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PubMed2006

Retinal pigment epithelial cells synthesize laminins, including laminin 5, and adhere to them through alpha3- and alpha6-containing integrins.

PURPOSE: Retinal diseases are often accompanied by changes in the structure of the multilayered extracellular matrix underlying the retina, Bruch's membrane (BrM). These structural revisions potentially lead to alterations in retinal pigment epithelium (RPE) adhesion, likely via modification of interactions with extracellular matrix (ECM) proteins including laminins in BrM. The purpose of this study was to identify specific laminins in BrM and their receptors in RPE cells. METHODS: The laminin composition of BrM was determined using biochemical, molecular biological, and immunohistochemical techniques of rat, bovine, and human tissue and cell lines. An adhesion assay was used to test RPE attachment to laminins and the receptors used for this attachment. RESULTS: BrM contained laminin chains that could form laminin heterotrimers including laminins 1, 5, 10, and 11. RPE cells synthesized these laminin chains in vitro. Therefore, RPE cells may synthesize BrM laminins. The RPE cells preferentially adhered to potential BrM laminins. Although the cells adhered to the BrM component collagen IV, these cells preferentially adhered to laminins. Of the laminins tested, the RPE cells adhered preferentially to laminin 5. The cells interacted with these laminins via specific integrins and attained a different morphology on each laminin. In particular, the RPE cells rapidly attached and flattened on laminin 5. CONCLUSIONS: BrM contains specific laminins, and RPE cells express integrin receptors for those laminins. The interaction of these specific laminins and integrins most likely leads to differential behavior of RPE cells.

Animals↗
PubMed2005

Immunohistochemistry of adhesion molecules, metalloproteinases and NO-synthases in extravillous trophoblast of tubal pregnancy.

Trophoblast invasion in uterine pregnancy is fine-tuned for the remodelling of the uterine wall and its vascularization. Tubal pregnancy, which occurs in a limited number of patients, involves a dramatic trophoblast invasion in a context of a poor decidualization. By studying the histology of the extravillous trophoblast (EVC) in the anchoring villi, the Ki67 labelling, the location of several adhesion markers (cytokeratin-7, alpha1, alpha6, alphaV, beta1, beta4 integrin subunits and E-cadherin, V/E-cadherin), metalloproteinases (MMP-2, 9 and11), NOS2 and 3, we aimed to detect the specificity of tubal compared to intrauterine pregnancies. No difference could be observed between meso or anti-salpingial trophoblast proliferation or invasion using Ki67. Cytokeratin-7 allowed detection of spindle-shape EVCs and we identified some decidualized stromal cells. Integrins alpha1, beta1 and alphaV, and V/E-cadherin were expressed mainly in the distal EVC correspondingly to intrauterine pregnancy, with a poor expression of alpha1. Integrins alpha6 and beta4, E-cadherin were detected in the distal EVC in contrast to uterine pregnancy. MMP-2, 9, 11 were also shown in distal EVC. NOS2 and 3 labelled the perivascular EVC and NOS3 the endothelial cells of the tubal vessels. These changed distributions of adhesion molecules and MMP together with that of the basic and inducible NOS expressions could be related to mechanical effects in superficial implantation or to a failure of decidualization in tubal pregnancies.

Biomarkers↗
PubMed2003

Role of multiple beta1 integrins in cell adhesion to the disintegrin domains of ADAMs 2 and 3.

