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PubMed1998

Interleukin-2 induces beta2-integrin-dependent signal transduction involving the focal adhesion kinase-related protein B (fakB).

beta2 integrin molecules are involved in a multitude of cellular events, including adhesion, migration, and cellular activation. Here, we studied the influence of beta2 integrins on interleukin-2 (IL-2)-mediated signal transduction in human CD4(+) T cell lines obtained from healthy donors and a leukocyte adhesion deficiency (LAD) patient. We show that IL-2 induces tyrosine phosphorylation of a 125-kDa protein and homotypic adhesion in beta2 integrin (CD18)-positive but not in beta2-integrin-negative T cells. EDTA, an inhibitor of integrin adhesion, blocks IL-2-induced tyrosine phosphorylation of the 125-kDa protein but not other proteins in beta2-integrin-positive T cells. Likewise, a beta2 integrin (CD18) antibody selectively inhibits induction of the 125-kDa phosphotyrosine protein, whereas cytokine-mediated tyrosine phosphorylation of other proteins is largely unaffected. Immunoprecipitation experiments indicate that the IL-2-induced 125-kDa phosphotyrosine protein is the focal adhesion kinase-related protein B (fakB). Thus, IL-2 induces strong tyrosine phosphorylation of fakB in beta2-integrin-positive but not in beta2-integrin-negative T cells, and CD18 mAb selectively blocks IL-2-induced fakB-tyrosine phosphorylation in beta2-integrin-positive T cells. In parallel experiments, IL-2 does not induce or augment tyrosine phosphorylation of p125(FAK). In conclusion, our data indicate that IL-2 induces beta2-integrin-dependent signal transduction events involving the tyrosine kinase substrate fakB.

CD18 Antigens↗

PubMed1998

Rack1, a receptor for activated protein kinase C, interacts with integrin beta subunit.

The integrin beta subunit cytoplasmic domains are important for activation-dependent cell adhesion and adhesion-dependent signaling events. We report an interaction between integrin beta subunit cytoplasmic domain and Rack1, a Trp-Asp (WD) repeat protein that has been shown to bind activated protein kinase C. The Rack1-binding site on integrin beta 2 subunit resides within a conserved, membrane-proximal region. In the yeast two-hybrid assay, WD repeats five to seven of Rack1 (Rack1-WD5/7) interact with integrin beta 1, beta 2, and beta 5 cytoplasmic domain. In eukaryotic cells, Rack1 co-immunoprecipitates with at least two different beta integrins, beta 1 integrins in 293T cells and beta 2 integrins in JY lymphoblastoid cells. Whereas Rack1-WD5/7 binds integrins constitutively, the association of full-length Rack1 to integrins in vivo requires a treatment with phorbol esters, which promotes cell spreading and adhesion. These findings suggest that Rack1 may link protein kinase C directly to integrins and participate in the regulation of integrin functions.

Amino Acid Sequence↗

PubMed2002

Hyposialylation of integrins stimulates the activity of myeloid fibronectin receptors.

Despite numerous reports suggesting that beta(1) integrin receptors undergo differential glycosylation, the potential role of N-linked carbohydrates in modulating integrin function has been largely ignored. In the present study, we find that beta(1) integrins are differentially glycosylated during phorbol ester (PMA)-stimulated differentiation of myeloid cells along the monocyte/macrophage lineage. PMA treatment of two myeloid cell lines, U937 and THP-1, induces a down-regulation in expression of the ST6Gal I sialyltransferase. Correspondingly, the beta(1) integrin subunit becomes hyposialylated, suggesting that the beta(1) integrin is a substrate for this enzyme. The expression of hyposialylated beta(1) integrin isoforms is temporally correlated with enhanced binding of myeloid cells to fibronectin, and, importantly, fibronectin binding is inhibited when the Golgi disrupter, brefeldin A, is used to block the expression of the hyposialylated form. Consistent with the observation that cells with hyposialylated integrins are more adhesive to fibronectin, we demonstrate that the enzymatic removal of sialic acid residues from purified alpha(5)beta(1) integrins stimulates fibronectin binding by these integrins. These data support the hypothesis that unsialylated beta(1) integrins are more adhesive to fibronectin, although desialylation of alpha(5) subunits could also contribute to increased fibronectin binding. Collectively our results suggest a novel mechanism for regulation of the beta(1) integrin family of cell adhesion receptors.

