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Results for “Integrin alpha2beta1”

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PubMed2001

Adhesion, actin cytoskeleton organisation and the spreading of colon adenocarcinoma cells induced by EGF are mediated by alpha2beta1 integrin low clustering through focal adhesion kinase.

Both epidermal growth factor (EGF) and the extracellular matrix components have been implicated in the pathobiology of adenocarcinomas by somewhat poorly understood mechanisms. We have addressed this problem using an in vitro model comprising the colon adenocarcinoma cell line HT29-D4, wherein the role of EGF and type IV collagen on cell adhesion was examined. We demonstrated that the effect of EGF on HT29-D4 cell adhesion was regulated by type IV collagen in a time- and dose-dependent manner. The incorporation of a panel of monoclonal antibodies to integrins alpha1beta1, alpha2beta1 and alpha3beta1 in adhesion medium revealed that EGF-mediated increase in the cell adhesion was mediated essentially by alpha2beta1, and the use of flow cytometry led us to conclude that this EGF effect was mediated by an increase in alpha2beta1 activation and not by an increase in cell surface expression of integrin. An indirect immunofluorescence technique was employed to demonstrate that focal adhesion kinase (FAK) and alpha2beta1 integrin were present in focal complexes in large EGF-induced lamellipodia whereas actin cytoskeleton was organised in small tips that colocalised with FAK. This pattern was observed at early time points (15 min) with a strong FAK tyrosine phosphorylation and with an increase in mitogen-activated protein kinase activity (5-15 min) as measured by immunoprecipitation and immunoblotting. We conclude that at early time points of cell adhesion and spreading, EGF exerted an inside-out regulation of alpha2beta1 integrin in HT29-D4 cells. This regulation seemed to be mediated by EGF-dependent FAK phosphorylation entailing an increase in integrin activation and their recruitment in numerous focal complexes. Furthermore after activation, FAK induced aggregation of actin-associated proteins (paxillin, vinculin and other tyrosine phosphorylated proteins) in focal complexes, leading to organisation of actin cytoskeleton that is involved in lamellipodia formation. Finally, activated alpha2beta1 integrins intervened in all these processes clustered in small focal complexes but not in focal adhesions.

Actins↗

PubMedDate not supplied

Hepatocyte growth factor upregulates alpha2beta1 integrin in Madin-Darby canine kidney cells: implications in tubulogenesis.

It has been well established that hepatocyte growth factor (HGF) induces branching tubule formation of Madin-Darby canine kidney (MDCK) cells cultured in collagen gel. Tubulogenesis per se requires the involvement of cell proliferation, migration, focalization proteolysis, cell-cell interaction and differentiation. However, signaling pathways and proteins involved in HGF-induced tubulogenesis by MDCK cells have not been thoroughly studied. Because cell-matrix interactions play important roles in tubulogenesis, we analyzed whether HGF altered the expression of extracellular matrix receptor (alpha2, alpha3, beta1 and alphavbeta3 integrin). We found that among those proteins examined, alpha2beta1 integrin levels were enhanced by HGF. HGF-induced upregulation of alpha2beta1 integrin was mediated via upregulation of alpha2 integrin mRNA abundance. Cycloheximide blocked the HGF-induced increase in alpha2 integrin mRNA expression. To understand the signaling pathways leading to an HGF-induced increase in alpha2beta1 integrin levels, PD98059 (MEK1 inhibitor), LY294002 (PI3-kinase inhibitor), and GF109203X (PKC inhibitor) were used. We found that PD98059 blocked the HGF-induced increase in alpha2beta1 integrin expression. Furthermore, 5E8 (specific anti-alpha2beta1 integrin antibody) was employed to elucidate the potential role of HGF-induced upregulation of alpha2beta1 integrin in branching morphogenesis. 5E8 did not alter HGF-induced scattering effects but disrupted HGF-induced branching tubulogenesis in collagen gel via inhibition of cell-cell interactions and growth. Taken together, HGF upregulates alpha2beta1 integrin expression via an indirect pathway, the results of which contribute to the regulation of cell-cell interactions and cell growth during branching morphogenesis in collagen gel.

