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At least 595 records · Page 33Linked to original sources
PubMed1998

Hemidesmosome formation is initiated by the beta4 integrin subunit, requires complex formation of beta4 and HD1/plectin, and involves a direct interaction between beta4 and the bullous pemphigoid antigen 180.

Hemidesmosomes (HDs) are stable anchoring structures that mediate the link between the intermediate filament cytoskeleton and the cell substratum. We investigated the contribution of various segments of the beta4 integrin cytoplasmic domain in the formation of HDs in transient transfection studies using immortalized keratinocytes derived from an epidermolysis bullosa patient deficient in beta4 expression. We found that the expression of wild-type beta4 restored the ability of the beta4-deficient cells to form HDs and that distinct domains in the NH2- and COOH-terminal regions of the beta4 cytoplasmic domain are required for the localization of HD1/plectin and the bullous pemphigoid antigens 180 (BP180) and 230 (BP230) in these HDs. The tyrosine activation motif located in the connecting segment (CS) of the beta4 cytoplasmic domain was dispensable for HD formation, although it may be involved in the efficient localization of BP180. Using the yeast two-hybrid system, we could demonstrate a direct interaction between beta4 and BP180 which involves sequences within the COOH-terminal part of the CS and the third fibronectin type III (FNIII) repeat. Immunoprecipitation studies using COS-7 cells transfected with cDNAs for alpha6 and beta4 and a mutant BP180 which lacks the collagenous extracellular domain confirmed the interaction of beta4 with BP180. Nevertheless, beta4 mutants which contained the BP180-binding region, but lacked sequences required for the localization of HD1/plectin, failed to localize BP180 in HDs. Additional yeast two- hybrid assays indicated that the 85 COOH-terminal residues of beta4 can interact with the first NH2-terminal pair of FNIII repeats and the CS, suggesting that the cytoplasmic domain of beta4 is folded back upon itself. Unfolding of the cytoplasmic domain may be part of a mechanism by which the interaction of beta4 with other hemidesmosomal components, e.g., BP180, is regulated.

Animals↗
PubMed2006

Molecular phenotypes of notochordal cells purified from immature nucleus pulposus.

The immature nucleus pulposus (NP) is populated by cells of notochordal-origin that are larger and contain an extensive cytoskeletal network and numerous vacuoles. The disappearance of these cells with age is believed important in regulating metabolic shifts that may contribute to age-related disc degeneration. The precise biological function of these notochordal cells in the immature NP remains unclear, however, because of challenges in studying the mixed cell population in the NP. In this study, notochordal-like cells were purified from immature NP cells using a new fluorescence-activated cell sorting (FACS) protocol with auto-fluorescence and size analysis. The unique molecular phenotypes of sorted notochordal-like cells were characterized by the mRNA expression pattern for key matrix proteins and modulators, and by the expression of cell-matrix receptor integrin subunits. An FACS analysis showed that the immature NP contained a majority of cells that were larger than anulus fibrosus (AF) cells and with fluorescence higher than AF cells. In comparison with the small NP cells separated by the FACS protocol, sorted notochordal-like cells expressed lower mRNA levels of type I collagen, biglycan, TIMP1, HSP70 and c-fos, and did not express detectable mRNA levels of decorin, lumican, multiple MMPs or IL-1beta via real-time quantitative RT-PCR. A greater number of these notochordal-like cells also expressed the higher levels of alpha6, alpha1 and beta1 integrin subunits as compared to small NP cells. Together, our results point towards a unique molecular phenotype for these notochordal-like cells of NP, characterized by the absence of gene expression for specific small proteoglycans and higher protein expression of integrin subunits that regulate interactions with collagens and laminin. Future studies will be important for revealing if this unique molecular profile is coordinated with functional differences in pericellular matrix regions and/or integrin-mediated cell-matrix interactions for these notochordal-like cells within the NP.

Animals↗
PubMed2000

Renal lesions in von Hippel-Lindau disease: immunohistochemical expression of nephron differentiation molecules, adhesion molecules and apoptosis proteins.

