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PubMed2004

Effect of suture repair on expression of beta1 integrin subunit in wounded rat patellar tendon.

Integrins play key roles in wound healing by mediating cell adhesion events. The purpose of this study was to determine how to change the expression level of the beta1 integrin subunit (integrin beta1) in the restoration of a tendon and to investigate the influence of suture on its expression. The lateral half of the patellar tendon in rats was transected. Half the rats were sutured immediately and the other half were left as they were. The rats were killed at 4, 7, 10, 14, 28, and 56 days postsurgery. Integrin beta1 expression in each harvested tendon was analyzed using immunohistochemistry and real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Integrin beta1 was immunolocalized in fibroblasts adjacent to the wound and within the repair site itself. Although immunoreactivity for integrin beta1 in the unsutured group decreased on the tenth day, that in the sutured group continued to increase. In real-time quantitative RT-PCR, integrin beta1 mRNA expression level increased in both groups, but that in the unsutured group was higher than that in the sutured group. Our study indicates that suture influences the expression and mRNA level of integrin beta1, which is associated with tendon healing.

Animals↗
PubMed1997

Structural interlock between ligand-binding site and stalk-like region of beta1 integrin revealed by a monoclonal antibody recognizing conformation-dependent epitope.

Integrin activation and sebsequent ligand binding to it are regulated by intracellular mechanisms called inside-out signaling, which are not fully understood and are accompanied by dynamic structural changes of the integrin molecule itself. A monoclonal antibody recognizing a conformation-dependent epitope on human beta1 integrin was produced and characterized in detail. This antibody, AG89, reacted with human integrin beta1 chain regardless of the alpha subunit. AG89 can recognize resting state beta1 integrin on the cells, but the reactivity is increased approximately 2-fold upon integrin activation by activating anti-beta1 antibodies and approximately 3-fold by Mn2+. Furthermore, occupation of the ligand-binding pocket by a soluble ligand (RGD peptide for alpha(v)beta1 and CS-1 peptide for alpha4beta1) resulted in maximum binding of AG89, indicating that the epitope for AG89 is exposed during the conformational changes of beta1 integrin upon activation/ligation. Epitope mapping by using interspecies chimeric beta1 revealed that the epitope for AG89 lies within residues 426-587, which corresponds to the cysteine-rich repeat structure located in the middle of the beta1 chain. The fact that binding of AG89 itself could activate the resting beta1 integrin indicates that exposure of the AG89 epitope in the membrane-proximal stalk-like domain and "opening" of the ligand-binding pocket at the outermost domain are physically linked. We propose that the integrin "signaling" is mediated by this direct physical transduction of conformational information along the integrin molecule.

Antibodies, Monoclonal↗
PubMed1999

The muscle-specific laminin receptor alpha7 beta1 integrin negatively regulates alpha5 beta1 fibronectin receptor function.

alpha7 beta1 is the major integrin complex expressed in differentiated muscle cells where it functions as a laminin receptor. In this work we have expressed the alpha7 integrin subunit in CHO cells to investigate the functional properties of this receptor. After transfection with alpha7 CHO cells acquired the ability to adhere and spread on laminin 1 consistent with the laminin receptor activity of the alpha7 beta1. alpha7 transfectants, however, showed a 70% reduction in the ability to adhere to fibronectin and were unable to assemble a fibronectin matrix. The degree of reduction was inversely related to the level of alpha7 expression. To define the mechanisms underlying this adhesive defect we analyzed surface expression and functional properties of the alpha5 beta1 fibronectin receptor. Although cell surface expression of alpha5 beta1 was reduced by a factor of 20-25% in alpha7 transfectants compared to control untransfected cells, this slight reduction was not sufficient to explain the dramatic reduction in cell adhesion (70%) and matrix assembly (close to 100%). Binding studies showed that the affinity of 125I-fibronectin for its surface receptor was decreased by 50% in alpha7 transfectants, indicating that the alpha5 beta1 integrin is partially inactivated in these cells. Inactivation can be reversed by Mn2+, a cation known to increase integrin affinity for their ligands. In fact, incubation of cells with Mn2+ restored fibronectin binding affinity, adhesion to fibronectin, and assembly of fibronectin matrix in alpha7 transfectants. These data indicate that alpha7 expression leads to the functional down regulation of alpha5beta1 integrin by decreasing ligand binding affinity and surface expression. In conclusion, the data reported establish the existence of a negative cooperativity between alpha7 and alpha5 integrins that may be important in determining functional regulation of integrins during myogenic differentiation.