Animals↗

PubMed2003

Alpha2beta1 integrin and development of atherosclerosis in a mouse model: assessment of risk.

OBJECTIVE: The alpha2beta1 integrin serves as a collagen or collagen/laminin receptor on many cell types, including endothelial cells and platelets. Many studies indicate that the alpha2beta1 integrin is a critical mediator of platelet adhesion to collagen. Epidemiologic studies suggest a direct correlation between the genetically determined platelet surface density of the alpha2beta1 integrin and the risk of thrombotic diseases, such as myocardial infarction and stroke, in the young, which are well-established complications of atherosclerosis. We have now used the alpha2beta1 integrin-deficient mouse to evaluate the contributions of the alpha2beta1 integrin to the development of atherosclerosis. METHODS AND RESULTS: We generated wild-type (alpha2+/+) or alpha2beta1 integrin-deficient (alpha2-/-) mice that were also deficient in the apolipoprotein E (ApoE) gene (ApoE-/-) and compared atherosclerotic lesion development in alpha2+/+ ApoE-/- and alpha2-/- ApoE-/- mice that were fed a high-fat, cholesterol-containing diet for 6 or 15 weeks. Total lesional area did not differ significantly between the alpha2-null animals and the wild-type animals at either 6 or 15 weeks. CONCLUSIONS: Our results suggest that risk for arterial thrombotic disease associated with high-level alpha2beta1 integrin expression is not attributable to enhanced development of atherosclerosis per se but may rather be a consequence of thrombotic complications at the plaques.

Animals↗

PubMed2004

Binding of alpha2 monoclonal antibody to human cervical tumor cell (SiHa) surface alpha2beta1 integrin modulates MMP-2 activity.

OBJECTIVE(S): The purpose was to study the interrelationship between cell surface integrin receptor (alpha2beta1) and matrixmetalloproteinases. METHODS: Immunoprecipitation and cell adhesion assay were done to assay alpha2beta1 and alpha3beta1 on SiHa cell surface. Zymogram was developed to assay secreted MMP activity of cells grown in presence of alpha2 monoclonal antibody. Immunoblot was developed to assay expression of MMP-2, FAK, and p-FAK. Plasma membrane-dependent activation of MMP2 was performed by incubating pure MMP-2 with membrane-enriched fraction isolated from SiHa cells. RESULTS: Immunoprecipitation and cell adhesion assay results confirmed the presence of alpha2beta1 receptor on SiHa cells. Zymographic analysis of serum-free media collected at different time points from SiHa cells grown on alpha2 monoclonal antibody-coated culture dishes showed the expression and activation of MMP-2 within 2-4 h, confirmed by immunoblot. Western blot of cells grown on alpha2-coated dishes for 30 min-4 h showed increased phosphorylation of FAK. Membrane-enriched fraction isolated from SiHa cells was found to specifically activate proMMP-2 to its activated forms within 30 min. CONCLUSION(S): The experimental findings strongly indicate that SiHa cell surface alpha2beta1 regulates MMP-2 expression. Increased phosphorylation of focal adhesion kinase (FAK) strongly indicates the possible role of FAK in signaling cascade. Incubation of SiHa cell membrane fraction with pure MMP-2 strongly confirms the cell membrane-dependent activation of proMMP2.

Antibodies, Monoclonal↗

PubMed2004

Human fibroblasts with mutations in COL5A1 and COL3A1 genes do not organize collagens and fibronectin in the extracellular matrix, down-regulate alpha2beta1 integrin, and recruit alphavbeta3 Instead of alpha5beta1 integrin.