Amidohydrolases↗

PubMed1993

Immune complex-stimulated neutrophil LTB4 production is dependent on beta 2 integrins.

The beta 2 integrins (LFA-1, Mac-1, and p150,95) are critical for many adhesive functions of leukocytes. Although the binding of the IgG-opsonized particles occurs normally in the absence of beta 2 integrins, phagocytosis of IgG-opsonized particles by activated neutrophils (PMN) requires these integrins. This observation suggests a role for beta 2 integrins in phagocytosis subsequent to particle binding. To investigate the mechanism of involvement of beta 2 integrins in IgG-mediated functions, we examined the role of beta 2 integrins in adhesion to immune complex (IC)-coated surfaces. Initial adhesion and spreading on IC-coated surfaces were equivalent in control and beta 2-deficient phagocytes. However, both genetically beta 2-deficient PMN and PMN treated with the anti-beta 2 mAb IB4 subsequently detached from the IC-coated surfaces. To determine whether biochemical consequences of IgG activation were also affected by beta 2 deficiency, LTB4 production in response to Fc receptor ligation was assessed. LTB4 production by beta 2-deficient PMN adherent to IC-coated surfaces was markedly decreased in comparison with control PMN. Importantly, LTB4 production by PMN stimulated with fluid phase heat-aggregated IgG also required the beta 2 integrins, showing that the defect was not a simple consequence of abnormal adhesion. In contrast, superoxide production by IC-adherent PMN was equivalent in control and beta 2-deficient PMN. The initial rises in intracytoplasmic [Ca2+]i in response to aggregated IgG also were unaffected by inhibition of beta 2 integrins. These data show that lack of beta 2 integrins does not inhibit all FcR-dependent signal transduction. Finally, LTB4 production by normal PMN adherent to ICs was inhibited by antibodies to FcRII, but not FcRIII, showing that FcRII ligation was required for this effect. Together these data identify a role for the beta 2 integrins in a signal transduction pathway leading to sustained adhesion and LTB4 production in response to IC. Since both beta 2 integrins and FcRII are required for these effects, the data further suggest cooperation between these receptors in generating PMN activation in response to IC stimulation.

Actins↗

PubMed1995

Characterization of beta pat-3 heterodimers, a family of essential integrin receptors in C. elegans.

Members of the integrin family of cell surface receptors have been shown to mediate a diverse range of cellular functions that require cell-cell or cell-extracellular matrix interactions. We have initiated the characterization of integrin receptors from the nematode Caenorhabditis elegans, an organism in which genetics can be used to study integrin function with single cell resolution. Here we report the cloning of an integrin beta subunit from C. elegans which is shown to rescue the embryonic lethal mutation pat-3(rh54) and is thus named beta pat-3. Analysis of the deduced amino acid sequence revealed that beta pat-3 is more similar to Drosophila integrin beta PS and to vertebrate integrin beta 1 than to other integrin beta subunits. Regions of highest homology are in the RGD-binding region and in the cytoplasmic domain. In addition, the 56 cysteines present in the majority of integrin beta subunits are conserved. A major transcript of approximately 3 kilo-base pairs was detected by RNA blot analysis. Immunoblot analysis using a polyclonal antiserum against the cytoplasmic domain showed that beta pat-3 migrates in SDS-PAGE with apparent M(r) of 109 k and 120 k under nonreducing and reducing conditions, respectively. At least nine protein bands with relative molecular weights in the range observed for known integrin alpha subunits coprecipitate with beta pat-3, and at least three of these bands migrate in SDS-PAGE with increased mobility when reduced. This behavior has been observed for a majority of integrin alpha subunits. Immunoprecipitations of beta pat-3 from developmentally staged populations of C. elegans showed that the expression of several of these bands changes during development. The monoclonal antibody MH25, which has been postulated to recognize the transmembrane component of the muscle dense body structure a (Francis, G. R., and R. H. Waterston. 1985. Muscle organization in Caenorhabditis elegans: localization of proteins implicated in thin filament attachment and I-band organization. J. Cell Biol. 101:1532-1549), was shown to recognize beta pat-3. Finally, immunocytochemical analysis revealed that beta pat-3 is expressed in the embryo and in many cell types postembryonically, including muscle, somatic gonad, and coelomocytes, suggesting multiple roles for integrin heterodimers containing this beta subunit in the developing animal.

