matrices, which engage all of these integrins in combination. Consistent with important complementary and overlapping functions, combined antagonism of these integrins provided superior inhibition of angiogenesis in skin, indicating that multiplicity of integrin involvement should be considered in designing strategies for controlling neovascularization.

Animals↗

PubMed1996

Bone sialoprotein coated on glass and plastic surfaces is recognized by different beta 3 integrins.

Integrins have important roles in mediating cell-matrix interactions, essential for cell migration and signaling. In bone, integrins are suggested to play a role through their ability to mediate cell attachment to bone matrix proteins. In the present study, the subunit composition of integrins binding bone sialoprotein and osteopontin coated on either glass or plastic surfaces was analyzed using cells isolated from bone. Thus, integrin antibodies to alpha v beta 3, alpha IIb beta 3, alpha v, alpha IIb, and beta 3 and the peptides GRGDSP and KQAGDV were used to define the integrins involved in the attachment in vitro of a preparation of multinucleated cells expressing the enzyme tartrate-resistant acid phosphatase. Binding to osteopontin coated on either glass or plastic surfaces was mediated via the alpha v beta 3 integrin. Interestingly, the isolated cells bound to bone sialoprotein coated on plastic via the alpha v beta 3 integrin, but used a different integrin, alpha IIb beta 3, when the protein was coated on glass. It appears that bone sialoprotein when coated on glass and plastic, respectively, changes conformation, thereby altering the contact surface and subsequently the binding specificity. Alternatively, the protein contains two different binding sites, selectively exposed on glass or plastic as a result of different protein binding. The results demonstrate that bone sialoprotein contains domains, or can change conformation, such that it can interact with either the alpha IIb beta 3 or the alpha v beta 3 integrin. Whether the integrins were located on the multinucleated cells proper or on platelets bound to these cells could not be unequivocally concluded. The possible presence of platelets should, however, be considered when interpreting data from the isolated osteoclast system.

Acid Phosphatase↗

PubMed1995

The alpha 6 beta 1 and alpha 6 beta 4 integrins in human prostate cancer progression.

Prostatic secretions are formed by glands composed of basal and luminal cells and surrounded by a basal lamina. The normal basal cells express several integrins (extracellular matrix receptors) including alpha 2, 3, 4, 5, 6, v, beta 1 and beta 4. These integrin units are polarized at the base of the cells adjacent to the basal lamina. The integrin alpha 6 beta 4 is associated with hemidesmosomal-like structures. The natural history of prostate cancer involves the presence of prostatic intraepithelial neoplasia (PIN) lesions (considered precursor lesions), carcinoma in situ and invasive carcinoma. Hemidesmosomal proteins and the alpha 3 beta 1 and alpha 6 beta 1 integrins (laminin receptors) are retained in the early PIN lesions. Expression of the integrins alpha 2, alpha 4, alpha 5, alpha v and beta 4 is lost in carcinoma. The alpha 3 beta 1 and alpha 6 beta 1 integrins remain associated with invasive carcinoma, the latter being predominant. Integrin expression in carcinoma is diffuse in the plasma membrane and not restricted to the basal aspects of the cell. The alpha 6 beta 1 integrin is fully functional as judged by an ability to adhere to laminin and contains the wild type alpha 6A cytoplasmic signaling domain. The alpha 6 beta 1 integrin is a leading candidate for conferring the invasive phenotype in prostatic carcinoma. Tumor cells with high expression of alpha 6 integrin are more invasive when tested in a SCID mouse model system. Following intraperitoneal injection, the human tumor cells invade the mouse diaphragm and move through the muscle on the surface of the laminin coated muscle cells. Our current working hypothesis is that the production of alpha 6 beta 1 and laminin in human tumor cells contributes to the invasive phenotype. Invasion could occur on the surfaces of laminin coated structures such as the nerves, blood vessels or muscle and account for the known patterns of human prostate tumor progression. Blockage of the expression or function of alpha 6 beta 1 or laminin or preventing the loss of beta 4 would be essential steps in confining the carcinoma to the prostate gland where conventional treatment has already proven effective.

Amino Acid Sequence↗

PubMed2000

Cell-cell adhesion via the ECM: integrin genetics in fly and worm.