ADAM disintegrin domains can support integrin-mediated cell adhesion. However, the profile of which integrins are employed for adhesion to a given disintegrin domain remains unclear. For example, we suggested that the disintegrin domains of mouse sperm ADAMs 2 and 3 can interact with the alpha6beta1 integrin on mouse eggs. Others concluded that these disintegrin domains interact instead with the alpha9beta1 integrin. To address these differing results, we first studied adhesion of mouse F9 embryonal carcinoma cells and human G361 melanoma cells to the disintegrin domains of mouse ADAMs 2 and 3. Both cell lines express alpha6beta1 and alpha9beta1 integrins at their surfaces. Antibodies to the alpha6 integrin subunit inhibited adhesion of both cell lines. An antibody that recognizes human alpha9 integrin inhibited adhesion of G361 cells. VLO5, a snake disintegrin that antagonizes alpha4beta1 and alpha9beta1 integrins, potently inhibited adhesion of both cell lines. We next explored expression of the alpha9 integrin subunit in mouse eggs. In contrast to our ability to detect alpha6beta1, we were unable to convincingly detect alpha9beta1 integrin on the surface of mouse eggs. Moreover, treatment of mouse eggs with 250 nm VLO5, which is 250 fold over its approximately IC(50) for inhibition of somatic cell adhesion, had minimal effect on sperm-egg binding or fusion. We did detect alpha9 integrin protein on epithelial cells of the oviduct. Additional studies showed that antibodies to the alpha6 and alpha7 integrins additively inhibited adhesion of mouse trophoblast stem cells and that an antibody to the alpha4 integrin inhibited adhesion of MOLT-3 cells to these disintegrin domains: Our data suggest that multiple integrins (on the same cell) can participate in adhesion to a given ADAM disintegrin domain and that interactions between ADAMs and integrins may be important for sperm transit through the oviduct.

ADAM Proteins↗
PubMedDate not supplied

Different phenotypes in human prostate cancer: alpha6 or alpha3 integrin in cell-extracellular adhesion sites.

The distribution of alpha6/alpha3 integrin in adhesion complexes at the basal membrane in human normal and cancer prostate glands was analyzed in 135 biopsies from 61 patients. The levels of the polarized alpha6/alpha3 integrin expression at the basal membrane of prostate tumor glands were determined by quantitative immunohistochemistry. The alpha6/alpha3 integrin expression was compared with Gleason sum score, pathological stage, and preoperative serum prostate-specific antigen (PSA). The associations were assessed by statistical methods. Eighty percent of the tumors expressed the alpha6 or alpha3 integrin and 20% was integrin-negative. Gleason sum score, but not serum PSA, was associated with the integrin expression. Low Gleason sum score correlated with increased integrin expression, high Gleason sum score with low and negative integrin expression. Three prostate tumor phenotypes were distinguished based on differential integrin expression. Type I coexpressed both alpha6 and alpha3 subunits, type II exclusively expressed alpha6 integrin, and type III expressed alpha3 integrin only. Fifteen cases were further examined for the codistribution of vinculin, paxillin, and CD 151 on frozen serial sections using confocal laser scanning microscopy. The alpha6/alpha3 integrins, CD151, paxillin, and vinculin were present within normal glands. In prostate carcinoma, alpha6 integrin was colocalized with CD 151, but not with vinculin or paxillin. In tumor phenotype I, the alpha6 subunit did not colocalize with the alpha subunit indicating the existence of two different adhesion complexes. Human prostate tumors display on their cell surface the alpha6beta1 and/or alpha3beta1 integrins. Three tumor phenotypes associated with two different adhesion complexes were identified, suggesting a reorganization of cell adhesion structures in prostate cancer.

Alleles↗
PubMed1996

Cleavage of the alpha6A subunit is essential for activation of the alpha6Abeta1 integrin by phorbol 12-myristate 13-acetate.

The alpha6 integrin subunit is proteolytically cleaved during biosynthesis in a covalently associated heavy and light chain. To examine the importance of cleavage for the function of the alpha6 subunit, we introduced mutations in the cDNA encoding the RKKR (876-879) sequence, the presumed cleavage site, in which either one or two basic residues were replaced by glycine. Wild-type and mutant alpha6A cDNAs (alpha6GKKR, alpha6RKKG and alpha6RGGR) were transfected into K562 cells. The mutant alpha6A integrin subunits were expressed in association with endogenous beta1, at levels comparable to that of the wild-type alpha6Abeta1. A single alpha6A polypeptide chain (150 kDa) was precipitated from surface-labeled alpha6GKKR, alpha6RKKG, and alpha6-RGGR transfectants, while the separate heavy (120 kDa) and light chains (31 or 30 kDa) were precipitated from the wild-type alpha6RKKR transfectant. Thus, a change in the RKKR sequence prevents cleavage of alpha6. After activation by the anti-beta1 stimulatory mAb TS2/16 both cleaved and uncleaved alpha6Abeta1 integrins bound and spread on laminin-1. Remarkably, the phorbol ester phorbol 12-myristate 13-acetate, which activates wild-type alpha6Abeta1 to bind to laminin-1, did not activate uncleaved alpha6Abeta1. We conclude that uncleaved alpha6Abeta1 is capable of ligand binding and transducing outside/in signals, like wild-type alpha6A-beta1. However, inside/out signaling is affected. It appears that cleavage of alpha6 is required to generate the proper conformation in alpha6 that enables affinity modulation of the alpha6A-beta1 receptor by phorbol 12-myristate 13-acetate.