Amino Acid Sequence↗

PubMed2002

Expression of integrin alphaVbeta3 in pancreatic carcinoma: relation to MMP-2 activation and lymph node metastasis.

INTRODUCTION: Overexpression of integrin alphaVbeta3 had been demonstrated in various tumors. Studies have suggested that elevated levels of integrin alphaVbeta3 in melanoma cells are deeply involved in the mechanism of increased melanoma invasiveness. AIMS: To examine the expression of integrin alphaVbeta3 in pancreatic carcinoma and to evaluate the correlation between integrin expression accompanied by MMP-2 activation and clinicopathologic factors. METHODOLOGY: Integrin alphaVbeta3 specific antibody LM-609 was used for immunochemical analysis, and intracellular localization was determined in human pancreatic cancer cell lines cultured on vitronectin coating. Fifty pancreatic adenocarcinomas analyzed immunohistochemically and 26 frozen samples were analyzed gelatin-zymographically. RESULTS: Two of three pancreatic cancer cell lines demonstrated integrin alphaVbeta3 immunofluorescence with a membranous pattern, and 29 of 50 pancreatic carcinomas showed positive immunostaining of tumor cells. There was no significant correlation between integrin alphaVbeta3 expression and tumor size, tumor grade, or peripancreatic invasion. However, primary tumors with lymph node metastasis featured significantly higher expression of integrin alphaVbeta3 than those without node metastasis. Tumors with high integrin alphaVbeta3 expression showed significantly higher MMP-2 activation ratios than did tumors with low expression. CONCLUSION: Expression analysis in pancreatic cancer tissue demonstrated involvement of alphaVbeta3 integrin in lymph node metastasis rather than peripancreatic invasion. MMP-2 activation is linked, at least in part, to the expression of integrin alphaVbeta3 of pancreatic cancer cells.

Aged↗

PubMed2001

Cardiac expression of a gain-of-function alpha(5)-integrin results in perinatal lethality.

Communication between the extracellular matrix and the intracellular signal transduction and cytoskeletal system is mediated by integrin receptors. alpha(5)beta(1)-Integrin and its cognate ligand fibronectin are essential in development of mesodermal structures, myocyte differentiation, and normal cardiac development. To begin to explore the potential roles of alpha(5)beta(1)-integrin specifically in cardiomyocytes, we used a transgenic expression strategy. We overexpressed two forms of the human alpha(5)-integrin in cardiomyocytes: the full-length wild-type alpha(5)-integrin and a putative gain-of-function mutation created by truncating the cytoplasmic domain, designated alpha(5-1)-integrin. Overexpression of the wild-type alpha(5)-integrin has no detectable adverse effects in the mouse, whereas expression of alpha(5-1)-integrin caused electrocardiographic abnormalities, fibrotic changes in the ventricle, and perinatal lethality. Thus physiological regulation of integrin function appears essential for maintenance of normal cardiomyocyte structure and function. This strengthens the role of inside-out signaling in regulation of integrins in vivo and suggests that integrins and associated signaling molecules are important in cardiomyocyte function.

Animals↗

PubMed2000

Angiotensin II and alpha(v)beta(3) integrin expression in rat neonatal cardiac fibroblasts.