AIMS: Renal lesions in von Hippel-Lindau disease comprise clear cell simple cysts, atypical cysts and carcinomas. Although histological and molecular studies suggest that cystic lesions may represent precursors of carcinomas, there is no detailed phenotypic evidence of their relationship. METHODS AND RESULTS: To investigate such a possible relationship between cystic lesions and solid carcinomas, we studied the pathological and immunohistochemical features of 328 lesions of 33 kidneys originating from 23 patients with von Hippel-Lindau disease, using a panel of antibodies directed against cytoskeleton proteins, cell surface proteins, integrin subunits, adhesion molecules, lectins, and apoptosis and proliferation markers. Solid carcinomas (n = 175) were all of clear cell type and mostly nuclear grade 1. Cystic lesions (n = 138) consisted of cystic clear cell carcinomas (n = 15), atypical cysts (n = 20) and simple cysts (n = 103). Clear cells of the simple cysts, atypical cysts and solid carcinomas coexpressed cytokeratins (CK8, CK19) and vimentin, and expressed a similar pattern of tubular markers (CD24, tetraglonolobus), integrin subunits (alpha3, alpha5, alpha6, alphav, beta1) and cell adhesion molecules (ICAM 1, VCAM 1). In all lesions studied, proliferation rate (MIB1 index) was low, and apoptosis marker expression (fragmented DNA, p53, bcl-2) inconspicuous. CONCLUSIONS: Phenotypic alterations found in solid renal cell carcinomas are already present in simple and atypical renal cysts of von Hippel-Lindau disease.

Adenocarcinoma, Clear Cell↗
PubMed2002

H-Ras/mitogen-activated protein kinase pathway inhibits integrin-mediated adhesion and induces apoptosis in osteoblasts.

We have studied the relevance of H-Ras and its downstream effectors to osteoblast functions. 1) Purified human osteoblasts highly expressed integrins beta1, alpha4, alpha5, alpha6 and the activation epitope of beta1. However, these molecules were markedly down-regulated on osteoblasts transfected with expression vector encoding fully activated H-Ras(V12), H-Ras(V12)T35S, activating Raf-1/mitogen-activated protein kinase (MAPK), or an active Raf-1 but not on cells having H-Ras(V12)Y40C, a phosphoinositide 3-kinase (PI3K)-binding mutant. 2) Although osteoblasts spontaneously adhered to fibronectin and laminin in beta1-dependent manner, the expression of H-Ras(V12) or H-Ras(V12)T35S, but not H-Ras(V12)Y40C, in osteoblasts reduced their adhesion. 3) Osteoblasts bearing H-Ras(V12), H-Ras(V12)T35S, or Raf-1 failed to proliferate, whereas those with H-Ras(V12)Y40C proliferated well. (4) The up-regulation of Fas and down-regulation of Bcl-2 were observed in osteoblasts expressing H-Ras(V12), H-Ras(V12)T35S, or Raf-1. (5) Most of the cells having H-Ras(V12), H-Ras(V12)T35S, or Raf-1 became annexin-V(high)/propidium iodide (PI)(high or low) and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling (TUNEL)(high)/PI(low) after 24 and 72 h incubation, respectively. Thus, we propose that H-Ras signals followed by Raf-1/MAPK pathway but not PI3K not only reduces beta(1)-mediated adhesion of osteoblasts to matrix proteins but induces apoptosis presumably via the Fas up-regulation and Bcl-2 down-regulation.

Apoptosis↗
PubMedDate not supplied

Diffuse leiomyomatosis of the esophagus: disorder of cell-matrix interaction?

Diffuse leiomyomatosis (DL) is rare condition characterized by proliferation of smooth muscle in the upper gastrointestinal tract. Most cases are associated with X-linked Alport syndrome and have partial deletions in the genes encoding both the alpha5 and alpha6 chains of collagen type IV. We studied aspects of cell-matrix interaction of myocytes in an esophagogastrectomy specimen from a 12-year-old patient with DL. Myocytes had central areas of cytoplasmic rarefaction, which were actin positive and desmin poor, with the reverse pattern of staining at the cell periphery. Electron microscopy (EM) showed that the areas of rarefaction consisted of disorganized aggregates of filaments. The basement membranes ranged from thickened to thinned or absent. Immunohistochemical staining for the alpha1-alpha4 chains of collagen type IV, the alpha1, alpha2, beta2, and gamma1 chains of laminin, nidogen, type VI collagen, and fibronectin was normal. There was loss of the alpha5 and alpha6 chains of collagen type IV and the beta1 chain of laminin. Normal staining for alpha1, alpha2, alpha3, alpha4, alpha6, alpha8, and beta1 integrins was noted. Staining for alpha5 integrin varied from normal to reduced or negative in different cells. In DL, a primary abnormality of basement membrane may be associated with disorganization of the contractile apparatus and alterations of certain integrins. This may reflect a disturbance of cell-matrix interactions that play a role in cell differentiation and internal organization.