Dermal fibroblasts derived from types I and IV Ehlers-Danlos syndrome (EDS) patients, carrying mutations in COL5A1 and COL3A1 genes, respectively, synthesize aberrant types V and III collagen (COLL) and show defective organization of these proteins into the extracellular matrix (ECM) and high reduction of their functional receptor, the alpha(2)beta(1) integrin, compared with control fibroblasts. EDS cells also show reduced levels of fibronectin (FN) in the culture medium and lack an FN fibrillar network. Finally, EDS cells prevalently organize alpha(v)beta(3) integrin instead of alpha(5)beta(1) integrin. The alpha(v)beta(3) integrin, distributed on the whole EDS cell surface, shows FN binding and assembly properties when the cells are treated with purified FN. Treatment of EDS cells with purified COLLV or COLLIII, but not with FN, restores the control phenotype (COLL(+), FN(+), alpha(v)beta(3)(-), alpha(5)beta(1)(+), alpha(2)beta(1)(+)). Function-blocking antibodies to COLLV, COLLIII, or alpha(2)beta(1) integrin induce in control fibroblasts an EDS-like phenotype (COLL(-), FN(-), alpha(v)beta(3)(+), alpha(5)beta(1)(-), alpha(2)beta(1)(-)). These results show that in human fibroblasts alpha(2)beta(1) integrin organization and function are controlled by its ligand, and that the alpha(2)beta(1)-COLL interaction, in turn, regulates FN integrin receptor recruitment: high alpha(2)beta(1) integrin levels induce alpha(5)beta(1) integrin organization, while low alpha(2)beta(1) integrin levels lead to alpha(v)beta(3) integrin organization.

Adolescent↗

PubMed1998

Downstream events in mammary gland morphogenesis mediated by reexpression of the alpha2beta1 integrin: the role of the alpha6 and beta4 integrin subunits.

Our previous studies demonstrated that reexpression of the alpha2beta1 integrin by a poorly differentiated breast carcinoma cell line, Mm5MT, resulted in dramatic reversion of a malignant phenotype to a differentiated epithelial phenotype. We hypothesized that reexpression of the alpha2beta1 integrin may regulate expression of other genes, the expression of which contributed to the dramatic phenotypic change. We now show that reexpression of the alpha2beta1 integrin results in up-regulation of both the alpha6 and beta4 integrin subunits but no change in the alpha1, alpha3, alpha5, or beta1 integrin subunits or E-cadherin. To further investigate the role of the alpha6 and beta4 integrin subunits in mediating the phenotypic changes elicited by reexpression of the alpha2beta1 integrin, the alpha6 or beta4 integrin subunit was expressed in our Mm5MT model. Expression of either subunit increased adhesion to laminin-1. Although adhesion to collagen was unaltered, contraction of three-dimensional collagen gels was reduced. Expression of either the alpha6 or beta4 integrin subunit also restored some aspects of a less malignant phenotype, including the acquisition of contact inhibition and diminution of anchorage-dependent and anchorage-independent growth rates. The alpha6 and beta4 transfectants formed three-dimensional organized structures when grown in gels of reconstituted basement membrane but did not form the highly branched, duct-like structures formed by the alpha2 transfectants. In contrast to the reduced invasiveness of the alpha2 transfectants, the alpha6 and beta4 transfectants retained an invasive phenotype. These results suggest that expression of the alpha6beta4 integrin contributes to some but not all of the phenotypic changes elicited by reexpression of the alpha2 integrin subunit and modulates the function of other integrins on these cells. Using our Mm5MT model, we are defining the cascade of integrin expression required for maintenance of the differentiated mammary epithelial cell phenotype.

Animals↗

PubMed2007

What is the alpha2beta1 integrin doing in the epidermis?

The alpha2beta1 integrin is abundantly expressed by basal keratinocytes in intact skin and is required for re-epithelialization of human skin wounds. However, as Grenache et al. and Zweers et al. report, closure of mouse wounds does not require this receptor. The discrepancies between these models may reflect differences in the composition of the dermal matrices and in the proteinases expressed in response to injury.

Animals↗

PubMed2000

Increased expression of alpha2beta1-integrin in the peritoneal dissemination of human gastric carcinoma.

