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PubMed2006

beta1 integrins modulate p66ShcA expression and EGF-induced MAP kinase activation in fetal lung cells.

ShcA proteins mediate Erk1/Erk2 activation by integrins and epidermal growth factor (EGF), and are expressed as p46ShcA, p52ShcA, and p66ShcA. Although p52ShcA and p46ShcA mediate Erk1/Erk2 activation, p66ShcA antagonizes Erk activation. p66ShcA is spatially regulated during lung development, leading us to hypothesize that integrin signaling regulates p66ShcA expression and, consequently, EGF signaling. Fetal lung mesenchymal cells were isolated from E16 Swiss-Webster mice, stimulated with oligopeptide extracellular matrix analogs or anti-integrin antibodies, and subjected to ShcA Western analyses and EGF-stimulated Erk1/Erk2 kinase assays. p66ShcA expression was decreased by anti-alpha1 integrin antibody and DGEA collagen analog, and increased by anti-beta1, anti-alpha4, and anti-alpha5 integrin antibodies and RGDS fibronectin analog. Paradoxically, beta1 integrin stimulation increased EGF-induced Erk activation while increasing expression of the inhibitory p66ShcA isoform. This paradox was resolved by demonstrating that Erk inhibition attenuates integrin-mediated p66ShcA induction. These results suggest that p66ShcA is up-regulated as inhibitory feedback on integrin-mediated Erk activation.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Cellular expression of integrin-beta 1 is of critical importance for inducing therapeutic angiogenesis by cell implantation.

OBJECTIVES: Using cell-based therapy to induce therapeutic angiogenesis has been the focus of much recent attention. We used freshly collected CD117-positive stem cells (CD117(+) cells) and ex vivo expanded CD117(+) cells to investigate the role of cellular expression of several adhesion molecules in this therapeutic regimen. METHODS: CD117(+) cells were separated from the bone marrow mononuclear cells of C57/BL6 mice and cell expansion was done by 2 weeks of cultivation. The cellular expression of integrin-beta(1), integrin-beta(3) and VE-cadherin was analyzed by Western blot and real-time PCR. Three-dimensional culture was performed to observe the capillary-like tube formation. We also implanted cells into the ischemic limbs of mice and evaluated the survival and incorporation of these implanted cells and measured the blood flow and microvessel density of the ischemic limbs 2 weeks after treatment. RESULTS: The expression of integrin-beta(1) in the expanded cells decreased significantly, to about 30% of the freshly unexpanded CD117(+) cells. However, the expression of integrin-beta(3) did not change significantly and the VE-cadherin increased after ex vivo expansion of the CD117(+) cells. Antibody perturbation to integrin-beta(1) significantly inhibited the adhesion, growth and tube formation of cultured CD117(+) cells. Furthermore, the freshly unexpanded CD117(+) cells survived well and were incorporated in microvessels after implantation into the ischemic limbs of mice, resulting in a significant increase in blood flow and microvessel density. The cell survival and incorporation decreased, and the angiogenic potency was deprived by antibody perturbation to integrin-beta(1) before implantation. Conversely, these expanded cells had weak angiogenic potency because of the poor cell survival and incorporation after implantation, but the increase in integrin-beta(1) expression by subjecting them to 24-h hypoxia prestimulation increased cell survival and angiogenic potency significantly after implantation into the ischemic limbs. CONCLUSION: These data clearly show that integrin-beta(1) is a critical adhesion molecule for inducing therapeutic angiogenesis in cell-based therapy, by regulating cell survival and differentiation after implantation into ischemic tissue.

Animals↗

PubMed2004

Integrin expression and survival in human breast cancer.

BACKGROUND: Integrin cell adhesion molecules are fundamental to numerous cellular functions including anchorage, differentiation and proliferation. Reduced expression of certain alpha and beta integrin subunits in primary breast cancer cells has been correlated with increased invasion and metastasis. Conversely, over-expression of the alpha6 subunit has been linked to poorer survival. The objective of this study was to measure the survival of a cohort with breast carcinoma in relation to integrin expression and to evaluate their potential as prognostic indicators. METHOD: Integrin expression on samples from 99 consecutive patients with breast cancer was assayed using monoclonal antibodies to the subunits alpha(1,2,3,6,V) and beta(1,3,4,5). This cohort has now been followed prospectively for almost five years allowing for early assessment of survival in relation to integrin expression. RESULTS: Whilst analysis of the data confirmed the relation of survival to proven predictors of tumour grade, tumour size and vascular invasion, statistical significance was not demonstrated with regard to both lymph node status and all integrin subunits studied. CONCLUSION: Previous research correlating certain integrin subunits with survival has not been confirmed in this study. Despite proven molecular importance in tumour cell adhesion, invasion and metastasis, integrin expression would appear not to translate clinically as independent indicators of prognosis, at least in the short-term.