We recently demonstrated that alpha(v)beta(3) integrins are involved in the mechanisms of angiotensin II (Ang II)-induced DNA synthesis and collagen gel contractions in rat cardiac fibroblasts (CFBs), cellular mechanisms that are relevant for cardiac remodeling. The aim of the present study was to elucidate the effect of Ang II and other growth factors on the regulation of the alpha(v)beta(3) integrins in fibroblasts from neonatal rat hearts. The alpha(v)beta(3) integrin receptor expression was significantly increased (P<0.05) at the mRNA level after treatment with Ang II, transforming growth factor-beta(1) (TGF-beta(1)), and platelet-derived growth factor (PDGF) for 8 and 16 hours. The surface expression of the alpha(v) and beta(3) integrin subunits was elevated after 32 and 48 hours (P<0.05) as determined with flow cytometry. To investigate fibroblast motility, we performed chemotaxis experiments with transwell chambers. Ang II was chemotactic for CFBs, as tested with checkerboard experiments. The chemotactic effect was concentration dependent and was completely blocked by Ang II type 1 receptor blockers but not by Ang II type 2 receptor blocker PD 123319. Ang II- and PDGF-BB-mediated chemotaxis could be significantly inhibited by RGD peptides and the blocking antibodies against alpha(v)beta(3) integrin (both P<0.01). Adhesion of CFBs to vitronectin was partially inhibited by an antibody to alpha(v)beta(3) integrin but was mainly mediated by an alpha(v)beta(5) integrin. Relevant in vivo expression of alpha(v)beta(3) integrin by CFBs was confirmed with in situ hybridization with probes for alpha(v) and beta(3) mRNA in rat hearts. The present study demonstrates that the expression of alpha(v)beta(3) integrin is augmented by Ang II, PDGF, and TGF-beta(1) in neonatal CFBs. Furthermore, this integrin is involved in the chemotaxis, motility, and adhesion of CFBs. The present findings support the current concept that integrins participate in the control of fibroblast behavior during cardiac remodeling mechanisms.

Angiotensin II↗

PubMed2000

Talin controls the exit of the integrin alpha 5 beta 1 from an early compartment of the secretory pathway.

Talin is a major cytosolic protein that links the intracellular domains of beta1 and beta3 integrins to the cytoskeleton. It is required for focal adhesion assembly. However, its downregulation not only slows down cell spreading and organization of focal adhesions but also impairs the maturation of some beta1 integrins, including the fibronectin receptor alpha5beta1. To investigate this, we characterized the beta1 integrin synthesized in cells expressing talin anti-sense RNA (AT22 cells). We identified a large intracellular pool of beta1 integrins that is abnormally accumulated in an earlier compartment of the secretory pathway. In this report, we show that in talin-deficient AT22 cells, the aberrant glycosylation of integrin receptors is accompanied by a delay in the export of the integrin alpha5beta1. In normal cells, talin was found associated with beta1 integrins in an enriched membrane fraction containing Golgi and endoplasmic reticulum. Finally, microinjection of anti-talin antibodies resulted in accumulation of the integrins within the cells. These data strongly suggest that talin plays a specific role in the export of newly synthesized integrins. We propose that talin binding to the integrin may disclose a diphenylalanine export signal, which is present in the membrane-proximal GFFKR motif conserved in all integrin alpha chains.

Antisense Elements (Genetics)↗

PubMed2002

Use of an Immobilized Monoclonal Antibody to Examine Integrin alpha5beta1 Signaling Independent of Cell Spreading.

Cell attachment to the extracellular matrix (ECM) engages integrin signaling into the cell, but part of the signaling response also stem from cell spreading (3). To analyze specific integrin signaling-mediated responses independent of cell spreading, we developed a method engaging integrin signaling by use of an immobilized anti-integrin monoclonal antibody (mab) directed against the fibronectin (FN) receptor integrin alpha5beta1. ECV 304 cells were plated onto FN or immobilized mab JBS5 (anti-integrin alpha5beta1) or onto poly-L-lysin (P-L-L), which mediates integrin-independent attachment. Cells attached and spread on FN, while cells on JBS5 or P-L-L attached but did not spread. Importantly, plating onto FN or mab JBS5 gave rise to identical integrin-induced responses, including a down-regulation of the cyclin-dependent kinase (Cdk2) inhibitors p21(CIP1) and p27(KIP1), while attachment to P-L-L did not. We conclude that engagement of the FN-receptor integrin alpha5beta1 induces integrin signaling regulating the Cdk2-inhibitors independent of cell spreading and present a method for how integrin signaling can be analyzed separate from the effects of cell spreading.