Amino Acid Sequence↗
PubMed1998

Neural precursor cell chain migration and division are regulated through different beta1 integrins.

Proliferation and tangential migration of neural precursor cells are essential determinants of CNS development. We have established cell culture models of both these processes using neural precursor cells grown as neurospheres. The pattern of migration that we observe in these cells is homotypic and occurs in the absence of a glial or neuronal scaffold, and is therefore equivalent to that previously described as chain migration. To determine the role of integrins in proliferation and migration, we have analysed the expression pattern of integrins on neurosphere cells and then performed blocking peptide and antibody experiments. Neurosphere cells express five major integrins, alpha5 beta1, alpha 6Abeta1, alphav beta1, alphav beta5 and alpha vbeta8 and, in addition, express low levels of alpha 6Bbeta1. Chain migration is inhibited by blocking the alpha 6beta1 integrin. Proliferation, by contrast, is inhibited by blocking the other beta1 integrins, alphav beta1 and alpha5 beta1. These results show that integrins are important regulators of neural precursor cell behaviour, with distinct beta1 integrins regulating proliferation and migration. They also demonstrate a novel role for the alpha6 beta1 integrin in the cell-cell interactions underlying homotypic chain migration.

Animals↗
PubMed2003

beta1-integrin mediates asbestos-induced phosphorylation of AKT and ERK1/2 in a rat pleural mesothelial cell line.

Integrin-mediated signalling has been implicated in asbestos-induced carcinogenesis. In studies here, we examined signal transduction events associated with integrin-directed cell reactions triggered by crocidolite asbestos in the pleural mesothelial cell line 4/4 RM-4. Crocidolite fibres induced a significant time- and dose-dependent activation of the extracellular-signal-regulated kinases ERK1 and ERK2. ERK activation was specifically inhibited by integrin-blocking agents, that are integrin-binding peptides containing the sequence arginine-glycine-aspartic acid (RGD), and monoclonal antibodies against the integrin beta1-chain. Integrin-dependent activation of ERK1/2 in response to asbestos appeared to be independent of focal adhesion kinase pp125FAK (FAK) since FAK autophosphorylation remained unaffected in crocidolite-exposed mesothelial cells. Instead, we observed striking similarities in the kinetics of asbestos-induced ERK1/2 responses and phosphorylation of protein kinase B (AKT) at serine 473, a possible target residue for integrin-linked kinase. As with ERK activation, asbestos-induced AKT stimulation was significantly blocked by both the RGD-peptide and the beta1-integrin antibodies. These studies are the first to establish that in mesothelial cells ERK1/2 and AKT are simultaneously phosphorylated upon asbestos exposure in a beta1-integrin-dependent manner.

Animals↗
PubMed2004

Phosphatidylinositol-3-kinase activation mediates proline-rich tyrosine kinase 2 phosphorylation and recruitment to beta1-integrins in human CD34+ cells.

OBJECTIVE: beta1-integrins mediate hematopoietic stem and progenitor cell homing and retention in the bone marrow (BM) and inhibit hematopoietic proliferation and differentiation. Having no intrinsic kinase activity, integrins recruit intracellular kinases, such as the focal adhesion kinase (FAK) or the related proline-rich tyrosine kinase 2 (PYK2), to initiate signal transduction. Phosphatidylinositol-3-kinase (PI3K), which is involved in beta1-integrin signaling in many cell types, is physically and functionally associated with FAK in anchorage-dependent cells. Because PYK2 is the principal focal adhesion kinase expressed in primary human CD34+ cells, we assessed its functional relationship with PI3K in CD34+ cells in response to integrin engagement. METHODS: beta1-integrins on primary mobilized peripheral blood CD34+ cells and CD34+ KG1A cells were engaged by adhesion to fibronectin (FN) or by cross-linking with an anti-beta1 integrin antibody, respectively. PI3K activity and PYK2 phosphorylation were then assessed in the presence or absence of the PI3K inhibitor, wortmannin. Association between PI3K, PYK2, and the beta1-integrin subunit were also evaluated in co-immunoprecipitation experiments. RESULTS: beta1-integrin engagement induced PI3K activation, which was required for, and temporally preceded, PYK2 phosphorylation, indicating that PI3K lies upstream of PYK2 in CD34+ cells. Furthermore, although PYK2 and PI3K were constitutively associated, interaction of the PYK2/PI3K complex with beta1-integrins required prior integrin engagement and PI3K activation. CONCLUSION: Activation of PI3K following beta1-integrin engagement on human CD34+ cells results in subsequent phosphorylation of PYK2, and is required for the recruitment of the PI3K/PYK2 complex to beta1-integrins at the cell surface.