Adult↗

PubMed2005

A hemocyte-specific integrin required for hemocytic encapsulation in the tobacco hornworm, Manduca sexta.

Upon encountering an object recognized as foreign, insect hemocytes aggregate in multiple layers on the surfaces of the object in a process known as encapsulation. For encapsulation to occur, hemocytes must switch from their usual nonadherent state to an adherent state, presumably by regulating the activity of adhesion proteins. Although detailed knowledge exists regarding the adhesion receptors for cells of the mammalian immune system, comparable information on adhesion molecules of insect hemocytes and their function in immune responses is extremely limited. We report here the identification of an integrin present exclusively on the surface of hemocytes in the tobacco hornworm, Manduca sexta. Monoclonal antibodies MS13 and MS34, which bind to plasmatocytes and block encapsulation, were used for immunoaffinity chromatography to isolate their corresponding hemocyte antigen, which was revealed to be the same integrin beta subunit. A cDNA for this M. sexta integrin beta1 was cloned and characterized. Integrin-beta1 mRNA was detected by Northern analysis in hemocytes and not in other tissues tested. MS13 and MS34 were demonstrated to bind to a recombinant fragment of integrin beta1 consisting of the I-like domain, consistent with their blocking of a ligand-binding site and subsequent disruption of plasmatocyte adhesion. Injection of double stranded integrin-beta1 RNA into larvae resulted in decreased integrin beta1 expression in plasmatocytes and significantly suppressed encapsulation. These results indicate that activation of ligand-binding by the hemocyte-specific integrin plays a key role in stimulating plasmatocyte adhesion leading to encapsulation.

Amino Acid Sequence↗

PubMed2005

RGD peptides confer survival to hepatocytes via the beta1-integrin-ILK-pAkt pathway.

BACKGROUND/AIMS: Allogeneic cell transplantation is characterized by a lack of sustained survival of the transplanted cells in the recipient. Activation of the appropriate integrin-linked signaling pathways in cells can promote cell survival. The purpose of this study was to determine how presence or absence of anti-beta1 integrin chain antibodies or RGD peptides affects the survival of hepatocytes. METHODS: Hepatocytes of BN rats were isolated. Hepatocyte survival was tested after the hepatocytes had been cultured in the presence of anti-beta1 integrin antibodies or RGD peptides. Hepatocytes that had been given a different treatment were stained for caspase 3 (apoptosis marker) and phospho-Akt Ser 473 (survival marker) and were measured for their integrin-linked kinase (ILK) activity. RESULTS: Ligation of integrins using antibodies against the beta1 integrin chain or RGD peptides protected isolated hepatocytes from apoptosis and resulted in an increased ILK activity and persistent phosphorylation of protein kinase B/Akt at serine 473. CONCLUSIONS: Integrin activation in isolated hepatocytes contributes to the activation of ILK, phosphorylation of Akt on serine residue 473, and inhibition of apoptosis. Integrin signaling through the ILK-phospho Akt pathway protects isolated hepatocytes from apoptosis. This notion may potentially be applied to render the transplantation of hepatocytes more effective.

Animals↗

PubMed2006

The molecular basis of filamin binding to integrins and competition with talin.

The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Filamins are large, actin-crosslinking proteins that connect multiple transmembrane and signaling proteins to the cytoskeleton. Here, we describe the high-resolution structure of an interface between filamin A and an integrin adhesion receptor. When bound, the integrin beta cytoplasmic tail forms an extended beta strand that interacts with beta strands C and D of the filamin immunoglobulin-like domain (IgFLN) 21. This interface is common to many integrins, and we suggest it is a prototype for other IgFLN domain interactions. Notably, the structurally defined filamin binding site overlaps with that of the integrin-regulator talin, and these proteins compete for binding to integrin tails, allowing integrin-filamin interactions to impact talin-dependent integrin activation. Phosphothreonine-mimicking mutations inhibit filamin, but not talin, binding, indicating that kinases may modulate this competition and provide additional means to control integrin functions.