The prognosis of advanced gastric cancer remains poor, given the frequent incidence of peritoneal metastasis. beta1-integrin is known to be associated with metastasis, though few reports have addressed the expression of beta1-integrin subunits in gastric cancer at primary and peritoneal lesions from the perspective of individual cases. We studied specimens from primary tumors from 50 patients and from metastatic peritoneal lesions from 27 patients with gastric carcinoma, including specimens from 22 metastatic lesions taken from the same patients whose primary tumors were sampled. Expression of beta1-integrin subunits, alpha2-alpha6beta1 integrins, was studied using an immunohistochemical method. alpha2beta1-integrin was significantly expressed on a larger proportion of tumor cells in peritoneal metastasis (70.4%) than in primary tumors (48%) (p<0.05), though alpha3beta1, alpha4beta1, alpha5beta1 and alpha6beta1-integrins did not demonstrate significant discrepancy. The expression of alpha2beta1-integrin in peritoneal lesions was significantly increased compared with its expression in the primary lesion in the same individual. In contrast, no relationship was found between the expression level of beta1 integrins and clinicopathological parameters. Peritoneal implantation of gastric carcinoma might be closely associated with alpha2beta1-integrin.

Adult↗

PubMed2001

Modulation of alpha2beta1 integrin changes during mammary gland development by beta-oestradiol.

In order to study the role of cell-matrix interactions in mammary gland function, temporal changes in alpha2beta1 integrin, the major receptor for collagen and the influence of beta-oestradiol on its level and distribution in rat mammary gland at different stages of development were studied. The level of alpha2beta1 integrin determined by ELISA, was found to be high during different days of pregnancy, while in the lactating stage, it was significantly reduced. By immunocytochemical analysis, alpha2beta1 integrin was found to be localized towards the luminal side of acinar cells, both in the virgin and midpregnant stage, while it was not detected in the lactating stage. The possible role of hormones in modulating the level of integrin was examined in both in vitro and in vivo experiments using beta-oestradiol. Supplementing beta-oestradiol to isolated mammary epithelial cells from both virgin and lactating glands caused a concentration dependent increase in the incorporation of [35S]methionine into alpha2beta1 integrin associated with the cells. Administration of beta-oestradiol to virgin and lactating glands caused about 1.4-4-fold increase in the level of alpha2 integrin, indicating that upregulation of integrin during pregnancy may be due to oestrogen and as the oestrogen level falls during lactating phase, downregulation of alpha2beta1 integrin occurs. Treatment with beta-oestradiol also resulted in the appearance of alpha2beta1 integrin in the acinar region of the lactating tissue, while in the untreated controls no staining for integrin was seen. These results indicate that oestrogen, apart from directly affecting the cellular activity, can influence mammary tissue function by affecting cell-ECM interactions through the modulation of integrin receptors for matrix proteins.

Animals↗

PubMed2000

Expression of integrin alpha2beta1 in axons and receptive endings of neurons in rat, hairy skin.

Integrin alpha2beta1 has been considered as a mechano-chemical transducer in endothelial and muscle cells. However, little data is available to show whether integrins play a role in the process of mechanical transduction in peripheral mechanosensory neurons. Using immunohistochemistry, we demonstrate that cutaneous neurons express the extracellular matrix (ECM) receptor integrin alpha2beta1. Specifically, we show that integrins alpha2 and beta1 are co-localized with peripherin in the receptive endings of cutaneous neurons in rat, hairy skin. Integrin immunofluorescence was minimal along the axons of large diameter neurons. These results, together with findings by other investigators, provide evidence suggesting that integrin alpha2beta1 may be a linking agent between mechanical stress in the ECM and modulation of the neuronal response of mechanically sensitive neurons.

Animals↗

PubMed2005

Matrix metalloproteinase activity synergizes with alpha2beta1 integrins to enhance collagen remodeling.