Antigens, CD34↗
PubMed2007

Increase in beta1-6 GlcNAc branching caused by N-acetylglucosaminyltransferase V directs integrin beta1 stability in human hepatocellular carcinoma cell line SMMC-7721.

In this study, an enzymatic inactive mutant of GnT-V (delta cGnT-V) was constructed and transfected in SMMC 7721 cell line. Integrin beta1 in delta cGnT-V transfectants (delta c-7721) showed attenuation of the number of beta1-6 GlcNAc branching, whereas those in wtGnT-V transfectants (wt-7721) presented a beta1-6 GlcNAc-rich pattern. High integrin beta1 expression was observed in wt-7721 compared with mock cells (7721 cell transfected with the vector pcDNA3), while transfection of delta cGnT-V decreased the integrin beta1 expression, despite of no significant changes on integrin beta1 mRNA level in these cell lines. Pulse-chase experiment showed that Integrin beta1 in delta c-7721 was prone to quick degradation and its half-life was less than 3 h, on the contrary, the alleviating degradation of beta1 subunit was observed in wt-7721 where the beta1 subunit half-life was about 16 h, meanwhile, the degradation rate of beta1 subunit in mock cells was in between, about 10 h. More effective in promoting cell migration toward fibronectin and invasion through Matrigel was observed in wt-7721 while this was almost suppressed in delta c-7721. Our results suggest that the addition of beta1-6 GlcNAc branching caused more fully glycosylated mature form on integrin beta1 and inhibited beta1 protein degradation. Glycosylation caused by GnT-V directs integrin beta1 stability and more delivery to plasma membrane, subsequently promotes Fn-based cell migration and invasion.

Acetylglucosamine↗
PubMed2000

Molecular characterization and leukocyte distribution of a teleost beta1 integrin molecule.

The beta1 integrin, in combination with the alpha subunit, is responsible for migration of leukocytes into areas of inflammation. Although identified in mammalian species; the beta1 or CD29 molecule has yet to be identified in fish. The present investigation has identified a full-length channel catfish, Ictalurus punctatus, cDNA beta1 molecule composed of 2786 bases and a deduced amino acid sequence of 797 amino acids. The catfish molecule has an amino acid identity ranging from 71.87 to 74.12% with bovine, feline, human, and Xenopus. The channel catfish molecule retains several characteristics of mammalian beta1 molecules, such as four cysteine-rich repeat regions, and eight potential N-linked glycosylation sites. Based on Western blotting the channel catfish beta1 molecule has a molecular mass of approximately 130kDa, essentially the same as that for mammalian species. These results confirm the existence and expression of a beta1 gene in channel catfish, a species phylogenetically distant from mammals.

Amino Acid Sequence↗
PubMed1996

Impaired migration but not differentiation of haematopoietic stem cells in the absence of beta1 integrins.

Adhesive interactions mediated by integrins of the beta1 subfamily are thought to be critical in controlling differentiation and migration of blood cell precursors. Here we report that chimaeric mice generated with beta1-integrin-deficient embryonic stem (ES) cells lack beta1(-/-) cells in blood and in haematopoietic organs such as spleen, thymus and bone marrow. Chimaeric embryos contain beta1-null haematopoietic cells in the yolk sac and in fetal blood but not in fetal liver. We show that such beta1(-/-) haematopoietic stem cells derived from yolk sac of 10.5-day-old chimaeric embryos readily generate erythroid and myeloid colonies and that beta1(-/-) ES cells can differentiate into mature B lymphocytes in vitro. Our results indicate that haematopoietic stem cells lacking beta1 integrins can form and differentiate into different lineages but cannot colonize the fetal liver.