Amino Acid Sequence↗

PubMed2006

Molecular modeling of the thyroid hormone interactions with alpha v beta 3 integrin.

A cell surface receptor for thyroid hormone has recently been identified on the extracellular domain of integrin alphavbeta3. In a variety of human and animal cell lines this hormone receptor mediates activation by thyroid hormone of the cellular mitogen-activated protein kinase (MAPK) signal transduction cascade. An arginine-glycine-aspartate (RGD) recognition site on the heterodimeric integrin is essential to the binding of a variety of extracellular matrix proteins. Recent competition data reveal that RGD peptides block hormone-binding by the integrin and consequent MAPK activation, suggesting that the hormone interaction site is located at or near the RGD recognition site on integrin alphavbeta3. A deaminated thyroid hormone (l-thyroxine, T4) analogue, tetraiodothyroacetic acid (tetrac, T4ac), inhibits binding of T4 and 3,5,3'-triiodo-l-thyronine (T3) to alphavbeta3, but does not activate MAPK. Structural data show that the RGD cyclic peptide binds at the interface of the propeller of the alphav and the B domains on the integrin head [Xiong JP, Stehle T, Zhang R, Joachimiack A, Frech M, Goodman SL, et al. Crystal structure of the extracellular segment of integrin alphavbeta3 in complexing with an Arg-Gly-Asp ligand. Science 2002;296:151-5]. To model potential interactions of thyroid hormone analogues with integrin, we mapped T4 and T4ac to the binding site of the RGD peptide. Modeling studies indicate that there is sufficient space in the cavity for the thyroid hormone to bind. Since the hormone is smaller in overall length than the RGD peptide, the hormone does not interact with the Arg recognition site in the propeller domain from alphav. In this model, most of the hormone interactions are with betaA domain of the integrin. Mutagenic studies can be carried out to validate the role of these residues in directing hormone interactions.

Integrin alphaVbeta3↗

PubMed2004

The talin-tail interaction places integrin activation on FERM ground.

Integrins are essential receptors for the development and functioning of multicellular animals because they mediate cell migration and cell adhesion, and regulate cell proliferation and apoptosis. Cellular regulation of the affinity of integrins for ligands - so-called 'integrin activation' - is a central property of these receptors. Integrin activation controls cell adhesion, migration and extracellular matrix assembly, thereby contributing to processes such as angiogenesis, tumor cell metastasis, inflammation, the immune response and hemostasis. Recent studies indicate that a crucial, final step in integrin activation is the binding of talin, a cytoskeletal protein, to the cytoplasmic domain of the integrin beta subunit. These results provide a focus for unraveling the many biochemical pathways implicated in integrin activation and suggest a general structural model for the connections between integrins and diverse cellular signal transduction pathways.

Animals↗

PubMed2006

Granulocyte colony-stimulating receptor promotes beta1-integrin-mediated adhesion and invasion of bladder cancer cells.

OBJECTIVES: To determine whether granulocyte colony-stimulating factor receptor (G-CSFR) autocrine signaling promotes endothelial cell adhesion and invasion of bladder cancer cells through a beta1-integrin-mediated pathway. A significant fraction of invasive bladder carcinomas express both G-CSF and G-CSFR. Bladder carcinoma cell line 5637 constitutively secretes G-CSF but lacks G-CSFR expression. Thus, we studied the effects of G-CSFR expression on cell adhesion and invasion in this unique model system. METHODS: Flow cytometry and adhesion assay were performed to detect expression of beta1-integrin in G-CSFR-expressing 5637 cells and adhesion of these cells to human umbilical vein endothelial cell, respectively. Furthermore, an invasion chamber assay was done with the 5637 cells. Next, we used the G-CSF-specific antibody, siRNA, and a truncated version of G-CSFR (GR19) to block G-CSFR autocrine loop in these cells. We also used a beta1-integrin-specific neutralizing antibody in the adhesion and invasion assays with the 5637 cells. RESULTS: G-CSFR-mediated increased expression (approximately threefold) of beta1-integrin is significantly abrogated by G-CSF specific antibody or siRNA in 5637 cells. GR19 also completely blocked beta1-integrin expression. G-CSFR signaling increased adhesion (approximately 2.5-fold) of 5637 cells to human umbilical vein endothelial cells, which are potently blocked by beta1-integrin-specific antibody. G-CSF/G-CSFR autocrine signaling significantly increased the invasiveness of 5637 cells (approximately 10-fold), which was reduced by either attenuating G-CSF production (G-CSF-specific antibody and siRNA) or interfering with G-CSFR signaling (GR19). Furthermore, beta1-integrin-specific antibody completely blocked G-CSFR-mediated invasion of 5637 cells. CONCLUSIONS: Autocrine G-CSF/G-CSFR signaling in bladder cancer can significantly contribute to cancer cell adhesion and invasion in a beta1-integrin-dependent manner.