Amino Acid Sequence↗
PubMed2000

Establishment and characterization of a human gastric carcinoma cell line that is highly metastatic to lymph nodes.

The actual mechanisms by which carcinoma cells metastasize to lymph nodes are still unclear, and there is a need to establish in vivo experimental models suitable for the investigation of lymph node metastasis. For the purpose, we established a highly lymph node-metastasizing line, designated AZL5G, derived from a human gastric cancer cell line, AZ521, which had low capacity for lymph node metastasis. AZL5G cells transplanted orthotopically in the nude mouse stomach metastasize predominantly to the regional lymph nodes, showing little potential for hematogenous metastasis. AZL5G tumors developing in the stomach and regional lymph nodes showed poorly differentiated adenocarcinoma with medullary growth, and their histologic appearance strongly resembled that of parental AZ521. The growth activities in vitro of low-metastatic AZ521 and high-metastatic AZL5G were almost the same, but the tumorigenicity in vivo of AZL5G was significantly higher than that of AZ521. AZL5G cells also showed clearly higher abilities of cell locomotion and adhesion to type IV collagen and fibronectin in vitro as compared with AZ521 cells. Flow cytometric analysis demonstrated that the expression of integrin beta1 subfamily except for alpha6 integrin was generally increased in AZL5G cells than in AZ521 cells. Especially, the expression of alpha1 and alpha2 integrins in AZL5G cells was clearly higher than in AZ521, while alpha(v)beta3 integrin, E-cadherin, ICAM-1 and CD44H were not expressed by either cell line. The cell adhesion blocking assay showed that DGEA-containing peptide, which is composed of alpha2 integrin recognition sequence, significantly reduced the adhesiveness of AZL5G cells to type IV collagen as well as to type I collagen and laminin. Furthermore, the administration of anti-alpha2 integrin mAb or DGEA peptide in AZL5G-transplanted nude mice produced a significant reduction in the number of lymph node metastases. These data suggest that the up-regulation of alpha2 integrin expression by gastric cancer cells may play a critical role in the process of lymph node metastasis through the increased adhesiveness to type IV collagen. In conclusion, we established a gastric cancer cell line, AZL5G, with a highly metastatic potential to lymph nodes. This well-characterized line and its in vivo experimental model should be useful for investigation of the mechanisms of lymph node metastasis and for establishment of a new therapeutic approach for human gastric cancer.

Animals↗
PubMed2003

Low molecular weight fucoidan and heparin enhance the basic fibroblast growth factor-induced tube formation of endothelial cells through heparan sulfate-dependent alpha6 overexpression.

Basic fibroblast growth factor (FGF-2) activates its high-affinity receptors (FGFRs) but also acts through interaction with heparan sulfate proteoglycans (HSPG). Exogenous polysaccharides also modulate the angiogenic activity of FGF-2. We investigated the effect and mechanism of action of a low molecular weight fucoidan derivative (LMWF) on tube formation by human endothelial cells. LMWF has a better arterial antithrombotic potential in animals than low molecular weight heparin (LMWH). After stimulation of human umbilical vein endothelial cells (HUVEC) by FGF-2 and LMWF (or LMWH), we observed 1) using flow cytometry, an increase in the amount of the alpha6 integrin subunit; 2) using quantitative reverse transcription-polymerase chain reaction, an increase in alpha6 mRNA (higher with LMWF than with LMWH); and 3) using a Matrigel model, an increase in vascular tube formation (also higher with LMWF than with LMWH). A direct link between alpha6 overexpression and vascular tube formation was confirmed by use of an anti-alpha6 antibody: in its presence, there was no capillary network formation on Matrigel. Unexpectedly, an anti-FGFR blocking antibody had no effect on alpha6 over-expression, whereas stripping off the heparan sulfate with heparitinases abolished overexpression. Overall, our data suggest that FGF-2 stimulates alpha6 over-expression in HUVEC, through HSPG but independently from FGFR, and that LMWF (or LMWH) modulates this interaction. Expression of heparan sulfate proteoglycan increases after ischemic injury. Given its antithrombotic properties and its ability to potentiate tube formation of endothelial cells, LMWF may have to be considered for revascularization of ischemic areas.