Integrins are essential for the development of the two genetically tractable invertebrate model organisms, the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. Just two integrins are present in C. elegans: one putative RGD binding integrin alphapat-2betapat-3, corresponding to Drosophila alphaPS2betaPS and vertebrate alpha5beta1, alphaVbeta1 and alpha8beta1, and one putative laminin binding integrin alphaina-1betapat-3, corresponding to Drosophila alphaPS1betaPS and vertebrate alpha3beta1, alpha6beta1 and alpha7beta1. In this review, the function of this minimal set of integrins during the development of these two invertebrates is compared. Despite the differences in bodyplan and developmental strategy, integrin adhesion to the extracellular matrix is required for similar processes: the formation of the link that translates muscle contraction into movement of the exoskeleton, cell migration, and morphogenetic interactions between epithelia. Other integrin functions, such as regulation of gene expression, have not yet been experimentally demonstrated in both organisms. Additional proteins have been characterised in each organism that are essential for integrin function, including extracellular matrix ligands and intracellular interacting proteins, but so far different proteins have been found in the two organisms. This in part represents the fact that the characterisation of the full set of interacting proteins is not complete in either system. However, in other cases different proteins appear to be used for similar functions in the two animals. The continued use of genetic approaches to identify proteins required for integrin function in these two model organisms should lead to the identification of the minimal set of conserved components that form integrin adhesive structures.

Animals↗

PubMed2001

Integrin-mediated interactions between human bone marrow stromal precursor cells and the extracellular matrix.

To date, the precise interactions between bone marrow stromal cells and the extracellular matrix that govern stromal cell development remain unclear. The integrin super-family of cell-surface adhesion molecules represents a major pathway used by virtually all cell types to interact with different extracellular matrix components. In this study, purified populations of stromal precursor cells were isolated from the STRO-1-positive fraction of normal human marrow, by fluoresence-activated cell sorting, and then assayed for their ability to initiate clonogenic growth in the presence of various integrin ligands. Bone marrow-derived stromal progenitors displayed differential growth to fibronectin, vitronectin, and laminin, over collagen types I and III, but showed a similar affinity for collagen type IV. The integrin heterodimers alpha1beta1, alpha2beta1, alpha5beta1, alpha6beta1, alpha(v)beta3, and alpha(v)beta5 were found to coexpress with the STRO-1 antigen on the cell surface of CFU-F, using dual-color analysis. Furthermore, only a proportion of stromal precursors expressed the integrin alpha4beta1, while no measurable levels of the integrin alpha3beta1 could be detected. Subsequent adhesion studies using functional blocking antibodies to different integrin alpha/beta heterodimers showed that stromal cell growth on collagen, laminin, and fibronectin was mediated by multiple beta1 integrins. In contrast, cloning efficiency in the presence of vitronectin was mediated in part by alpha(v)beta3. When human marrow stromal cells were cultured under osteoinductive conditions, their ability to form a mineralized matrix in vitro was significantly diminished in the presence of a functional blocking monoclonal antibody to the beta1 integrin subunit. The results of this study indicate that beta1 integrins appear to be the predominant adhesion receptor subfamily utilized by stromal precursor cells to adhere and proliferate utilizing matrix glycoproteins commonly found in the bone marrow microenvironment and bone surfaces. Furthermore, these data suggest a possible role for the beta1 integrin subfamily during the development of stromal precursor cells into functional osteoblast-like cells.

Antibodies, Monoclonal↗

PubMed2002

Adaptor protein-2 exhibits alpha 1 beta 1 or alpha 6 beta 1 integrin-dependent redistribution in rhabdomyosarcoma cells.