Adhesiveness↗

PubMed2005

Epithelial membrane protein-2 regulates surface expression of alphavbeta3 integrin in the endometrium.

The four-transmembrane protein epithelial membrane protein-2 (EMP2) was recently identified as an endometrial protein necessary for blastocyst implantation, but the mechanism of this role is uncertain. In other cell types, EMP2 controls delivery of certain classes of proteins to the cell surface, including various integrin isoforms (a class of receptors implicated in endometrial-blastocyst interaction). Since alphavbeta3 integrin is an important endometrial molecule involved in blastocyst interaction, we evaluated the role of EMP2 in modulating integrin expression in the HEC1A endometrial cell line and endometrial epithelium in vivo. Elevation of EMP2 expression in HEC1A cells selectively increased the expression of alphavbeta3 integrin on the plasma membrane and was functional as judged by increased cell binding to an alphavbeta3 ligand, fibronectin. Conversely, reduction in EMP2 expression using an EMP2 specific ribozyme decreased the cell alphavbeta3 surface expression. The influence of EMP2 on alphavbeta3 integrin was also observed in vivo as reduction of EMP2 using ribozymes or short hairpin RNA diminished alphavbeta3 integrin expression in glandular and luminal uterine epithelium. Colocalization and coimmunoprecipitation studies suggested that EMP2 and alphavbeta3 integrin predominantly exist in a physically associated state. This study demonstrates for the first time the influence of EMP2 on alphavbeta3 surface expression and suggests that surface trafficking of integrin alphavbeta3 by EMP2 during the window of implantation may be a mechanism for its requirement in endometrial-blastocyst interaction.

Animals↗

PubMed2003

Beta4 integrin and laminin 5 are aberrantly expressed in polycystic kidney disease: role in increased cell adhesion and migration.

Extracellular matrix alterations have been suggested to be part of the early events occurring in Autosomal Dominant Polycystic Kidney Disease (ADPKD), a disease characterized by formation of renal cysts and progressive renal failure. Here we report that cDNA array analysis identified beta(4) integrin aberrant expression in ADPKD cells. Furthermore, laminin 5 (Ln-5), the main alpha(6)beta(4) integrin ligand, was also found to be abnormally expressed in ADPKD. Studies performed with ADPKD cyst-lining epithelial cells (CC) by comparison with normal tubular cells indicate that integrin alpha(6)beta(4)-Ln-5 interactions are involved in cellular events of potential importance for cystogenesis: 1) laminin 5 is a preferential adhesion substrate for CC, mainly through alpha(6)beta(4) interaction, 2) CC increased haptotactic and chemotactic motility depends on the presence of Ln-5 and requires integrin alpha(3)beta(1) cooperation, and 3) CC haptotactic or chemotactic migration is specifically increased by mAb-mediated beta(4) integrin ligation, through an alpha(3)beta(1) integrin-dependent and independent pathway, respectively. These results highlight the role of Ln-5 and alpha(6)beta(4) integrin in adhesive and motility properties of cyst-lining epithelial cells, and further suggest that integrins and extracellular matrix modifications may be of general relevance to kidney epithelial cell cyst formation.

Adult↗

PubMed2003

beta 1C Integrin expression in human endometrial proliferative diseases.

Integrins are ubiquitous cell adhesion molecules that are involved in maintaining normal tissue morphology and have been implicated in the aggressive behavior of several malignancies. beta 1C integrin is an alternatively spliced variant of the beta 1A integrin subunit that, at variance with beta 1A, inhibits epithelial cell proliferation. beta 1C integrin is expressed in non-proliferative, benign prostatic epithelium and is down-regulated in prostatic adenocarcinoma. In the current study, we examined beta 1C expression at mRNA and protein levels in 18 endometrial adenocarcinoma and in 20 endometrial hyperplastic tissues, using Northern and Western blotting analysis and immunohistochemistry. The pattern of integrin expression was compared to that of the endometrium of 14 normal cycling women. The results of this study document inhibited beta 1C integrin expression in endometrial adenocarcinoma, both at the mRNA and protein levels, at variance with significantly up-regulated beta 1C mRNA expression in endometrial hyperplasia, in comparison with normal proliferative endometria. Our data suggest a key role of the regulation of beta 1C integrin expression in the pathogenesis of endometrial proliferative diseases: beta 1C integrin may act as growth modulator in cancer cells, playing a role in downstream intracellular signaling.