Cells, Cultured↗
PubMed1999

Biogenesis of alpha6beta4 integrin in a human colonic adenocarcinoma cell line involvement of calnexin.

The heterodimer alpha6beta4 is a major integrin and the main laminin receptor in epithelia. The alpha6 integrin subunit is proteolytically cleaved, probably by furin, and glycosylated during its biosynthesis. In the present work, we have investigated the kinetics of the assembly process of alpha6beta4 heterodimers in the colonic adenocarcinoma cell line HT29-D4. We demonstrate that the association of alpha6 and beta4 precursors occurs within the ER, while the endoproteolytic cleavage of pro-alpha6 occurs later, probably in the trans-Golgi network. When pro-alpha6 was blocked within the ER by treatment with brefeldin A, its maturation processing was completely prevented without any consequence on its association with beta4 subunit. Low temperature (20 degrees C) also blocked pro-alpha6 maturation, like brefeldin A, but in addition impaired the integrin assembly. Calnexin, an ER resident protein chaperone, was found to be associated with both the alpha6 and beta4 subunit precursors. Our data suggest that calnexin might be responsible for the prolonged retention of pro-alpha6 within the ER compartment and for the defect of integrin subunit association observed at low temperature.

Adenocarcinoma↗
PubMed2000

Alpha integrin subunits regulate human (Caco-2) intestinal epithelial proliferation and phenotype.

BACKGROUND/AIMS: Cell-matrix interactions influence intestinal epithelial biology, but the whether specific integrin heterodimers exert different effects is unclear. METHODS: We used functional antibodies to investigate effects of the alpha2, alpha3, alpha5, and alpha6 integrin subunits on proliferation and differentiation of human intestinal Caco-2 cells on laminin. Cells seeded onto laminin-coated inserts in defibronectinized medium were treated with functional antibodies or normal IgG for 72 hrs and proliferation, alkaline phosphatase and dipeptidyl dipeptidase specific activity were measured. RESULTS: Caco-2 adhesion to antibody to each alpha-integrin subunit stimulated tyrosine phosphorylation of Focal Adhesion Kinase and paxillin, suggesting that these antibodies intiate integrin-related tyrosine signalling. Proliferation was inhibited by anti-alpha2 and anti-alpha3, but stimulated by anti-alpha6. Alkaline phosphatase and dipeptidyl dipeptidase specific activity were promoted by alpha2 blockade but decreased after a6 blockade. Proliferative blockade using mitomycin C or hydroxyurea prevented the effects of alpha2 ligation on differentiation, but the decrease in alkaline phosphatase specific activity observed after a6 integrin subunit blockade was preserved even after proliferative blockade. CONCLUSION: lntegrin heterodimers modulate human Caco-2 intestinal epithelial biology on laminin in an alpha-subunit specific manner. The different effects of anti-alpha2 and anti-alpha6 may reflect competitition by these antibodies with integrin subunit interactions with laminin as well as initiation of their own signals or different functions for the alpha6 integrin subunit

Antibodies↗
PubMed2002

The PDZ domain of TIP-2/GIPC interacts with the C-terminus of the integrin alpha5 and alpha6 subunits.

Different cDNA libraries were screened by the yeast two-hybrid system using as a bait the cytoplasmic sequence of integrin alpha6A or alpha6B subunits. Surprisingly, the same PDZ domain-containing protein, TIP-2/GIPC, was isolated with either of the variants, although their sequences are different. Direct interaction assays with the cytoplasmic domain of the integrin alpha1--7 subunits revealed that in addition to alpha6A and alpha6B, TIP-2/GIPC reacted also with alpha5, but not other alpha integrin subunits. The specificity of the interaction was confirmed by in vitro protein binding assays with purified peptides corresponding to integrin cytoplasmic domains. Further analysis with either truncation fragments of TIP-2/GIPC or mutated integrin cytoplasmic domains indicated that the interaction occurs between the PDZ domain of TIP-2/GIPC and a consensus PDZ domain-binding sequence, SDA, present at the C-terminus of the integrin alpha5 and alpha6A subunits. The integrin alpha6B subunit terminates with a different sequence, SYS, which may represent a new PDZ domain-binding motif.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Effects of leptin, interleukin-1alpha, interleukin-6, and transforming growth factor-beta on markers of trophoblast invasive phenotype: integrins and metalloproteinases.