Barrett Esophagus↗
PubMed2005

Epigenetic activation of alpha4, beta2 and beta6 integrins involved in cell migration in trichostatin A-treated Hep3B cells.

The epigenetic modulation by histone deacetylase (HDAC) inhibitors including trichostatin A (TSA) has been known to block cell proliferation, induce apoptosis and inhibit cell migration in human cancer cells that represents the potential therapeutic agents for cancers and fibrosis. However, more than 55% of Hep3B cells remained alive after our initial study of 100 nM TSA treatment. To further study the epigenetic modulation and the biological function of newly activated genes by HDAC inhibitor involved in HCC progression and metastasis, we profiled 23 integrin genes including 15alpha and 8beta in TSA-treated Hep3B cells. Six integrins including three down-regulated alpha6, alpha10, beta8 and three significant up-regulated alpha4, beta2, beta6 integrins were revealed after semi-quantitative RT-PCR. To confirm the epigenetic modulation and explore their biological functions, we selected the three significantly up-regulated integrins for confirmation of protein up-regulation, hyperacetylated-histones by ChIP assays, and functional inhibition by specific neutralizing antibodies of integrins. Our results indicated that epigenetic modulation in TSA-treated Hep3B cells up-regulated new integrins including alpha4, beta2 and beta6 and reduced migration activities by specific neutralizing antibodies to 61.3%, 42.4% and 34.5%, respectively. Our novel findings provided a better understanding of the epigenetic modulation of integrins and suggested that targeting the epigenetic up-regulated integrins to abrogate the migration activity might be a promising strategy to prevent HCC progression.

Base Sequence↗
PubMed2000

Enrichment and transplantation of spermatogonial stem cells.

Spermatogenesis is a complex, highly organized process originated from stem cell spermatogonia. Because there are very few stem cells and they can only be defined by their function, the identification and isolation of these cells has been very difficult. By using a spermatogonial transplantation assay system, we have identified alpha6-and beta1-integrin expression on stem cells, and cells isolated with these antigens were significantly enriched in stem cells. This is the first demonstration of spermatogonial stem cell-associated antigens. Analysis of two infertile mouse models, Steel/SteelDickie (Sl/Sld) and experimental cryptorchidism, showed that the number of stem cells is reduced in Sl/Sld testis. Whereas cryptorchid testes are greatly enriched for stem cells, and one in 200 cells is a stem cell. These techniques will provide an important starting point for further purification and characterization of spermatogonial stem cells.

Animals↗
PubMed1999

Identification of the hemidesmosomal 500 kDa protein (HD1) as plectin.

HD1 is a 500 kDa hemidesmosomal plaque protein recognized by monoclonal antibody mAb-121. Recent research on inherited skin disease has suggested that it might be identical to plectin or an isoform. To cast light on this question, we have prepared several monoclonal antibodies that recognize a 500 kDa protein in the hemidesmosome fraction. Unexpectedly, some staining pattern heterogeneity was observed on immunofluorescence microscopy. Attention was focused on two monoclonal antibodies which gave different localization in bovine skin and retinal pigment epithelial cells. Determination of the amino-terminal sequence of an antigenic 100 kDa polypeptide fragment derived from the 500 kDa component of an insoluble fraction of bovine hepatocytes revealed it was identical to that of plectin. Using the two antibodies, we screened a cDNA library derived from BMGE+H, a bovine mammary gland epithelial cell line. The isolated cDNA clones corresponded to the rod domain of bovine plectin, with two separate epitope regions for each of the antibodies. From these results we conclude that the hemidesmosomal 500 kDa component HD1 is identical to plectin. As judged on rough estimation of molar ratios on this basis, hemidesmosomes are composed of plectin, BP230, the integrin beta4 subunit, and alpha6 in a 1:1:1:1 ratio.