Downregulation of several signaling pathways, such as those stimulated by growth factor receptors, occurs by internalization of signaling receptors through clathrin-coated pits. The first step in internalization or endocytosis is interaction with AP-2, which results in coated pit formation by assembly of clathrin to AP-2. Changes in endocytosis are reflected in the distribution of AP-2 molecules at the cell surface. Integrins are receptors which mediate attachment to the extracellular matrix and also stimulate numerous intracellular signaling pathways; however, it is not known how signaling through integrins is terminated or downregulated. Endocytosis through clathrin-coated pits offers an attractive mechanism for this. This work explores the relationship between AP-2 and beta(1) integrins. RD cells grown for 24 h on collagen or laminin exhibit a redistribution of AP-2 to the cell periphery relative to those grown on fibronectin or polylysine. The total AP-2 protein levels in the cells are unaffected. Blocking alpha(1)beta(1) integrin ligand binding on collagen prevents this redistribution fully. On laminin where alpha(1)beta(1) and alpha(6)beta(1) integrins are engaged, both receptors must be simultaneously blocked to prevent AP-2 redistribution, confirming that the redistribution depends on the specific engagement of the receptors. Immunofluorescence reveals that the majority of alpha(1)beta(1) integrins colocalize with alpha(6)beta(1) integrins in linear structures identified as focal adhesions. A separate fraction of alpha(1)beta(1) integrins colocalize with AP-2 in coated pits. Interestingly, alpha(6)beta(1) integrins are not located in coated pits, demonstrating that integrin colocalization with AP-2 is not necessary to induce redistribution of AP-2.

Adaptor Proteins, Vesicular Transport↗

PubMed1996

The alpha1beta1 integrin is expressed during neointima formation in rat arteries and mediates collagen matrix reorganization.

Remodeling of the extracellular matrix by activated mesenchymal cells (myofibroblasts) is a critical aspect of wound repair in all adult organs. Collagen-dependent gel contraction, a process requiring integrin function, is an established in vitro assay thought to mimic in vivo matrix remodeling. Numerous data have implicated the alpha2beta1 integrin in various cell types as the primary collagen receptor responsible for collagen gel contraction. However, evidence from the literature suggests that the major collagen binding integrin expressed on mesenchymally derived cells in situ is the alpha1beta1 integrin, not the alpha2beta1 integrin. In this report, we use a rat vascular injury model to illustrate that the alpha1beta1 integrin is the major collagen receptor expressed on vascular smooth muscle cells after injury. Using two smooth muscle cell lines, expressing either the alpha1beta1 integrin alone or both the alpha1beta1 and alpha2beta1 integrins, along with Chinese hamster ovary cells transfected with the alpha1 integrin, we demonstrate that alpha1beta1 supports not only collagen-dependent adhesion and migration, but also gel contraction. These data suggest that in vivo the alpha1beta1 integrin is a critical collagen receptor on mesenchymally derived cells potentially involved in matrix remodeling after injury.

Animals↗

PubMed2000

Alpha 4 integrin-dependent leukocyte recruitment does not require VCAM-1 in a chronic model of inflammation.

Rats immunized with Mycobacterium butyricum in Freund's adjuvant develop a chronic vasculitis, with large increases in leukocyte rolling and adhesion in mesenteric postcapillary venules that are significantly inhibited with an alpha 4 integrin Ab. Using intravital microscopy to visualize chronically inflamed microvessels, we demonstrated that alpha 4 integrin-dependent leukocyte rolling and adhesion was inhibited with a beta 1 integrin, but not a beta 7 integrin Ab. To date, VCAM-1 has been presumed to be the primary ligand for alpha 4 beta 1 integrin in the vasculature. However, alpha 4 beta 1 integrin-dependent interactions were not reduced by monoclonal or polyclonal VCAM-1 Abs or a VCAM-1 antisense oligonucleotide despite increased VCAM-1 expression in the mesenteric vasculature. To ensure that the VCAM-1 Abs were functional and used at saturating concentrations, blood from Ab-treated rats was perfused over monolayers of CHO cells transfected with rat VCAM-1. Sufficient alpha 4 integrin or VCAM-1 Ab was present to inhibit leukocyte interactions with rat VCAM-1 by 95-100%. Under in vitro flow conditions, only mononuclear leukocytes were recruited from blood of control rats onto purified VCAM-1. However, neutrophils were also recruited onto VCAM-1 from whole blood of adjuvant-immunized animals via alpha 4 integrin. Another ligand for alpha 4 beta 1 integrin is the connecting segment-1 (CS-1) region of fibronectin. An Ab to the CS-1 portion of fibronectin, which did not reduce rolling and adhesion in adjuvant arthritis animals, completely inhibited leukocyte adhesion to CS-1 under static conditions. These findings provide the first evidence that alpha 4 beta 1 integrin-dependent leukocyte rolling and adhesion can occur in vivo via a mechanism other than VCAM-1.