Journal Article↗

PubMed2001

Role of alphavbeta3 integrin receptor in the invasive potential of human cervical cancer (SiHa) cells.

One of the most important cell surface receptors in tumor development is alphavbeta3. To study the role of the alphavbeta3 integrin receptor in the invasive properties of tumor cells, we used human cervical tumor cells SiHa (cell surface alphavbeta3 integrin receptor-positive) and HeLa cells (cell surface alphavbeta3 integrin receptor-negative). Cell adhesion assay showed that SiHa and HeLa cells can bind very efficiently to extracellular matrix proteins fibronectin, laminin, and collagen IV, but the binding of HeLa cells to vitronectin is very poor compared to that of SiHa cells. Comparative invasion assay demonstrated a much lower invasive potential of HeLa cells than SiHa cells. Cell surface alphav and beta3 integrin receptor subunit assay showed the expression of alphavbeta3 integrin receptor on the SiHa cell surface, whereas the HeLa cell surface lacks functional alphavbeta3 heterodimer. The zymogram demonstrated a higher gelatinase/MMP-2 activity in culture medium, whole cell, and membrane extract of SiHa cells than that in HeLa cells. The alphavbeta3 integrin receptor-associated MMP-2 activity of SiHa and HeLa cells was tested in a comparative zymography that clearly showed very high gelatinase/MMP-2 activity in alphav mAb-immunoprecipitated fraction of SiHa cell (containing alphavbeta3 heterodimer) but not in the alphav mAb-immunoprecipitated fraction of HeLa cell membrane extract (containing only the beta3 subunit). Immunoblot assay of alphav monoclonal antibody-immunoprecipitated alphavbeta3 integrin receptor from SiHa cell membrane extract with MMP-2 monoclonal antibody demonstrated the association of MMP-2 protein with alphavbeta3 integrin receptor. We concluded that alphavbeta3 integrin receptor is one of the most important cell surface molecules regulating the invasive property of cervical tumor cells because of its associated gelatinase/MMP-2 activity. Our findings will contribute to a better understanding of the role of integrin receptors, especially of the alphavbeta3 integrin receptor, in the invasive property of cancer cells and possibly affect future therapeutic approaches to cancer invasion and metastasis.

Cell Membrane↗

PubMed2001

Loss of motility-related protein 1 (MRP1/CD9) and integrin alpha3 expression in endometrial cancers.

BACKGROUND: MRP1/CD9 and integrin alpha3 have played crucial roles in cell adhesion, motility, and signaling events. The loss of MRP1/CD9 and integrin alpha3 has been involved in tumor growth and metastasis of cancer cells. The aim of the current study was to clarify the clinical significance of MRP1/CD9 and integrin alpha3 in endometrial cancer. METHODS: The expression of MRP1/CD9 and integrin alpha3 from the same tissue sample were examined immunohistochemically in 15 patients with normal endometrium and in 56 patients with uterine endometrioid adenocarcinoma. Disease-free survival curves were estimated using the Kaplan-Meier method and analyzed by the log-rank test between the positive and reduced expression statuses of both MRP1/CD9 and integrin alpha3. These expressions and clinicopathologic variables were analyzed univariately and multivariately. RESULTS: In normal endometrium, MRP/CD9 was expressed at the cell membrane of cell contact sites, and the expression of integrin alpha3 was detected also at the cell membrane of cell contact sites and at borders of stromal tissues. In patients with endometrioid adenocarcinoma, 17 cases showed reduced expression of MRP1/CD9, and 20 cases had reduced expression of integrin alpha3. Fourteen cases indicated a reduced expression of both MRP1/CD9 and integrin alpha3. Each reduced expression of MRP1/CD9 or integrin alpha3 was significantly correlated with histologic grade and metastasis. Multivariate analysis using the Cox regression model disclosed that age at surgery, metastasis, and expression status of MRP1/CD9 were significant prognostic factors for disease-free survival. CONCLUSIONS: These findings suggested that the analysis for the expression statuses of MRP1/CD9 and integrin alpha3 may provide important information on the clinical behavior of endometrial cancer.