Animals↗
PubMed2000

A novel experimental mouse model of peritoneal dissemination of human gastric cancer cells: different mechanisms in peritoneal dissemination and hematogenous metastasis.

We established a new cell line, AZ-P7a, with high peritoneal-metastatic potential in nude mice. AZ-P7a cells were derived from the human gastric carcinoma line AZ-521, which has low capacity for peritoneal dissemination. AZ-P7a cells developed peritoneal metastasis in 11 / 14 (78.6%) mice, whereas the parental AZ-521 cells developed metastasis in 2 / 6 (33.3%) mice. The metastatic foci in the peritoneum showed essentially the same histological appearance as those induced by parental cells. The tumorigenicity and the motile activity of AZ-P7a cells were stronger than those of the parental AZ-521 cells; in contrast, adhesion to the extracellular matrix and the production of vascular endothelial growth factor by AZ-P7a cells were decreased. In fluorescence-activated cell sorter (FACS) analysis, AZ-P7a cells expressed significantly greater levels of integrins alpha2, alpha3, alpha5, alpha6 and alphavbeta5, as compared with AZ-521 cells. However, alpha1, alpha4, alphavbeta3, hCD44H, hCD44v3, hCD44v6 and hCD44v10 were not expressed in either cell line. AZ-P7a cells developed no liver metastasis when administered by the intrasplenic injection method, though the highly liver metastatic cell line AZ-H5c showed the same rate of peritoneal dissemination as that exhibited by AZ-P7a cells after intraabdominal injection. These findings suggested that the mechanism of peritoneal dissemination differed from that of hematogenous metastasis. Moreover, the latter appears to be controlled by more complex mechanisms than the former. Thus, this cell line might be useful for investigating the mechanism of peritoneal dissemination of human gastric cancer.

Adenocarcinoma↗
PubMed2005

[Identification of human corneal epithelial stem cells].

OBJECTIVE: To investigate the molecular markers of corneal epithelial stem cells. METHODS: The anatomy structure of corneal limbus was analyzed by histological examination. Fluorescence microscopy and laser scan confocal microscopy (LSCM) were used to evaluate the expression of un differentiation markers as p63, ABCG2, alpha6, alpha9 and beta1 integrin, alpha-enolase, EGFR, cytokeratin 19 (CK19) and CD71 in cornea-limbus sections and whole mount cornea tissue using immunohistochemistry staining. Semiquantitative RT-PCR and in situ hybridization (ISH) were used to evaluate gene expression of corneal and limbal epithelia. RESULTS: The limbal area in horizontal cut direction showed that limbal epithelial cells were as papilloma-form to correspond to the Palisades of Vogt environment. The expressions of beta1 integrin, K19, alpha-enolase and EGFR were much stronger in limbal basal cells than superficial cells. Un differentiation markers p63, ABCG2, alpha9 integrin were detected only in the basal limbal epithelial cells. LSCM and RT-PCR results showed that the protein and mRNA of p63, ABCG2 and alpha9 integrin were only detected in limbal epithelia. ISH showed that p63 mRNA only expressed in the limbal basal epithelial layer. CONCLUSIONS: The corneal limbal epithelial area is papilloma-form. Limbal stem cells have complex markers as p63 expressing in the nuclei, ABCG2 in the cytoplasm and alpha9 integrin expressing in the membrane. With these markers complex, it is easy to distinguish limbal stem cells from other epithelial cells in cornea.

Biomarkers↗
PubMed2005

Tumor cell invasiveness correlates with changes in integrin expression and localization.