Adjuvants, Immunologic↗

PubMed2000

Potential role of alphav and beta1 integrins as oocyte adhesion molecules during fertilization in pigs.

Integrin molecules are cell adhesion molecules that are thought to be involved in sperm-oocyte interaction in rodents and humans. The objective of this study was to evaluate whether integrin molecules were present on the surface of pig oocytes, consistent with involvement in sperm-oocyte interaction in this species. Immunocytochemistry and confocal microscopy were used to evaluate the presence of beta1, and alpha1, alpha2, alpha3, alpha4, alpha5, alpha6 and alphav integrin subunits on the plasma membrane of pig oocytes. The beta1 and alphav integrin subunits were present consistently at the surface of pig oocytes; however, the remaining alpha integrin subunits evaluated were not routinely detected. The antibodies to the beta1 and alphav integrin subunits recognized appropriately sized protein bands on western blots of partially purified oocyte plasma membrane. These two antibodies also recognized oocyte plasma membrane protein isolated from a sperm plasma membrane affinity column. Sperm plasma membrane proteins of 137 and 93 kDa appeared to be the ligands for the beta1 integrin subunit as revealed by a western sandwich blot. Antibody to an extracellular domain of the beta1 integrin subunit reduced pig sperm-oocyte binding (P < 0.05), also indicating an assisting role for a beta1 oocyte integrin subunit in sperm-oocyte interaction in pigs. These results are consistent with an alphavbeta1 pig oocyte integrin interacting with a ligand on the sperm plasma membrane during fertilization.

Animals↗

PubMed1996

Selective changes in laminin adhesion and alpha 6 beta 4 integrin regulation are associated with the initial steps in keratinocyte maturation.

In skin, the distribution of integrins is compartmentalized. Whereas the alpha 6 beta 4 integrin complex is polarized to the basal portion of proliferating cells in the basal layer juxtaposed to the basement membrane, alpha 3 beta 1 integrin receptors are localized on the cell surface surrounding basal and suprabasal cells, suggesting beta 1 integrins mediate both cell-matrix and cell-cell interactions. As initiation of maturation in skin is associated with the detachment of cells from the basement membrane, the early loss of alpha 6 beta 4, but not alpha 3 beta 1, integrin expression could be a determining factor in the transition from the proliferating to a differentiating keratinocyte. We have studied the regulation of adhesion potential and integrin expression during differentiation of mouse basal keratinocytes culture in 0.05 mM Ca2+ medium and induced to differentiate in 0.12 mM Ca2+ medium. Within 12-24 h after elevation of Ca2+, a selective loss of the alpha 6 beta 4 integrin complex is associated with the induction of the spinous cell marker keratin 1. This early differentiation phenotype coincides with loss of cell attachment mediated by alpha 6 beta 4 to laminins 1 and 5 but not a fibronectin or collagen IV. Selective loss of attachment to laminin is also detected in spinous cells isolated from newborn epidermis in vivo. The loss of alpha 6 and beta 4 protein expression is a consequence of transcriptional and posttranscriptional events, including reduction in mRNA transcripts, reduced synthesis of the alpha 6 protein, and enhanced processing of the alpha 6 and beta 4 chains as determined by Western blots and pulse-chase experiments in metabolically labeled keratinocytes. Selective processing of the beta 4 intracellular domain is detected before loss of beta 4 from the cell surface in basal keratinocytes, and this process is accelerated during differentiation. Whereas early keratinocyte maturation is linked to the selective loss of the alpha 6 beta 4 complex, loss of both beta 1 and beta 4 integrin mRNA and protein occurs as cells proceed to later stages in the differentiation program as induced by 0.5 mM Ca2+ or suspension culture. These conditions are characterized by accelerated expression of transglutaminase; reduced keratin 1 protein; loss of adhesion to fibronectin, laminin 1, laminin 5, and collagen IV; and rapid cell death. Contributing to the down-regulation of beta 1 integrins during terminal differentiation is a selective sensitivity of alpha 3 beta 1 but not alpha 6 beta 4 to down-regulation by transforming growth factors beta 1 and beta 2, factors that are also expressed differentially in normal skin. This study indicates that down-regulation of the alpha 6 beta 4 but not beta 1 integrins occurs during the initial steps of keratinocyte differentiation and is associated with detachment from the laminin matrix. Such changes could contribute an important signal to initiate the process of terminal keratinocyte differentiation.