Adenocarcinoma↗

PubMed2002

The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis.

The alpha(2)beta(1) integrin is a collagen/laminin receptor expressed on platelets, endothelial cells, fibroblasts, and epithelial cells. To define the role of the alpha(2)beta(1) integrin in vivo, we created a genetically engineered mouse in which expression of the alpha(2)beta(1) integrin was completely eliminated. Mice deficient in the alpha(2)beta(1) integrin are viable, fertile, and develop normally with no excess lethality of homozygotes. Both alpha(2)beta(1)-integrin protein and alpha(2) mRNA were undetectable in the alpha(2)-null mice. Gross and histological evaluation of the heart, lungs, kidneys, gastrointestinal tract, pancreas, skin, and reproductive tracts revealed no abnormalities. However, quantitative analysis of mammary gland branching morphogenesis demonstrated that branching complexity is markedly diminished in the alpha(2)-deficient animals. Studies in the alpha(2)-deficient animals do not support the proposed roles for the alpha(2)beta(1) integrin on fibroblasts and keratinocytes in wound healing. When compared to platelets from wild-type littermates, platelets from alpha(2)-null mice failed to adhere to type I collagen under either static or shear-stress conditions. Although platelets from alpha(2)-deficient animals aggregated in response to collagen, they did so with prolonged lag time and lessened intensity. The alpha(2)beta(1) integrin-null mouse thus exhibits diverse, sometimes subtle, phenotypes consistent with the widespread pattern of alpha(2)beta(1) integrin expression.

Animals↗

PubMed2003

Blocking of alpha 5 integrin stimulates production of TGF-beta and PAI-1 by human mesangial cells.

Expression of integrin, which mediates cell-matrix interaction, is affected by several cytokines, in particular by transforming growth factor-beta (TGF-beta). However, it is unknown whether, in an opposite way, a specific integrin is involved in cytokine synthesis. We tested this hypothesis. Function-blocking anti-alpha 5 integrin (fibronectin receptor) antibody increased TGF-beta secretion in growth-arrested human mesangial cells (2.3-fold) compared with control IgG or anti-alpha v beta 3 integrin (receptor for several matrix proteins) antibody. It also increased the secretion of plasminogen activator inhibitor-1 (PAI-1), a protein associated with matrix increase, by 3.2-fold. The increase in PAI-1 secretion induced by anti-alpha 5 integrin antibody was not abrogated by anti-TGF-beta neutralizing antibody. These results indicate that function-blocking of anti-alpha 5 integrin stimulates TGF-beta as well as PAI-1 production, suggesting that alpha 5 integrin is involved in fibrotic process. Function-modulation of a specific integrin thus appears to play a role in glomerular remodeling.

Antibodies↗

PubMed2003

FRET detection of cellular alpha4-integrin conformational activation.

Integrins are cell adhesion receptors, expressed on every cell type, that have been postulated to undergo conformational changes upon activation. Here, different affinity states were generated by exposing alpha4-integrins to divalent ions or by inside-out activation using a chemokine receptor. We probed the dynamic structural transformation of the integrin on live cells using fluorescence resonance energy transfer (FRET) between a peptide donor, which specifically binds to the alpha4-integrin, and octadecyl rhodamine B acceptors incorporated into the plasma membrane. We analyzed the data using a model that describes FRET between a random distribution of donors and acceptors in an infinite plane. The distance of closest approach was found to vary with the affinity of the integrin. The change in distance of closest approach was approximately 50 A between resting and Mn2+ activated receptors and approximately 25 A after chemokine activation. We used confocal microscopy to probe the lateral organization of donors and acceptors subsequent to integrin activation. Taken together, FRET and confocal results suggest that changes in FRET efficiencies are primarily due to the vertical extension of the integrin. The coordination between the extension of alpha4-integrin and its affinity provides a mechanism for Dembo's catch-bond concept.