In nontumorigenic mammary epithelial cells (EpH4), transforming growth factor-beta (TGFbeta1) causes cell cycle arrest/apoptosis, but induces epitheliomesenchymal transition (EMT) in Ha-Ras-transformed EpH4 cells (EpRas). EMT is closely correlated with late-stage tumor progression and results in fibroblastic, migratory cells displaying a mesenchymal gene expression program (FibRas). EpRas and FibRas cells showed strongly increased cell substrate adhesion to fibronectin, collagens I/IV and laminin 1. Furthermore, Ras transformation caused enhanced or de-novo expression of the integrin subunits beta1, alpha2 and alpha3, or alpha5 and alpha6, respectively, the latter subunits being even more strongly expressed in FibRas cells. Importantly, polarized EpRas cells expressed integrin subunits beta1 and alpha6 at distinct (apical and lateral) membrane domains, while FibRas cells coexpressed these integrins and alpha5 at the entire plasma membrane. During EMT, EpRas cells formed an alpha5beta1 complex and deposited its ligand fibronectin into the extracellular matrix. Function-blocking alpha5 antibodies attenuated migration, and caused massive apoptosis in EpRas cells undergoing TGFbeta1-induced EMT in collagen gels, but failed to affect EpRas- or FibRas-derived structures. We conclude that functional alpha5beta1 integrin is centrally implicated in EMT induction. Importantly, FibRas cells also failed to deposit the alpha6beta4 ligand laminin 5, suggesting that alpha6beta4 is no longer functional after EMT and replaced by mesenchymal integrins such as alpha5beta1.

Breast↗
PubMed2006

Integrins are markers of human neural stem cells.

The identification of markers for the isolation of human neural stem cells (hNSCs) is essential for studies of their biology and therapeutic applications. This study investigated expression of the integrin receptor family by hNSCs as potential markers. Selection of alpha6(hi) or beta1(hi) cells by fluorescence-activated cell sorting led to an enrichment of human neural precursors, as shown by both neurosphere forming assays and increased expression of prominin-1, sox2, sox3, nestin, bmi1, and musashi1 in the beta1(hi) population. Cells expressing high levels of beta1 integrin also expressed prominin-1 (CD133), a marker previously used to isolate hNSCs, and selection using integrin beta1(hi) cells or prominin-1(hi) cells was found to be equally effective at enriching for hNSCs from neurospheres. Therefore, integrin subunits alpha6 and beta1 are highly expressed by human neural precursors and represent convenient markers for their prospective isolation.

AC133 Antigen↗
PubMed2003

Beta1 integrin/focal adhesion kinase-mediated signaling induces intercellular adhesion molecule 1 and receptor activator of nuclear factor kappaB ligand on osteoblasts and osteoclast maturation.

We have assessed characteristics of primary human osteoblasts, shedding light on signaling mediated by beta1 integrin. beta1 integrins are major receptors for these matrix glycoproteins. 1) Integrins beta1, alpha2, alpha3, alpha4, alpha5, alpha6, and alphav were highly expressed on primary osteoblasts. 2) Engagement of beta1 integrins on osteoblasts by cross-linking with specific antibody or ligand matrices, such as fibronectin or collagen, augmented expression of intercellular adhesion molecule 1 (ICAM-1) and receptor activator of nuclear factor kappaB ligand (RANKL) on the surface. 3) Up-regulation of ICAM-1 and RANKL on osteoblasts by beta1 stimulation was completely abrogated by pretreatment with herbimycin A and genistein, tyrosine kinase inhibitors, or transfection of dominant negative truncations of focal adhesion kinase (FAK). 4) Engagement of beta1 integrins on osteoblasts induced tartrate-resistant acid phosphatase-positive multinuclear cell formation in the coculture system of osteoblasts and peripheral monocytes. 5) Up-regulation of tartrate-resistant acid phosphatase-positive multinuclear cell formation by beta1 stimulation was completely abrogated by transfection of dominant negative truncations of FAK. Our results indicate that beta1 integrin-dependent adhesion of osteoblasts to bone matrices induces ICAM-1 and RANKL expression and osteoclast formation via tyrosine kinase, especially FAK. We here propose that beta1 integrin/FAK-mediated signaling on osteoblasts could be involved in ICAM-1- and RANKL-dependent osteoclast maturation.

Antibodies, Monoclonal↗
PubMed2001

Identification of insulin receptor substrate 1 (IRS-1) and IRS-2 as signaling intermediates in the alpha6beta4 integrin-dependent activation of phosphoinositide 3-OH kinase and promotion of invasion.