Animals↗

PubMed1997

Immunolocalization of integrins in the normal lung and in pulmonary carcinomas.

Cryosections of normal adult lung (n = 7) and pulmonary epithelial tumors, including squamous (n = 8), adeno (n = 8), bronchioloalveolar (n = 5), and large cell (n = 4) carcinomas (SCC, ACC, BAC, LCC), carcinoids (Cd, n = 7), and neuroendocrine carcinomas (NEC) of variable grades (n = 14) were immunostained by the avidin-biotin peroxidase (ABC) method with monoclonal antibodies to the alpha1-6 and alpha(v) and the beta1-4 integrin subunits. Normal adult alveolar septae showed variably intense immunoreactivity for alpha1,3,6 and beta1, whereas reactions for alpha5 and alpha(v) were weaker and uneven; the remaining integrin subunits were not detected. Bronchial and bronchiolar epithelium showed variably intense staining for alpha2.3,6,v and beta1,4. Reactions were often, though not invariably, basally polarized. SCC, ADC, and LCC showed variably intense reactions for alpha2.3,6,v and beta1,4. BAC were strongly and uniformly stained for alpha1.3 and beta1. In Cd, alpha1,2,3,v and beta1 reactions were noted, whereas in NEC, weak alpha1,3 and beta1 staining was detected with only traces of alpha6 and alpha(v). We conclude that alveolar epithelial cells do not express the hemidesmosome-associated, laminin-binding integrin alpha6beta4 of the bronchial epithelium but rather the alpha1beta1 and alpha3beta1, collagen IV, and laminin receptors, respectively. SCC, ADC, and sampled LCC express an integrin repertory qualitatively similar to that of the bronchial epithelium. Distinct from the latter, the integrin repertory of BAC parallels that of the alveolar epithelium by its strong expression of the multipotential alpha1beta1 and alpha3beta1 integrins. NEC tumors do not display the laminin receptors alpha6beta4 and alpha6beta1 shown by SCC and ADC but express instead alpha1beta1, a collagen IV-laminin receptor rarely found in epithelial neoplasms except for BAC. In NEC tumors, integrins, especially alpha2, decrease with dedifferentiation. Notably distinct from epithelial mesotheliomas, the major fibronectin-binding integrin alpha5beta1 was not found in any type of lung carcinoma.

Adenocarcinoma↗

PubMed2000

Up-regulation of VCAM-1 and differential expansion of beta integrin-expressing T lymphocytes are associated with immunity to pulmonary Mycobacterium tuberculosis infection.

Immune responses rely on an intricate system of adhesion molecules to coordinate the homing and retention of lymphocytes in both secondary lymphoid tissues and at sites of infection. To define the events associated with pulmonary immune responses, the expression of endothelial addressins and integrins on T cells was analyzed during Mycobacterium tuberculosis infection. In infected lung, expression of endothelial VCAM-1, but not mucosal addressin cell adhesion molecule-1, was up-regulated from 4 wk postinfection and persisted to at least 12 wk. Subsequent analysis of the corresponding integrins expressed on lung CD4+ and CD8+ T cells revealed an accumulation of beta1high/beta7-/low, and to a lesser extent beta7high, integrin-expressing T cells during infection. Examination of integrin heterodimers showed that while alpha4 integrin was predominantly expressed on beta1high/beta7-/low cells, alphaE integrin was primarily associated with beta7high. The majority of activated/memory T cells recruited during infection expressed high levels of beta1 integrin and undetectable or low levels of beta7 integrin. These T cells were capable of producing IFN-gamma, a cytokine crucial for controlling M. tuberculosis infection. Rapid expansion of beta1high, beta7-, and beta7high T cell populations in the lung upon secondary mycobacterial infection indicates the participation of these populations in the acquired immune response to the infection. Furthermore, treatment of infected mice with mAb to alpha4 or alpha4beta7 integrin led to a reduction in lymphocytes and increase in granulocytes in the pulmonary infiltrate. These results reveal a crucial role for adhesion molecules in the generation of an effective pulmonary immune response to M. tuberculosis infection.