Cell-matrix interactions transmit a wealth of information about the extracellular environment. In return, a variety of responses from the cell are initiated by changes in the matrix. One such response involves the positive regulation of matrix metalloproteinases (MMPs) by alpha2beta1 integrin attaching to a specific extracellular matrix component, collagen. This study explores the relationship between mechanical and biochemical functions of alpha2beta1 integrins as it pertains to regulating matrix remodeling. To understand this relationship, the individual influences of MMP activity and alpha2beta1 integrin function on collagen gel contraction were studied. We have observed little evidence of mutual participation in matrix remodeling by the alpha2beta1 integrin and MMP activity in cell models where alpha2 is minimally expressed. In cells expressing high levels of alpha2, we see an increase in gel contraction that is enhanced by MMP activity. Measuring tension as it builds within the gel reveals that alpha2beta1 integrin presence correlates with force output but is insensitive to MMP activity. These data strongly suggest that alpha2beta1 regulates collagen gel remodeling through multiple simultaneous mechanisms including force generation and modulation of MMP activity.

Bone Remodeling↗

PubMed1999

Integrin alpha2beta1 mediates isoform-specific activation of p38 and upregulation of collagen gene transcription by a mechanism involving the alpha2 cytoplasmic tail.

Two collagen receptors, integrins alpha1beta1 and alpha2beta1, can regulate distinct functions in cells. Ligation of alpha1beta1, unlike alpha2beta1, has been shown to result in recruitment of Shc and activation of the Ras/ERK pathway. To identify the downstream signaling molecules activated by alpha2beta1 integrin, we have overexpressed wild-type alpha2, or chimeric alpha2 subunit with alpha1 integrin cytoplasmic domain in human osteosarcoma cells (Saos-2) lacking endogenous alpha2beta1. The chimeric alpha2/alpha1 chain formed a functional heterodimer with beta1. In contrast to alpha2/alpha1 chimera, forced expression of alpha2 integrin resulted in upregulation of alpha1 (I) collagen gene transcription in response to three-dimensional collagen, indicating that the cytoplasmic domain of alpha2 integrin was required for signaling. Furthermore, signals mediated by alpha2beta1 integrin specifically activated the p38alpha isoform, and selective p38 inhibitors blocked upregulation of collagen gene transcription. Dominant negative mutants of Cdc42, MKK3, and MKK4 prevented alpha2beta1 integrin-mediated activation of p38alpha. RhoA had also some inhibitory effect, whereas dominant negative Rac was not effective. Our findings show the isoform-specific activation of p38 by alpha2beta1 integrin ligation and identify Cdc42, MKK3, and MKK4 as possible downstream effectors. These observations reveal a novel signaling mechanism of alpha2beta1 integrin that is distinct from ones previously described for other integrins.

Collagen↗

PubMed2003

Integrin alphavbeta3 mediates platelet-derived growth factor-BB-stimulated collagen gel contraction in cells expressing signaling deficient integrin alpha2beta1.

The interplay between the collagen-binding integrin, alpha2beta1, and platelet-derived growth factor (PDGF) receptors in the context of functional interactions with collagen was studied. We expressed either wild-type alpha2beta1 (alpha2beta1A) or alpha2beta1 with a Y783/795F mutation in the cytoplasmic tail of the beta1 subunit (alpha2beta1Amut) in the beta1-null fibroblastic cell line, GD25. GD25 cells lack endogenous expression of the alpha1 and alpha2 integrin subunits and do not adhere to collagen even after transfection with beta1A. Cells expressing alpha2beta1Amut contracted three-dimensional collagen lattices less efficiently than those expressing alpha2beta1A. PDGF-BB significantly stimulated lattice contraction by GD25-alpha2beta1Amut cells. Both cell types responded chemotactically to PDGF-BB. Focal adhesion kinase (FAK) and p130(Cas) were phosphorylated when GD25-alpha2beta1A cells, but not GD25-alpha2beta1Amut cells were seeded on collagen-coated dishes. Subsequent treatment with PDGF-BB further increased phosphorylation of FAK and p130(Cas) only in GD25-alpha2beta1A cells. However, when cultured within collagen lattices, FAK and p130(Cas) phosphorylation were stimulated in both alpha2beta1A- and alpha2beta1Amut-expressing cells but further phosphorylation, in response to subsequent treatment with PDGF-BB, was seen only in GD25-alpha2beta1A cells. We show that the stimulatory effects of PDGF-BB on collagen gel contraction and chemotaxis by GD25-alpha2beta1Amut cells were mediated by the alphavbeta3 integrin. Phosphorylation of p130(Cas), but not FAK, in GD25-alpha2beta1Amut cells seeded in collagen lattices also depended on alphavbeta3. Our results show that PDGF-BB stimulation of fibroblast-collagen interactions is mediated by the alphavbeta3 integrin when beta1 integrin function is impaired.