Phenotypic changes of integrin and metalloproteinase secretion of the invasive human cytotrophoblast are regulated by cytokines and growth factors, but how this occurs is not completely understood. We used 24-h cytotrophoblast cultures from first trimester pregnancies to investigate the effects of leptin and cytokines on the expression of the alpha2, alpha5, and alpha6 integrin subunits and on the activity of metalloproteinase-2 (gelatinase A) and metalloproteinase-9 (gelatinase B). The alpha2 subunit was marginally upregulated by leptin and interleukin-1alpha (IL-1alpha). All compounds tested upregulated, in some degree, the alpha5 expression. The a6 integrin subunit was massively upregulated, by leptin, interleukins, and transforming growth factor-beta. None of the factors tested affected metalloproteinase-2 activity, but the activity of metalloproteinase-9 was upregulated by leptin and IL-1alpha. In conclusion, leptin and IL-1alpha actively induce some of the changes that cytotrophoblasts undergo to achieve a more invasive phenotype. A novel role for leptin is proposed during early pregnancy: leptin might be an autocrine/paracrine regulator of cytotrophoblast invasiveness during implantation and placentation.

Antigens, CD↗
PubMed1997

An all-D amino acid peptide model of alpha1(IV)531-543 from type IV collagen binds the alpha3beta1 integrin and mediates tumor cell adhesion, spreading, and motility.

Type IV collagen promotes integrin-mediated cell adhesion, spreading, and motility. Several regions within the triple-helical domain of type IV collagen have been identified as tumor cellular recognition sites. Among these regions, the alpha1(IV)531-543 sequence, designated L-Hep-III, promotes integrin-mediated tumor cell adhesion and directly binds to the alpha3beta1 integrin [Miles, A. J., et al. (1994) J. Biol. Chem. 269, 30939-30945; Miles, A. J., et al. (1995) J. Biol. Chem. 270, 29047-29050]. We have presently compared the activities of the all-d enantiomeric peptide model of alpha1(IV)531-543, designated D-Hep-III, with L-Hep-III, for promoting the adhesion, spreading, and motility of metastatic melanoma and breast carcinoma cells. D-Hep-III was found to support melanoma and breast carcinoma cell adhesion, spreading, and motility in a dose-dependent fashion similar to that of L-Hep-III. The adhesions of melanoma and breast carcinoma cells to both type IV collagen and fibronectin were effectively inhibited by L-Hep-III and D-Hep-III. Melanoma cell invasion of the basement membrane was also inhibited by D-Hep-III. Characterization of the cell surface receptor for D-Hep-III was acheived via cell adhesion assays and affinity chromatography using monoclonal antibodies against integrin subunits. Immunoprecipitation analysis following EDTA elution from a D-Hep-III affinity column indicated that D-Hep-III binds to the alpha3beta1 integrin but not to the alpha2 or alpha6 integrin subunits. In summary, these studies demonstrate that an all-D model of the alpha1(IV)531-543 sequence mimics the biological activities of the all-L peptide. D-Hep-III is the first all-D peptide that has been shown to promote tumor cell adhesion, spreading, and migration, inhibit tumor cell adhesion and migration on type IV collagen and invasion of the basement membrane, and bind directly to an integrin. Due to the resistance to proteolysis, all-D receptor-binding peptides such as D-Hep-III have great potential for in vivo studies and as therapeutic agents.

Antibodies, Monoclonal↗
PubMed1997

Laminin E8 alveolarization site: heparin sensitivity, cell surface receptors, and role in cell spreading.