Expression of the alpha6beta4 integrin increases the invasive potential of carcinoma cells by a mechanism that involves activation of phosphoinositide 3-OH kinase (PI3K). In the present study, we investigated the signaling pathway by which the alpha6beta4 integrin activates PI3K. Neither the alpha6 nor the beta4 cytoplasmic domain contains the consensus binding motif for PI3K, pYMXM, indicating that additional proteins are likely to be involved in the activation of this lipid kinase by the alpha6beta4 integrin. We identified insulin receptor substrate 1 (IRS-1) and IRS-2 as signaling intermediates in the activation of PI3K by the alpha6beta4 integrin. IRS-1 and IRS-2 are cytoplasmic adapter proteins that do not contain intrinsic kinase activity but rather function by recruiting proteins to surface receptors, where they organize signaling complexes. Ligation of the alpha6beta4 receptor promotes tyrosine phosphorylation of IRS-1 and IRS-2 and increases their association with PI3K, as determined by coimmunoprecipitation. Moreover, we identified a tyrosine residue in the cytoplasmic domain of the beta4 subunit, Y1494, that is required for alpha6beta4-dependent phosphorylation of IRS-2 and activation of PI3K in response to receptor ligation. Most importantly, Y1494 is essential for the ability of the alpha6beta4 integrin to promote carcinoma invasion. Taken together, these results imply a key role for the IRS proteins in the alpha6beta4-dependent promotion of carcinoma invasion.

Amino Acid Motifs↗
PubMed2002

Integrin expression by human osteoblasts cultured on degradable polymeric materials applicable for tissue engineered bone.

The use of biodegradable polymers in the field of orthopaedic surgery has gained increased popularity, as surgical pins and screws, and as potential biological scaffolds for repairing cartilage and bone defects. One such group of polymers that has gained considerable attention are the polyesters, poly(lactide-co-glycolide) (PLAGA) and polylactic acid (PLA), because of their minimal tissue inflammatory response, favorable biocompatibility and degradation characteristics. The objective of this study was to evaluate human osteoblastic cell adherence and growth on PLAGA and PLA scaffolds by examining integrin receptor (alpha2, alpha3, alpha4, alpha5, alpha6 and beta1) expression. Primary human osteoblastic cells isolated from trabecular bone adhered efficiently to both PLAGA and PLA, with the rate of adherence on PLAGA comparable to that of control tissue culture polystyrene (TCPS), and significantly higher than on PLA polymers at 3, 6 and 12 h. Human osteoblastic phenotypic expression, alkaline phosphatase (ALP) activity was positive on both degradable matrices, whereas osteocalcin levels were significantly higher on cells grown on PLAGA than on PLA composites. Interestingly, the integrin subunits, alpha2, alpha3, alpha4, alpha5, alpha6 and beta1 were all expressed at higher levels by osteoblasts cultured on PLAGA than those on PLA as analyzed by westerns blots and by flow cytometry. Among the integrins, alpha2, beta5 and beta1 showed the greatest difference in levels between the two surfaces. Thus, both PLA and PLAGA support osteoblastic adhesion and its accompanying engagement of integrin receptor and expression of osteocalcin and ALP. However PLAGA consistently appeared to be a better substrate for osteoblastic cells based on these parameters. This study is one of the first to investigate the ability of primary human osteoblastic cells isolated from trabecular bone to adhere to the biodegradable polymers PLAGA and PLA, and to examine the expression of their key adhesion receptors (integrins) on these substrates.

Absorbable Implants↗
PubMed2001

Traction forces mediated by alpha6beta4 integrin: implications for basement membrane organization and tumor invasion.