Animals↗
PubMed1998

Differential expression of activation epitopes of beta1 integrins in psoriasis and normal skin.

In the epidermis, beta1 integrin expression is normally confined to the basal layer; however, suprabasal expression of beta1 integrins in keratinocytes has been found in psoriasis, and it has been suggested that it could be a pathogenic factor of the disease. We have investigated herein the functional state of beta1 integrins of human keratinocytes in normal skin and psoriasis. The expression of beta1-activation-reporter epitopes was monitored with two monoclonal antibodies, HUTS-21 and MG5A7, that recognize epitopes whose expression parallels functional activity of beta1 integrins and correlates with the ligand binding activity of these heterodimeric glycoproteins. We have found that keratinocytes express activation epitopes of beta1 integrins, and that these epitopes can be modulated by manganese. The expression of activation epitopes of beta1 integrins was related to an enhanced adhesion to fibronectin and collagen. Immunohistochemical studies of normal and psoriatic skin with HUTS-21 and other monoclonal antibodies indicate that, although there is suprabasal expression of beta1 integrins in psoriasis, these molecules seem to be in an inactive state. Moreover, most beta1 integrins in lateral and apical surfaces of basal keratinocytes of psoriasis are also in a nonactive conformation, implying a decrease of activity compared with normal skin, in which active beta1 integrins are distributed all over the basal keratinocytes.

Cells, Cultured↗
PubMed2003

A newly developed angiotensin II type 1 receptor antagonist, CS866, promotes regression of cardiac hypertrophy by reducing integrin beta1 expression.

Previous studies have demonstrated that integrins link the extracellular matrix to the hypertrophic response pathway of cardiac myocytes in vitro. To examine the direct relation between integrin beta1 and cardiac hypertrophy in vivo, we studied the effects of a newly developed angiotensin II type 1 (AT1) blocker, CS866 (ARB; 10 mg/kg/day), an angiotensin-converting enzyme inhibitor, temocapril (ACEI, 10 mg/kg/day), or both on modulation of integrin beta1 in the hypertrophied hearts of stroke-prone spontaneously hypertensive rats (SHRSP) 6 to 12 weeks of age. Treatments with ARB, ACEI, and combination therapy significantly reduced systolic blood pressure. However, the reduction in cardiac hypertrophy was greater in SHRSP treated with ARB or combination therapy than in those treated with ACEI. Multiplex reverse transcription-polymerase chain reaction revealed significantly higher mRNA expression of atrial natriuretic factor, AT1 receptor, and integrin beta1 in untreated SHRSP than in normotensive Wistar-Kyoto rats (WKY). The mRNA levels of ANP, AT1 receptor, and integrin B1 in SHRSP were significantly decreased by treatment with ARB, ACEI, or combination therapy. Decreased mRNA expression of ANP, AT1 receptor, and integrin beta1 in the treated SHRSP was associated with reductions in blood pressure; ARB and combination therapy produced greater decreases in expression than did ACEI. These observations suggest that CS866 has a beneficial effect on myocyte hypertrophy and that down-regulation of AT1 receptor and suppression of integrin beta1 participate in the regression of pressure-induced cardiac hypertrophy in vivo. The correlation between the expression of integrin beta1 and AT1 receptor was significant. Our results also suggest that integrin expression by myocytes might be modulated by angiotensin II via AT1 receptor.

Angiotensin II Type 1 Receptor Blockers↗
PubMed1998

Intracellular calcium requirements for beta1 integrin activation.