Cell adhesion to amino acids 2179-2198 (SN-peptide) of the laminin-1 alpha1-chain is required for lung alveolar formation in vitro (M. L. Matter and G. W. Laurie. J. Cell Biol. 124: 1083-1090, 1994). The nature of the SN-peptide receptor(s) was probed with neutralizing anti-integrin monoclonal antibodies (MAb), cells lacking integrin subunits, soluble heparin, and SN-peptide columns. Cell adhesion and spreading studies confirmed the specificity of SN-peptide and revealed adhesion to be unaffected by inclusion of anti-beta1-, anti-alpha(2-6)- or anti-alpha(V)beta5-integrin MAb. Cells lacking beta1- or alpha6-integrin subunits were fully adherent. Adhesion was heparin, but not chondroitin sulfate or heparinase, sensitive, much as is alpha-dystroglycan-laminin-1 binding. Heparin eluted approximately 155- and 180-kDa cell-surface proteins from SN-peptide columns. An additional approximately 91-kDa protein was eluted by EDTA. All were unrecognized by anti-beta1-integrin MAb. SN-peptide therefore interacts with three cell-surface proteins for which the identity remains to be determined.

Amino Acid Sequence↗
PubMed1999

Upregulated expression of fibronectin receptors underlines the adhesive capability of thymocytes to thymic epithelial cells during the early stages of differentiation: lessons from sublethally irradiated mice.

A 250-cGy whole-body gamma-radiation dose was used to induce thymus regression in mice, and to study the expression and function of extracellular matrix (ECM) receptors in distinct thymocyte subsets emerging during repopulation of the organ. The onset of regeneration was detected from day 2 to 3 postirradiation (P-Ir), when a remarkable increase in the absolute counts of CD3(-)CD25(hi)CD44(+) and CD3(-)CD25(in/hi)CD44(-) cells occurred. Enhanced expression of L-selectin, alpha4, and alpha5 integrin chains (L-selhi alpha4(hi) alpha5(hi)) was also exhibited by these cells. This pattern of expression was maintained until the CD4(+)CD8(+) (DP) young stage was achieved. Afterward, there was a general downregulation of these ECM receptors in DP as well as in CD4(+) or CD8(+) single positive (SP) thymocytes (L-selin alpha4(in) alpha5(in)). In some recently generated SP cells, alpha4 expression was downregulated before the alpha5 chain, and L-selectin was upregulated in half of more mature cells. The expression of the alpha6 integrin chain was downregulated only in maturing CD4(+) cells. Importantly, the increased expression of L-selectin and alpha4 and alpha5 chains in thymocytes was strongly correlated with their adhesiveness to thymic epithelial cells (TEC) in vitro. Blocking experiments with monoclonal antibody or peptides showed the following: (1) that the LDV rather than the REDV cell attachment motif in the IIIC segment of fibronectin is targeted by the alpha4 integrin during thymocyte/TEC adhesion; (2) that the RGD motif of the 120-kD fragment of fibronectin, a target for alpha5 integrin, has a secondary role in this adhesion; and (3) that the YIGSR cell attachment motif of the beta1 chain of laminin/merosin recognized by a nonintegrin receptor is not used for thymocyte adherence. In conclusion, our results show that an upregulated set of receptors endows CD25(+) precursors and cells up to the young DP stage with a high capability of interacting with thymic ECM components.

Animals↗
PubMed1998

Persistent adhesion of corneal epithelial tissue on synthetic lenticules in vivo.

PURPOSE: In intact cornea, firm anchorage of the epithelium to its underlying stroma is provided by a system of adhesive structures, which include the epithelial basement membrane, adhesion complexes and associated alpha6beta4 integrin receptors. In the present study we sought to determine whether the sustained epithelialization of synthetic lenticules observed in vivo involved the formation of adhesive structures at the epithelial-lenticule interface similar to those present in intact tissue. METHODS: Collagen I-coated microporous polycarbonate membranes were implanted in the anterior stroma of adult cats. Successfully epithelialized lenticules were maintained on eye for 9-12 weeks, after which time the epithelial-lenticule interface was examined for evidence of adhesive structures using immunohistochemistry and electron microscopy. RESULTS: Immunohistochemistry identified laminin, hemidesmosomal plaque, collagen VII and alpha6 integrin at the tissue lenticule interface. Ultrastructural examination showed evidence of assembly of these components into a basement membrane and adhesion complexes. CONCLUSIONS: The formation of these adhesive structures is likely to have contributed to the sustained epithelialization observed clinically on the collagen-coated synthetic lenticules.

Animals↗
PubMed1999

The nonintegrin laminin binding protein (p67 LBP) is expressed on a subset of activated human T lymphocytes and, together with the integrin very late activation antigen-6, mediates avid cellular adherence to laminin.