Antigens, CD↗

PubMed1993

Coordinate expression of beta 1 and beta 2 integrin "activation" epitopes during T cell responses in secondary lymphoid tissue.

The monoclonal antibodies (mAb) 15/7 and 24 recognize unique activation-dependent, conformational epitopes on beta 1 and beta 2-integrins, respectively. The expression of both of these epitopes closely correlates with the ligand binding ability of their respective integrins, and thus serves as indicators of functional integrin "activation". Here, we have used six-parameter flow cytometry to examine the expression of these epitopes and conventional beta 1- and beta 2-integrin epitopes during human T cell activation in secondary lymphoid tissues in vivo, focusing particularly on the virgin to memory/effector cell transition. Fresh tonsil lymphocytes were stained with mAb against conventional or activation-dependent integrin epitopes, followed by staining with mAb against CD3, CD45RA, and CD45RO, thus allowing the determination of integrin epitope expression on virgin (CD3+) T cells (CD45RA+/RO-to+/-), memory/effector (CD45RA-/RO++) T cells, and T cells undergoing the virgin to memory/effector transition: transition region-1 (T1; CD45RA+to++/RO+); -2 (T2; CD45RA++/RO++); and -3 (T3; CD45RA+/RO++). Conventional beta 1- and beta 2-integrin epitopes progressively increase during the virgin to T3 stages of the transition in tonsil, in keeping with the generally higher levels of these adhesion molecules on memory/effector vs. virgin T cells. Expression of both the beta 1 (15/7)- and beta 2 (24)-integrin activation epitopes first appears on transitional T cells, and is maintained on a relatively constant number of cells (averaging 25-30%) throughout the T1-T3 stages. These epitopes are also noted on a subset of activated memory/effector T cells. Importantly, on both transitional and activated memory/effector T cell subsets, the expression patterns of the 15/7 and 24 epitopes vs. a variety of T cell activation antigens are identical, and the expression of these epitopes relative to each other is linearly correlated, findings strongly supporting the coordinate activation of beta 1 and beta 2 integrins during T cell activation in vivo. These results provide the first evidence of integrin activation during an in vivo immunologic response, and demonstrate the usefulness of mAb recognizing conformational epitopes and multiparameter flow cytometry in delineating the dynamic interplay of adhesion molecules during complex physiologic processes.

Adolescent↗

PubMed1992

Immunohistochemical localization of beta 1-integrins in anterior cruciate and medial collateral ligaments of human and rabbit.

The integrins are a family of adhesion-mediating cell surface receptors that play critical roles in cell-extracellular matrix interactions and have been shown to be important in the healing response in several tissues. We have studied integrin expression in normal human and rabbit anterior cruciate (ACL) and medial collateral (MCL) ligaments of the knee as a preamble to studies of beta 1-integrin expression in healing ligaments. Histologic sections of human and rabbit ACL and MCL were probed for integrin expression utilizing integrin-specific monoclonal antibodies (mAbs) followed by immunoperoxidase detection. Staining of human specimens with mAbs revealed the presence of beta 1-, alpha 1-, and alpha 5-integrin chains on the tissue fibroblasts of both ACL and MCL, while staining of rabbit specimens with rabbit integrin-reactive monoclonals revealed the presence of beta 1- and alpha 5-integrin on these ligaments. Equivalent amounts of the integrins studied were present on normal ACL and MCL. We conclude that the rabbit is an appropriate model for analyzing the expression and functional role of integrins in ligament wound healing.