Biophysical Phenomena↗

PubMed2003

Detecting rapid and transient upregulation of leukocyte integrin affinity induced by chemokines and chemoattractants.

The majority of integrins expressed on circulating leukocytes are quiescent and do not mediate adhesion. In the process of emigrating from blood into tissues, leukocytes are exposed to a variety of stimuli, including chemokines, which rapidly activate integrin function through changes in affinity and/or avidity. High affinity is brought about by a change in integrin conformation and results in formation of a stable bond with ligand. This can be measured in soluble ligand-binding assays. Integrin conformation changes also result in exposure of previously masked epitopes that can be detected with monoclonal antibodies. In this report, methods used to detect high affinity integrins are reviewed. Four different approaches are discussed, including detection of masked epitopes with monoclonal antibodies, and binding of soluble ligands, ligand-coated beads, and ligand-mimetic peptides. Improved techniques to measure rapid changes in integrin affinity in real time may be valuable both to study mechanisms of inside-out integrin activation and as a tool to screen for effective inhibitors of integrin activation in inflammatory disease models.

Antibodies, Monoclonal↗

PubMed2003

Engineered fibronectin type III domain with a RGDWXE sequence binds with enhanced affinity and specificity to human alphavbeta3 integrin.

Fibronectin is an extracellular matrix protein with broad binding specificity to cell surface receptors, integrins. The tenth fibronectin type III domain (FNfn10) is a small, autonomous domain of fibronectin containing the RGE sequence that is directly involved in integrin binding. However, in isolation FNfn10 only weakly bind to integrins. We reasoned that high-affinity and high-specificity variants of FNfn10 to a particular integrin could be engineered by optimizing residues surrounding the integrin-binding RGD sequence in the flexible FG loop. Affinity maturation of FNfn10 to alphavbeta3 integrin, an integrin up-regulated in angiogenic endothelial cells and in some metastatic tumor cells, yielded alphavbeta3-binding FNfn10 mutants with a novel RGDWXE consensus sequence. We characterized one of the RGDWXE-modified clones, FNfn10-3JCLI4, as purified protein. FNfn10-3JCLI4 binds with high affinity and specificity to purified alphavbeta3 integrin. Alanine scanning mutagenesis suggested that both the tryptophan and glutamic acid residues following the RGD sequence are required for maximal affinity and specificity for alphavbeta3. FNfn10-3JCLI4 specifically stained alphavbeta3-positive cells as detected with flow cytometry and it inhibited alphavbeta3-dependent cell adhesion. As with the anti-alphavbeta3 antibody LM609, FNfn10-3JCLI4 can interfere with in vitro capillary formation. Taken together, these data show that FNfn10-3JCL14 is a specific, high-affinity alphavbeta3-binding protein that can inhibit alphavbeta3-dependent cellular processes similar to an anti-alphavbeta3 monoclonal antibody. These properties, combined with the small, monomeric, cysteine-free and highly stable structure of FNfn10-3JCLI4, may make this protein useful in future applications involving detection and targeting of alphavbeta3-positive cells.

Alanine↗

PubMed2003

Integrin receptors: the dynamic modulators of endometrial function.

Cell-cell and cell-extracellular matrix (ECM) interactions play a critical role in various developmental processes, including differentiation, proliferation and migration of cells. ECM proteins can influence cellular function thus creating a complex feedback mechanism. The adhesion of cells to each other, their ECM proteins and endothelial surfaces is mediated by a variety of membrane proteins collectively known as adhesion molecules. Adhesion molecules have been further divided into five subfamilies, the integrins, the selectins, the cadherins, the mucins and the immunoglobulin superfamily. Members of the integrin family of cell surface adhesion receptors are important mediators of cell-ECM contact. Integrin receptors are alpha beta heterodimers with a transmembrane segment, a short cytoplasmic domain and a large extracellular domain. The role of integrins in reproduction has been established. Several reasons make these molecules very attractive due to their constant involvement from egg to birth. They participate in sperm-egg interaction, fertilization, implantation and placentation in many species including humans. Integrins provide signals to individual cells essential for growth and development of different tissues. In the present review, we describe (1) the regulatory pathways for controlling expression of integrins in the endometrium, (2) various biomarkers and their role in endometrial function, (3) reproductive disorders in women related to aberrant integrin expression in the endometrium and (4) the functional significance of integrins available from gene knockout studies.

Animals↗