Animals↗

PubMed2001

Platelet collagen receptor alpha2beta1 integrin and glycoprotein IIIa Pl(A1/A2) polymorphisms are not associated with nephropathy in type 2 diabetes.

Platelet glycoprotein receptors play a role in the pathogenesis of chronic diabetic complications. Genetic polymorphisms of the alpha2beta1 integrin and glycoprotein IIIa (GPIIIa) have been associated with myocardial infarction, stroke, and diabetic retinopathy. To identify risk factors for their development in a cohort of patients with type 2 diabetes, we evaluated clinical variables and genetic polymorphisms in the alpha2beta1 integrin and GPIIIa genes. Two hundred thirty-four subjects with type 2 diabetes (126 patients with and 108 patients without diabetic nephropathy), as well as 217 nondiabetic healthy subjects, were recruited for this study. Clinical factors for investigation included sex, age at diagnosis, duration of diabetes, body mass index (BMI), and fasting plasma glucose, hemoglobin A(1c) (HbA(1c)), total cholesterol, and triglyceride levels. Genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism analyses. No difference in the Bgl II polymorphism of the alpha2beta1 integrin gene was found between patients with type 2 diabetes with or without nephropathy (11 [8.7%], 47 [37.3%], and 68 patients [54.0%] versus 10 [9.3%], 32 [29.6%], and 66 patients [61.1%] for Bgl II+/+, Bgl II+/-, and Bgl II-/-, respectively; P = 0.271). Multiple logistic regression analyses showed that duration of diabetes, BMI, hypertension, and poor glycemic control were four independent predictors for the development of diabetic nephropathy. No contribution of the Bgl II+ allele of the alpha2beta1 integrin was found for the risk for nephropathy (odds ratio, 1.258; 95% confidence interval, 0.655 to 2.418; P = 0.490). The Pl(A2) allele genotype was not found among our studied subjects. In conclusion, age, duration of diabetes, BMI, and HbA(1c) level are strong predictors for nephropathy in patients with type 2 diabetes. However, the Bgl II polymorphism of the alpha2beta1 integrin gene and the Apa I polymorphism of the platelet GPIIIa gene do not have a major role in the development of diabetic nephropathy in our population.

Blood Platelets↗

PubMed2003

The alpha2beta1 integrin inhibitor rhodocetin binds to the A-domain of the integrin alpha2 subunit proximal to the collagen-binding site.

Rhodocetin is a snake venom protein that binds to alpha2beta1 integrin, inhibiting its interaction with its endogenous ligand collagen. We have determined the mechanism by which rhodocetin inhibits the function of alpha2beta1. The interaction of alpha2beta1 with collagen and rhodocetin differed: Ca(2+) ions and slightly acidic pH values increased the binding of alpha2beta1 integrin to rhodocetin in contrast with their attenuating effect on collagen binding, suggesting that rhodocetin preferentially binds to a less active conformation of alpha2beta1 integrin. The alpha2A-domain [von Willebrand factor domain A homology domain (A-domain) of the integrin alpha2 subunit] is the major site for collagen binding to alpha2beta1. Recombinant alpha2A-domain bound rhodocetin, demonstrating that the A-domain is also the rhodocetin-binding domain. Although the interaction of alpha2beta1 with rhodocetin is affected by altering divalent cations, the interaction of the A-domain was divalent-cation-independent. The rhodocetin-binding site on the alpha2A-domain was mapped first by identifying an anti-alpha2 antibody that blocked rhodocetin binding and then mapping the epitope of the antibody using human-mouse alpha2A-domain chimaeras; and secondly, by binding studies with alpha2A-domain, which bear point mutations in the vicinity of the mapped epitope. In this way, the rhodocetin-binding site was identified as the alpha3-alpha4 loop plus adjacent alpha-helices. This region is known to form part of the collagen-binding site, thus attaining a mainly competitive mode of inhibition by rhodocetin.