Animals↗

PubMed2001

Abnormal pattern of integrin expression at the implantation window in endometrium from fertile women treated with clomiphene citrate and users of intrauterine device.

UNLABELLED: Determine quantitative expression of endometrial integrins that reflect receptivity during implantation window in fertile women treated with clomiphene citrate (CC), and in intrauterine device users (IUD) as compared to fertile controls. Comparative study of the quantitative expression of a1, a4, av and b3 integrins in epithelial and stromal cells in mid-secretory endometrium of CC treated fertile women, IUD users and controls. All subjects included in this study had regular and ovulatory menstrual cycles. SUBJECTS: Ten women treated with a daily dose of 50 mg of CC. Six women T-Cu device users and nine fertile controls. Age ranges for all groups were similar, 29-41 years old (mean 36.3). Tissue samples were taken at the mid-secretory phase or implantation window. A histological dating of the endometrial biopsies was assessed according to Noyes criteria. Ovulation was assessed by repeated transvaginal ultrasonography. The expression of a1, a4, aV and b3 integrins in dispersions of epithelial (EEC) and stromal (ESC) cells isolated from endometrial biopsies was quantitatively determined by flow cytometry using specific monoclonal antibodies. Immunohistochemistry was also used to detect integrin expression. Biopsies from CC-treated women had a high incidence of out-of-phase endometria. Interestingly, CC-treated women over-expressed a1, aV and b3-ESC integrins and under-expressed b3-EEC subunit (P<0.05). IUD users over-expressed the a1-EEC and under-expressed a4-ESC (P<0.05) at the time of the implantation window. CC treatment in fertile women provokes a high frequency of out-of-phase endometrium and desynchronises the expression of endometrial integrins at the implantation window. The epithelial b3 integrin was under-expressed in all CC-treated patients. The T-Cu intrauterine device alters endometrial receptivity by a different mechanism independent of the expression of the epithelial b3 integrin. However, both CC and IUD use alter the expression of some epithelial and stromal integrins during the implantation window.

Adult↗

PubMed2006

Domain 1 of the urokinase-type plasminogen activator receptor is required for its morphologic and functional, beta2 integrin-mediated connection with actin cytoskeleton in human microvascular endothelial cells: failure of association in systemic sclerosis endothelial cells.

OBJECTIVE: In systemic sclerosis (SSc) microvascular endothelial cells (MVECs), angiogenesis is blocked by matrix metalloproteinase 12-dependent cleavage of domain 1 of the urokinase-type plasminogen activator receptor (uPAR). Since integrins are associated with the invasive activity of uPAR in angiogenesis, this study was undertaken to show whether full-size and truncated uPAR are differentially associated with integrins and with motor components of the cytoskeleton. METHODS: SSc and normal MVECs were isolated from human skin biopsy specimens and studied by confocal laser scanning microscopy and immunoprecipitation to assess the mechanisms of association of truncated and full-size uPAR with integrins and the actin cytoskeleton. The integrin composition of the MVECs was studied by reverse transcription-polymerasechain reaction. Cell migration and capillary morphogenesis were studied on fibrinogen substrates. Involvement of Rac and Cdc42 was evaluated by Western blotting. RESULTS: Only full-size uPAR showed a connection with the actin cytoskeleton in ECs. This connection was mediated by the uPAR-associated alphaMu- and alphaX-subunits of beta2 integrin, and was absent from SSc MVECs. The cleaved uPAR was not associated with beta2 integrins or with actin. beta3 integrins were associated with both the full-size and cleaved uPAR at focal contacts. The uncoupling of uPAR from beta2 integrins in SSc MVECs impaired the activation of Rac and Cdc42 (thus inhibiting their mediation of uPAR-dependent cytoskeletal rearrangements and cell motility) and blocked the integrin-engagement-delivered signals to the actin cytoskeleton. Invasion and capillary morphogenesis on fibrinogen-coated substrates indicated that ligation of uPAR by uPA empowers the beta2/beta3 integrin-dependent invasion of fibrinogen, and that this system is impaired in SSc MVECs. CONCLUSION: The reduced angiogenic properties of SSc MVECs can be explained by the effects of uPAR truncation and the subsequent loss of the beta2 integrin-mediated connection of uPAR with the actin cytoskeleton in these ECs.