Human polymorphonuclear leukocytes (PMNs) express beta1 integrins that mediate adhesion to extracellular matrix proteins following stimulation with agonists that induce an increase in intracellular calcium. The purpose of these studies was to determine the contribution made by alterations in intracellular calcium ([Ca++]i) to inside-out activation of beta1 integrins using dimethyl sulfoxide (DMSO)-differentiated granulocytic HL60 cells as a model of human PMNs. Activation of beta1 integrins was determined by measuring the expression of an activation-dependent epitope on the beta1 subunit that is recognized by monoclonal antibody (mAb) 15/7. Exposure of granulocytic HL60 cells to calcium ionophore ionomycin (800 nM) alone did not increase the binding of mAb 15/7 to the cell surface, nor did it increase beta1 integrin-mediated adhesion of the cells to fibronectin. Similarly, exposure of the cells to the direct protein kinase C (PKC) activator, dioctanoylglycerol (di-C8) at 100 microM, neither increased binding of mAb 15/7 to these cells nor adhesion to fibronectin. Simultaneous addition of di-C8 and ionomycin, however, caused a significant increase in the expression of the 15/7 epitope and cell adhesion, suggesting synergy between elevating [Ca++]i and stimulating PKC in beta1 integrin activation. Chelation of [Ca++]i with Quin-2 and EGTA reduced both basal (unstimulated) expression of the 15/7 epitope and basal adhesion of granulocytic HL60 cells to fibronectin. In addition, chelation of [Ca++]i caused a significant decrease in 15/7 binding and adhesion stimulated by low (1 ng/ml) concentrations of phorbol myristate acetate (PMA). The inhibitory effect of [Ca++]i chelation on beta1 integrin activation was reversed by repleting [Ca++]i with ionomycin in a Ca++-containing buffer, or by the addition of higher concentrations of PMA (10 ng/ml). These data suggest a role for [Ca++]i in inside-out activation of beta1 integrins, probably through a synergistic effect with PKC activation.

Antibodies, Monoclonal↗
PubMed2000

Beta1 integrin expression during normal and low score normal avian myogenesis.

Skeletal muscle development is, in part, regulated by myoblast-extracellular matrix interactions mediated by the transmembrane integrin family of heterodimeric receptors. The avian genetic muscle weakness, low score normal (LSN), exhibits modified myotube and sarcomere structure that may be associated with altered integrin expression. Protein expression of the beta1 integrin subunit was measured during normal and LSN Pectoralis major muscle development at 14, 16, and 18 d of embryonic development, and 1 d and 1 and 6 wk posthatch. During embryonic development, integrin expression was downregulated. However, by 1 wk posthatch, integrin levels were upregulated and remained elevated through 6 wk posthatch. This pattern was observed in both normal and LSN muscle development. Overall, beta1 integrin levels were lower in the LSN P. major muscle. In normal and LSN satellite cell cultures, beta1 integrin expression was low during proliferation. In early differentiation, beta1 integrin expression increased and was then downregulated. As observed in the muscle extracts, LSN beta1 integrin expression was significantly lower during differentiation. These results suggest that the regulation of beta1 integrin expression is critical to the progression of myogenesis, and, during LSN myogenesis, decreased expression of beta1 integrin may be associated with modifications in muscle structure.

Animals↗
PubMed1998

Loss of beta1 integrin function results in a retardation of myogenic, but an acceleration of neuronal, differentiation of embryonic stem cells in vitro.