Animals↗

PubMed1995

Distribution and quantification of alpha 1-integrin subunit in rat organs.

The alpha 1 beta 1-integrin is known to be a receptor for collagen and laminin mediating cell-matrix interactions. A monoclonal antibody, 33.4, which specifically inhibits the alpha 1-integrin-mediated in vitro cell-collagen binding of rat hepatocytes and hepatoma-derived A-cells (Löster et al., 1994), was used to purify by immunoaffinity chromatography the alpha 1-integrin subunit from rat liver in large quantities for inducing a polyclonal antiserum. In immunoblot analysis on membrane extracts of several rat organs this polyclonal antiserum recognized only a 190 kDa-band, suggesting that it is highly specific for the alpha 1-integrin subunit. A sandwich-ELISA with monoclonal antibody 33.4 and the polyclonal antiserum against the alpha 1-integrin subunit, respectively, enabled the quantitative expression pattern of the alpha 1-integrin subunit to be studied in different rat organs. With the exceptions of brain (not detectable) and muscle (low concentration), the alpha 1-integrin subunit was detectable in almost all organs of the digestive, respiratory and urogenital system as well as in lymphatic organs. The highest relative concentrations of alpha 1-integrin subunit were found in uterus, lung and spleen, whereas in seminal vesicle, stomach, parotid gland, epididymis, kidney and liver only modest concentrations were evident. The organ distribution and localization of alpha 1-integrin subunit were studied by immunohistochemistry with monoclonal and polyclonal antibodies. Immunoreactivity was present in the plasma membranes of all smooth muscle cells, vascular endothelial cells of many organs and fibrocyte-fibroblast sheaths in the heart and kidney. Since these cells are in close contact with collagen-containing basal membranes as well as reticular fibrils, strong evidence exists that in rat tissues the alpha 1-integrin subunit is expressed at sites where collagen is present and might be involved in vivo in cell-collagen binding.

Animals↗

PubMed2001

Differential expression of integrin alpha v and beta 3 in serosal tissue of human intraperitoneal organs and adhesion.

OBJECTIVE: To assess the expression of integrin alpha v and beta 3 in the serosal tissue of intraperitoneal organs and adhesions in persons with and without adhesions. DESIGN: Prospective study. SETTING: Academic research centers. PATIENT(S): Fifty-seven patients undergoing abdominal or pelvic surgery. MAIN OUTCOME MEASURE(S): Integrin alpha v and beta 3 messenger RNA (mRNA) expression was evaluated by quantitative reverse transcription polymerase chain reaction. RESULT(S): The serosal tissue of the parietal peritoneum, uterus, fallopian tubes, ovary, and the large and small bowel, as well as peritoneal adhesions, skin, fascia, subcutaneous tissue, and omentum, expresses integrin alpha v and beta 3 mRNA. The level of alpha v and beta 3 mRNA expression varied among these tissues; expression of the former substance was highest in uterine serosa and lowest in the skin and small bowel, and expression of the latter substance was highest in the fallopian tubes and skin and lowest in the uterine serosa. Parietal peritoneum and adhesions express equal levels of integrin alpha v; however, integrin beta 3 expression was >100-fold lower in adhesions than in peritoneum. The level of integrin beta 3 expression in omentum, small and large bowels, and subcutaneous tissue was 100-fold to 10,000-fold lower than in other tissues. CONCLUSION(S): Serosal tissue of peritoneal organs and adhesions express variable levels of integrin alpha v and beta 3 mRNA. On the basis of such variation and the knowledge that tissue injury alters local integrin expression, integrins may play a key role in adhesion development, particularly in tissue with higher integrin expression.

Adult↗

PubMed1998

Downregulation of the beta4 integrin subunit in prostatic carcinoma and prostatic intraepithelial neoplasia.