Actins↗

PubMed2000

alpha5beta1 integrin expression and luminal edge fibronectin matrix assembly by smooth muscle cells after arterial injury.

Fibronectin is secreted from the cell as a soluble protein that must then polymerize to regulate cell function. To elucidate the process of fibronectin matrix assembly in vascular disease, we immunostained sections of balloon-injured rat carotid artery for the fibronectin-binding alpha5beta1 integrin. Whereas alpha5beta1 integrin was not evident in the normal carotid artery, its expression was induced after a vascular injury. By 14 days, the alpha5beta1 integrin was localized exclusively to the less differentiated smooth muscle cells (SMCs) at the luminal surface of the neointima. Platelet-derived growth factor-BB, dominant in neointimal formation, selectively increased the expression of the alpha5beta1 integrin by human SMCs in culture. To track the assembly of fibronectin fibers, fluorescence-labeled soluble fibronectin protomers were added to cultured SMCs and to fresh segments of normal and balloon-injured rat carotid arteries. Fibronectin fiber formation in cultured SMCs could be detected within 10 minutes, and was blocked by an RGD peptide, an anti-beta1 integrin antibody, and an anti-alpha5beta1 integrin antibody, but not by an anti-beta3 integrin antibody. En face confocal microscopy of arterial segments revealed that soluble fibronectin had polymerized on the alpha5beta1 integrin-expressing SMCs of the luminal surface of the injured arterial neointima, but not on the alpha5beta1 integrin-negative neointimal SMCs below this or on the endothelial cells of uninjured arteries. Furthermore, in situ fibronectin assembly by the neointimal SMCs was inhibited by an RGD peptide and by an anti-beta1 integrin antibody. These studies indicate that a subpopulation of SMCs in the repairing artery wall orchestrates integrin-mediated fibronectin assembly.

Actins↗

PubMed2004

Redox modulation of integrin [correction of integin] alpha IIb beta 3 involves a novel allosteric regulation of its thiol isomerase activity.

The molecular mechanisms involved in regulating the activation-dependent conformational switch in integrins are not known although recent evidence suggests that integrins are a direct target for redox modulation. We have identified an endogenous integrin thiol isomerase activity that may be responsible for regulating integrin activation states. The purpose of this study was to examine the effects of redox conditions elicited by nitric oxide and glutathione on the thiol isomerase activity of the platelet integrin alphaIIbbeta3 and also on the activation status of this integrin in intact platelets. The universal integrin activator, Mn2+, stimulates the thiol isomerase activity in purified alphaIIbbeta3. Kinetic analysis reveals that alphaIIbbeta3 is an allosteric enzyme which displays positive cooperativity in the presence of Mn2+ with an apparent Hill coefficient of 1.9. Also, addition of Mn2+ to platelets results solely in activation of the integrin as demonstrated by the binding of the antibody PAC-1. The addition of the nitric oxide donors SNP, SIN-1, and SNOAC in combination with glutathione can directly reverse the activation state of the platelet integrin induced by Mn2+. These compounds have no effect on platelet secretory responses indicating a direct effect on the integrin. In the presence of nitric oxide and glutathione, the enzymatic activity of alphaIIbbeta3 also displays positive cooperativity (apparent Hill coefficient of 1.9), and a significant increase in the saturability of the enzyme was observed. Thus, redox agents simultaneously modulate the thiol isomerase activity of purified alphaIIbbeta3 and its active conformation in intact platelets, suggesting a molecular mechanism for integrin regulation.

Allosteric Regulation↗