Integrin cell surface receptors play an important role for cell adhesion, migration, and differentiation during embryonic development by mediating cell-cell and cell-matrix interactions. Less is known about the function of integrins during commitment and lineage determination of early embryogenesis. Homozygous inactivation of the beta1 integrin gene results in embryonal death in mice around the time of implantation. In vitro, differentiation of embryonic stem (ES) cells which lack beta1 integrin (beta1-/-) into the cardiogenic lineage is delayed and results in a disordered cellular specification (Fässler et al., J. Cell Sci. 109, 2989-2999, 1996). To analyze beta1 integrin function during myogenesis and neurogenesis we studied differentiation of beta1-/- ES cells via embryoid bodies into skeletal muscle and neuronal cells in vitro. beta1-/- cells showed delayed and reduced myogenic differentiation compared to wildtype and heterozygous (beta1+/-) ES cells. RT-PCR analysis demonstrated delayed expression of skeletal muscle-specific genes in the absence of beta1 integrin. Immunofluorescence studies with antibodies against the sarcomeric proteins myosin heavy chain, titin, nebulin, and slow C-protein showed that myotubes formed, but their number was reduced and the assembly of sarcomeric structures was retarded. In contrast, neuronal cells differentiating from beta1-/- ES cells appeared earlier than wildtype and heterozygous (beta1+/-) ES cells. This was shown by the accelerated expression of neuron-specific genes and an increased number of neuronal cells in beta1-/- embryoid bodies. However, neuronal outgrowth was retarded in the absence of beta1 integrin. No functional difference between wildtype and beta1-/- cells was found with respect to secretion of gamma-aminobutyric acid, the main neurotransmitter of ES cell-derived neuronal cells. The lineage-specific effects of loss of beta1 integrin function, that is the inhibition of mesodermal and acceleration of neuroectodermal differentiation, were supported by differential expression of genes encoding lineage-specific transcription factors (Brachyury, Pax-6, Mash1) and signaling molecules (BMP-4 and Wnt-1). Because of the reduced and delayed expression of the BMP-4 encoding gene in beta1-/- cells, we analyzed in wildtype and beta1-/- cells the regulatory role of exogenously added BMP-4 on the expression of the mesodermal and neuronal marker genes, Brachyury and wnt-1, respectively. The data suggest that BMP-4 plays a regulatory role during differentiation of wildtype and beta1-/- cells by modifying mesodermal and neuronal pathways. The reduced expression of BMP-4 in beta1-/- cells may account for the accelerated neuronal differentiation in beta1-/- ES cells.

Animals↗
PubMed2005

Role of integrin-linked kinase in regulating phosphorylation of Akt and fibroblast survival in type I collagen matrices through a beta1 integrin viability signaling pathway.

A beta1 integrin phosphatidylinositol 3-kinase/Akt pathway regulates fibroblast survival in collagen matrices. When fibroblasts attach to collagen, Akt becomes phosphorylated, providing a survival signal. In contrast, in response to mechanical forces generated during collagen contraction, Akt is dephosphorylated and fibroblasts undergo apoptosis. The kinase(s) responsible for regulating Akt phosphorylation in response to matrix-derived mechanical signals are unclear. Integrin-linked kinase (ILK) is associated with the beta1 integrin in the focal adhesion complex and as such is a candidate kinase that may regulate Akt phosphorylation and fibroblast viability. Nevertheless, there is no direct evidence that matrix-derived mechanical forces regulate cell viability by modulating ILK activity. Here, we show that ILK activity decreased in response to collagen matrix contraction, which correlated with Akt dephosphorylation and induction of fibroblast apoptosis. In contrast, enforced activation of beta1 integrin by activating antibody preserved ILK and Akt activity during collagen matrix contraction, and this is associated with protection from collagen contraction-induced apoptosis. Knock-down of ILK by small, interfering RNA (siRNA) attenuated Akt phosphorylation in response to ligation of beta1 integrin by collagen or activating antibody and enhanced fibroblast apoptosis in response to collagen contraction. Kinase dead ILK attenuated Akt phosphorylation and enhanced fibroblast apoptosis, whereas hyperactive and wild type ILK augmented Akt phosphorylation and protected fibroblasts from apoptosis. Constitutively active Akt preserved Akt activity and rescued ILK siRNA-treated fibroblasts from collagen contraction-induced apoptosis. These data establish that matrix-derived mechanical forces sensed by beta1 integrin are capable of modulating ILK activity which regulates fibroblast viability via an Akt-dependent mechanism.

Apoptosis↗
PubMed2005

Fc gammaRIIIB stimulation promotes beta1 integrin activation in human neutrophils.