Integrins are adhesion receptors thought to be important in the process of cancer cell invasion and metastasis. Unlike other integrins, which attach a cell to extracellular matrix molecules, the alpha6beta4 integrin participates in the formation of hemidesmosomes, attaching epithelial cells to the basement membrane. Investigations of the alpha6beta4 integrin in human prostatic carcinoma have yielded conflicting results and have been primarily qualitative rather than quantitative. Expression of the beta4 integrin subunit was determined using rat monoclonal antibody 439-9B and image analysis in regions of benign prostatic epithelium (BPE), high-grade prostatic intraepithelial neoplasia (PIN), and prostatic carcinoma (CaP) in 38 patients treated by radical prostatectomy for clinically localized CaP. The beta4 integrin subunit was significantly downregulated in CaP compared with BPE; PIN stained intermediate in intensity between BPE and CaP. Thirty-four of 35 patients showed downregulation of the beta4 integrin subunit, and all 15 patients with PIN had downregulation of beta4 in PIN as compared with BPE. Degree of downregulation of the beta4 integrin subunit did not add prognostic significance to the information present at initial biopsy (age, clinical stage, clinical grade, and serum prostate-specific antigen level). There was no correlation between intensity of staining of CaP, absolute change in staining, or percent loss of beta4 integrin subunit staining with age, pathological stage, or Gleason's score. Downregulation of the beta4 integrin in CaP and PIN compared with BPE may be correlated with neoplastic transformation of the prostate and loss of hemidesmosomes or basal epithelial cells.

Aged↗

PubMed2003

AlphaV- and beta1-integrin subunits are commonly expressed in malignant effusions from ovarian carcinoma patients.

OBJECTIVE: The objective was to study expression of alphav- and beta1-integrin subunits in effusions, primary tumors, and solid metastases of ovarian carcinoma patients, as well as to evaluate its potential association with previously studied metastasis-associated molecules and clinicopathologic parameters. METHODS: Sections from 121 malignant effusions and 30 corresponding primary and metastatic lesions were evaluated for protein expression of the alphav- and beta1-integrin subunits using immunohistochemistry (IHC). A subset of effusions was additionally studied using immunoblotting (IB) and flow cytometry (FCM). mRNA in situ hybridization (ISH) was performed in 58 effusions and 30 biopsies. RESULTS: Protein expression of alphav- and beta1-integrin subunits was detected in carcinoma cells in 116/121 (96%) and 113/121 (93%) effusions, respectively. alphav protein expression was limited to carcinoma cells. IB and FCM confirmed IHC results. mRNA for alphav- and beta1-integrin subunits was detected in carcinoma cells in 37/58 (64%) and 33/58 (57%) effusions, respectively. Both protein and mRNA expression were higher in peritoneal effusions, significantly for alphav mRNA (P = 0.042) and beta1 protein (P = 0.023). beta1 protein expression in effusions was more frequently detected in better-differentiated tumors (P = 0.006). alphav-integrin subunit expression correlated with that of the previously studied matrix metalloproteinase-9 (MMP-9) (P = 0.006) and the MMP inducer EMMPRIN (P = 0.001). Expression of beta1-integrin subunit showed an association with that of EMMPRIN (P = 0.029), basic fibroblast growth factor (P < 0.001), and the MMP inhibitor TIMP-2 (P = 0.025). In carcinoma cells of solid lesions, alphav protein was uniformly present, while beta1 expression was limited to 15/30 (50%) specimens. As in effusions, protein expression of alphav subunit was cancer-specific, while beta1 protein was detected also in stromal fibroblasts and endothelial cells. CONCLUSIONS: The alphav- and beta1-integrin subunits are frequently expressed in ovarian carcinoma cells in effusions, and the alphav-integrin subunit is a powerful diagnostic marker for carcinoma cells. The reduced expression of the beta1-integrin subunit in solid lesions may be attributed to the role of other subunits at these stages, such as the beta3 subunit as part of the alphavbeta3-vitronectin receptor. The high expression of integrin subunits with a role of binding mesothelium, invasion, and angiogenesis in carcinoma cells in both peritoneal and pleural effusions suggests that cells at both sites have metastatic potential.

Adult↗