Antibodies, Monoclonal↗

PubMed2002

Trimucytin, a collagen-like snake venom protein, activates platelets independent of I-domain within alpha2 subunit of alpha2beta1 integrin.

Trimucytin is a powerful platelet aggregation inducer isolated from the venom of Taiwan habu snake (Trimeresurus mucrosquamatus). In this study, we found that the snake venom protein, crovidisin, which prevents collagen-platelet interaction through its high-affinity binding to collagen, inhibited competitively trimucytin-induced aggregation of washed human platelets with a pA(2) value of 6.65. The ability of trimucytin in triggering platelet aggregation was suppressed by a monoclonal antibody (A2-IIE10) raised against the alpha2 subunit of alpha2beta1 integrin (glycoprotein Ia/IIa), indicating that platelet alpha2beta1 integrin plays a central role in trimucytin's platelet reactivity. Many studies have localized the major reactive site of alpha2beta1 integrin to the I-domain of alpha2 subunit. However, Escherichia coli-produced recombinant alpha2 I-domain (GST-alpha2 fusion protein) blocking collagen-induced platelet aggregation failed to inhibit aggregation of platelets in response to trimucytin. Based on these findings, it is concluded that the platelet reactivity of trimucytin is alpha2beta1 integrin-dependent, while the I-domain present in the alpha2 subunit is not involved. This novel snake venom protein would be useful for mapping the functional domain of alpha2beta1 integrin.

Animals↗

PubMed2003

BglII gene polymorphism of the alpha2beta1 integrin gene is a risk factor for diabetic retinopathy in Caucasians with type 2 diabetes.

Platelets are thought to be involved in the pathogenesis of diabetic retinopathy. The BglII gene polymorphism of the alpha2beta1 integrin, which is a platelet collagen receptor, has been suggested as a genetic risk factor for diabetic retinopathy in Japanese subjects. The aim of this study was to look for a relationship between the BglII gene polymorphism of the alpha2beta1 integrin gene and the development of diabetic retinopathy in Caucasians with type 2 diabetes. Subjects with type 2 diabetes and diabetic retinopathy (n=163) were compared with diabetic subjects without diabetic retinopathy (n=95). A significantly higher frequency of the BglII (+/+) genotype of the gene polymorphism of the alpha2beta1 integrin gene was found in patients with diabetic retinopathy compared with patients without diabetic retinopathy (19.6% vs 7.4%; P=0.008). The present study demonstrates that the BglII (+/+) genotype of the gene polymorphism of the alpha2beta1 integrin gene is an independent risk factor (odds ratio: 2.4, 95% confidence interval 1.0-6.0; P<0.05) for diabetic retinopathy in Caucasians with type 2 diabetes.

Aged↗

PubMed2006

Endorepellin, the C-terminal angiostatic module of perlecan, enhances collagen-platelet responses via the alpha2beta1-integrin receptor.

Endorepellin, a C-terminal fragment of the vascular basement membrane proteoglycan perlecan, inhibits angiogenesis via the alpha2beta1-integrin receptor. Because this integrin is also implicated in platelet-collagen responses and because endorepellin or its fragments are generated in response to injury and inflammation, we hypothesized that endorepellin could also affect platelet biology. We discovered that endorepellin supported alpha2beta1-dependent platelet adhesion, without appreciably activating or aggregating platelets. Notably, endorepellin enhanced collagen-evoked responses in platelets, in a src kinase-dependent fashion, and enhanced the collagen-inhibitory effect of an alpha2beta1-integrin function-blocking antibody. Collectively, these results suggest that endorepellin/alpha2beta1-integrin interaction and effects are specific and dependent on cell type, differ from those emanated by exposure to collagen, and may be due to cellular differences in alpha2beta1-integrin activation/ligand affinity state. These studies also suggest a heretofore unrecognized role for angiostatic basement membrane fragments in platelet biology.

Angiostatic Proteins↗