The molecular stimuli involved in receptor-induced integrin activation are still poorly defined. We have investigated the role of receptors for the Fc portion of immunoglobulin G molecules (Fc gammaR) on activation of integrins in human neutrophils. Cross-linking of Fc gammaRIIA induced an increase in surface expression of beta2 integrins but had no effect on beta1 integrins. In contrast, cross-linking of Fc gammaRIIIB not only increased beta2 integrins on the cell surface but also induced beta1 integrin activation, as indicated by an increase in binding to fibronectin and the appearance of an activation epitope detected by the monoclonal antibody 15/7. The Fc gammaRIIIB-induced increase of beta2 integrins required Src-family tyrosine kinases, Syk kinase, and phosphatidylinositol-3 kinase (PI-3K), as the corresponding, specific inhibitors, PP2, Piceatannol, and LY294002, completely blocked it. Contrary to this, Fc gammaRIIIB-induced beta1 integrin activation was not blocked by PP2 or LY294002. It was, however, enhanced by Piceatannol. After Fc gammaRIIIB cross-linking, colocalization of Fc gammaRIIIB and active beta1 integrins was detected on the neutrophil membrane. These data show, for the first time, that cross-linking of Fc gammaRIIIB induces an inside-out signaling pathway that leads to beta1 integrin activation. This activation is independent of Src-family kinases, and PI-3K and may be induced in part by the interaction of Fc gammaRIIIB with beta1 integrins.

Adult↗
PubMed2000

Molecular cloning and characterization of the pig homologue to human CD29, the integrin beta1 subunit.

BACKGROUND: CD29 is the beta1 subunit, a member of the integrin gene superfamily that function as receptor for cell adhesion molecules of the extracellular matrix. Porcine integrin beta1 subunit is involved in rejection of pig-to-human tissue xenografts as target of the natural antibodies present in the human serum. Moreover since CD29, as part of the beta1 integrins very late antigen 4 (VLA-4) and VLA-6, is involved in homing and differentiation of haematopoietic progenitor cells, its characterization in pig is critical to study the interaction of porcine adhesion molecules with human ligands in the induction of donor-specific tolerance toward porcine antigens, a process extremely desirable to prevent rejection of xenogeneic organs. METHODS: The porcine CD29 cDNA has been isolated from a cDNA library and its structure determined. In addition, reverse transcription-polymerase chain reaction (RT-PCR) was performed to determine the expression of CD29 in different tissues. RESULTS: The nucleotide sequence of the porcine cDNA includes an open reading frame encoding a polypeptide of 798 amino acids. Expression analysis showed that porcine CD29 is expressed in all lymphoid tissues tested and, in lower amounts, in nonlymphoid tissues. Pig CD29 deduced amino acid sequence displays extensive conservation compared with CD29 sequences from other species and a common structural feature with all the other CD29 molecules analyzed in mammals, including the 12 potential N-glycosilation sites. Punctual changes between human and swine CD29 molecule into the ligand binding domain, and/or into the regulatory domain, suggest potential differences between human and porcine CD29 relative to the human CD29 ligands. CONCLUSIONS: Cloning of the swine CD29 gene offers a new tool for an alternative protocol of removing xenoreactive antibodies in the recipient. In addition, the determination of the differences between human and swine CD29 will help to understand the adhesion molecule-ligand interactions and their function across the swine-human barrier in xenotransplantation.

Amino Acid Sequence↗
PubMed2005

Endocytosis of beta1 integrins is an early event in migration promoted by the cell adhesion molecule L1.

Directional cell motility is a complex process requiring orchestration of signals from diverse cell adhesion receptors for proper organization of neuronal groups in the brain. The L1 cell adhesion molecule potentiates integrin-dependent migration of neuronal cells and stimulates integrin endocytosis but its mechanism of action is unclear. The hypothesis was investigated that L1 stimulates cell motility by modulating surface levels of integrins through intracellular trafficking using a model cell system. Antibody-induced clustering of L1, which mimics ligand binding, induced formation of cell surface complexes of L1 and beta1 integrins in L1-expressing HEK293 cells. L1 formed cell surface complexes with integrin beta1 and alpha3 subunits but not with integrin alpha1. Following cell surface clustering, beta1 integrins and L1 became rapidly internalized into Rab5+ early endosomes. Internalization of L1 and beta1 integrins was prevented by treatment with monodansyl cadaverine (MDC), an inhibitor of clathrin-dependent endocytosis, and by deletion of the AP2/clathrin binding motif (RSLE) from the L1 cytoplasmic domain. MDC treatment coordinately inhibited L1-potentiated haptotactic migration of HEK293 cells to fibronectin in Transwell assays. These results suggested that downregulation of adhesive complexes of L1 and beta1 integrin at the plasma membrane by clathrin-mediated endocytosis is a potential mechanism for enhancing cell motility.

Cadaverine↗