A search for genes expressed in activated T cells revealed that the nonintegrin, 67-kDa laminin binding protein (p67 LBP) is expressed on the surface of a subset (10-15%) of activated peripheral blood T cells. Surface p67 LBP expression is detectable by FACS using the anti-p67 LBP mAb, MLuC5, within 6 h of T cell activation with phorbol dibutyrate and ionomycin, peaks 18-36 h postactivation, and persists for 7-10 days. The subset of T cells expressing p67 LBP is composed of mature, single-positive cells (85% CD4+8-, 15% CD4-8+) of memory cell phenotype (100% CD45 RO+/CD45 RA-). The p67 LBP+ T cells also express the integrin alpha6 chain (CD49f), which is known to associate with p67 LBP on tumor cells. In addition, the p67 LBP+ T cells express the integrin beta1, which associates with alpha6 in the laminin-specific integrin receptor very late activation Ag (VLA)-6 (alpha6beta1). Expression of an exogenous cDNA encoding the 37-kDa LBP precursor (p37 LBPP) confers p67 LBP surface expression on a p67 LBP-negative Jurkat T cell line (B2.7). Expression of p67 LBP induces B2.7 transfectants to adhere to laminin, but avid laminin binding depends on coexpression of VLA-6. Taken together, these data indicate that p67 LBP is an activation-induced surface structure on memory T cells that, together with VLA-6, mediates cellular adherence to laminin.

Cell Adhesion↗
PubMed1999

Expression of alpha6 and beta4 integrin subunits throughout the menstrual cycle: no correlation with uterine receptivity.

OBJECTIVE: To compare the expression of alpha6 and beta4 integrin subunit levels throughout the menstrual cycle in the endometrium of healthy women and infertile women. DESIGN: Prospective study. SETTING: An academic teaching hospital. PATIENT(S): Endometrium was collected from 58 women, including healthy subjects (n = 28) and patients undergoing diagnostic testing for infertility (n = 30). INTERVENTION(S): Endometrial biopsies were performed throughout the menstrual cycle in healthy women and infertile women. MAIN OUTCOME MEASURE(S): Immunohistochemical staining intensity of alpha6 and beta4 using the semiquantitative immunohistochemical score, compared using regression analysis and analysis of variance with Scheffé's correction. RESULT(S): There was no correlation between menstrual cycle phase and endometrial integrin subunit alpha6 or beta4 on glandular or luminal epithelium. Even women with identified luteal phase defects had indistinguishable patterns of expression for these integrin subunits during the window of implantation. CONCLUSION(S): The integrin subunits alpha6 and beta4 are expressed uniformly throughout the menstrual cycle on glandular and luminal epithelium. These integrins may have a housekeeping role in anchoring endometrial epithelium and do not appear to be useful markers of uterine receptivity.

Adult↗
PubMed2004

Dorsal root ganglion neurons up-regulate the expression of laminin-associated integrins after peripheral but not central axotomy.

The favorable prognosis of regeneration in the peripheral nervous system after axonal lesions is generally regarded as dependent on the Schwann cell basal lamina. Laminins, a heterotrimeric group of basal lamina molecules, have been suggested to be among the factors playing this supportive role. For neurons to utilize laminin as a substrate for growth, an expression of laminin binding receptors, integrins, is necessary. In this study, we have examined the expression of laminin binding integrin subunits in dorsal root ganglion (DRG) neurons after transection to either their peripherally projecting axons, as in the sciatic nerve, followed by regeneration, or the centrally projecting axons in dorsal roots, followed by no or weak regenerative activity. In uninjured DRG, immunohistochemical staining revealed a few neurons expressing integrin subunit alpha6, whereas integrin subunits alpha7 and foremost beta1 were expressed in a majority of neurons. After an injury to the sciatic nerve, mRNAs encoding all three integrins were up-regulated in DRG neurons. By anterograde tracing, immunoreactivity for all studied integrins was also found in association with growing axons after a sciatic nerve crush lesion in vivo. In contrast, mRNA levels remained constant in DRG neurons after a dorsal root injury. Together with previous findings, this suggests that integrin subunits alpha6, alpha7, and beta1 have an important role in the regenerative response following nerve injury and that the lack of regenerative capacity following dorsal root injury could in part be explained by the absence of response in integrin regulation.

Animals↗