The integrin alpha6beta4, a laminin receptor that stabilizes epithelial cell adhesion to the basement membrane (BM) through its association with cytokeratins, can stimulate the formation and stabilization of actin-rich protrusions in carcinoma cells. An important, unresolved issue, however, is whether this integrin can transmit forces to the substrate generated by the acto-myosin system. Using a traction-force detection assay, we detected forces exerted through alpha6beta4 on either laminin-1 or on an anti-alpha6 antibody, demonstrating that this integrin can transmit forces without the need to engage other integrins. These alpha6beta4-dependent traction forces were organized into a compression machine localized to the base of lamellae. We hypothesized that the compression forces generated by alpha6beta4 result in the remodeling of BMs because this integrin plays a major role in the interaction of epithelial and carcinoma cells with such structures. Indeed, we observed that carcinoma cells are able to remodel a reconstituted BM through alpha6beta4-mediated compression forces by a process that involves the packing of BM material under the cells and the mechanical removal of BM from adjacent areas. The distinct signaling functions of alpha6beta4, which activate phosphoinositide 3-OH kinase and RhoA, also contribute to remodeling. Importantly, we demonstrate remodeling of a native BM by epithelial cells and the involvement of alpha6beta4 in this remodeling. Our findings have important implications for the mechanism of both BM organization and tumor invasion.

Antigens, Surface↗
PubMed2002

Integrins in head and neck squamous cell carcinoma invasion.

OBJECTIVE: To relate the invasive properties of different squamous cell cancer cell lines to the function and expression of the integrins. STUDY DESIGN: A series of in vitro and in vivo experiments were designed to assess and compare integrin expression and function in two different head and neck squamous cell carcinoma cell lines. METHODS: Invasive properties of two squamous cell carcinoma cell lines (UM-SCC-1 and JHU-022-SCC) were assessed using an in vitro artificial matrix assay as well as an in vivo system with orthotopically implanted tumor cells in mice. Whole cell and surface expression levels of integrin subunits (alpha2, alpha3, alpha5, alpha6, beta1, and beta4) were determined for each cell line using Western blot analysis and flow cytometry. We compared the ability of JHU-022-SCC and UM-SCC-1 cells to bind the extracellular matrix elements collagen IV, fibronectin, laminin 5, and laminin10 using an in vitro adhesion assay. Contributions of the different integrins to the adhesive properties were determined by selective antibody blocking of different subunits. RESULTS: The UM-SCC-1 cell line is 50% more invasive in vitro and displays a greater propensity for perineural and lymphatic invasion in vivo. The UM-SCC-1 cells exhibited greater adherence to fibronectin than JHU-022-SCC cells. Alpha6 and beta4 expression is approximately twofold greater in the JHU-022-SCC cells. Alpha2, alpha3, and beta1 expression appears to be upregulated in UM-SCC-1 cells. CONCLUSION: The UM-SCC-1 carcinoma cells are more invasive than JHU-022-SCC cells and may be related to differential expression of the integrins alpha6beta4, alpha3beta1, and alpha2beta1.

Animals↗
PubMed2004

alpha4beta1- and alpha6beta1-integrins are functional receptors for midkine, a heparin-binding growth factor.

Midkine is a heparin-binding growth factor that promotes the growth, survival, migration and differentiation of various target cells. So far, receptor-type protein tyrosine phosphatase zeta, low-density-lipoprotein-receptor-related protein and anaplastic lymphoma kinase have been identified as receptors for midkine. We found beta1 integrin in midkine-binding proteins from 13-day-old mouse embryos. beta1-Integrin bound to a midkine-agarose column and was eluted mostly with EDTA. Further study revealed that the alpha-subunits capable of binding to midkine were alpha4 and alpha6. Purified alpha4beta1- and alpha6beta1-integrins bound midkine. Anti-alpha4 antibody inhibited the midkine-dependent migration of osteoblastic cells, and anti-alpha6 antibody inhibited the midkine-dependent neurite outgrowth of embryonic neurons. After midkine treatment, tyrosine phosphorylation of paxillin, an integrin-associated molecule, was transiently increased in osteoblastic cells. Therefore, we concluded that alpha4beta1- and alpha6beta1-integrins are functional receptors for midkine. We observed that the low-density-lipoprotein-receptor-related-protein-6 ectodomain was immunoprecipitated with alpha6beta1-integrin and alpha4beta1-integrin. The low-density-lipoprotein-receptor-related-protein-6 ectodomain was also immunoprecipitated with receptor-type protein tyrosine phosphatase zeta. alpha4beta1- and alpha6beta1-Integrins are expected to co-operate with other midkine receptors, possibly in a multimolecular complex that contains other midkine receptors.

Alleles↗