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Results for “Integrin alpha2”

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PubMed2004

Reversion of the Jun-induced oncogenic phenotype by enhanced synthesis of sialosyllactosylceramide (GM3 ganglioside).

In the mouse fibroblast cell line C3H 10T1/2 and the chicken fibroblast cell line DF1, the ganglioside GM3 is the major glycosphingolipid component of the plasma membrane. Expression of the viral oncoprotein Jun (v-Jun) induces transformed cell clones with greatly reduced levels of GM3 and GM3 synthase (lactosylceramide alpha2,3-sialyltransferase) mRNA in both 10T1/2 and DF1 cell cultures. Compared with nontransformed controls, v-Jun transfectants show enhanced ability of anchorage-independent growth, and their growth rates as adherent cells are increased. When the mouse GM3 synthase gene is transfected with the pcDNA vector into v-Jun-transformed 10T1/2 cells, the levels of GM3 synthase and corresponding mRNA are restored to those of control cells. Reexpression of GM3 correlates with a reduced ability of the cells to form colonies in nutrient agar. Similarly, when the newly cloned chicken GM3 synthase gene is transfected into v-Jun-transformed DF1 with the pcDNA vector, the GM3 synthase level is restored to that of control cells, and the ability of the cells to form agar colonies is reduced. The levels of GM3 in the cell also affect membrane microdomains. The complex of GM3 with tetraspanin CD9 and integrin alpha5beta1 inhibits motility and invasiveness. The amounts of this complex are greatly reduced in transformed cells. Expression of GM3 and consequent reversion of the transformed phenotype results in increased levels of that microdomain complex.

Animals↗

PubMed2003

Benzyl-N-acetyl-alpha-D-galactosaminide induces a storage disease-like phenotype by perturbing the endocytic pathway.

The sugar analog O-benzyl-N-acetyl-alpha-d-galactosaminide (BG) is an inhibitor of glycan chain elongation and inhibits alpha2,3-sialylation in mucus-secreting HT-29 cells. Long-term exposure of these cells to BG is associated with the accumulation of apical glycoproteins in cytoplasmic vesicles. The mechanisms involved therein and the nature of the vesicles have not been elucidated. In these cells, a massive amount of BG metabolites is synthesized. Because sialic acid is mainly distributed apically in epithelial cells, it has been proposed that the BG-induced undersialylation of apical membrane glycoproteins is responsible for their intracellular accumulation due to a defect in anterograde traffic and that sialic acid may constitute an apical targeting signal. In this work, we demonstrate that the intracellular accumulation of membrane glycoproteins does not result mainly from defects in anterograde traffic. By contrast, in BG-treated cells, endocytosed membrane proteins were retained intracellularly for longer periods of time than in control cells and colocalized with accumulated MUC1 and beta(1) integrin in Rab7/lysobisphosphatidic acid(+) vesicles displaying features of late endosomes. The phenotype of BG-treated cells is reminiscent of that observed in lysosomal storage disorders. Sucrose induced a BG-like, lysosomal storage disease-like phenotype without affecting sialylation, indicating that undersialylation is not a requisite for the intracellular accumulation of membrane glycoproteins. Our findings strongly support the notion that the effects observed in BG-treated cells result from the accumulation of BG-derived metabolites and from defects in the endosomal pathway. We propose that abnormal subcellular distribution of membrane glycoproteins involved in cellular communication and/or signaling may also take place in lysosomal storage disorders and may contribute to their pathogenesis.

Acetylgalactosamine↗

PubMed2004

The hemostatic system.

The hemostatic system comprises platelet aggregation, coagulation and fibrinolysis also termed primary, secondary and tertiary hemostasis. From the platelet transcriptome 6000 mRNA species and represent receptors, ion channels, signalling molecules, kinases, phosphatases, and structural, metabolic and regulatory proteins. This abundance of regulatory proteins points towards the importance of signal transduction in platelet function. First platelets adhere to collagen, this induces activation signals such as TXA(2) that induces further Ca(2+) increase. Consecutively, fibrinogen binds to the integrin alpha(IIb)beta(3) resulting in aggregation.This self-amplifying process is controlled by signals, from endothelial cells, to restrict the platelet plug to the site of vessel injury. Secondary hemostasis (coagulation) consists of an extrinsic and intrinsic pathway. Thrombin is generated via Factor Xa resulting from the extrinsic tenase reaction that is turned of by tissue factor pathway inhibitor. While thrombin generation is maintained via positive feedback mechanisms activating factors V, VIII and XI. Excess thrombin is inhibited by antithrombin or by autodownregulation via activation of protein C. Since minor injuries are common, platelets and plasma clotting factors constantly produce clots to stop bleeding. If clots remained after the tissue healing, the vascular bed would become obstructed with clots therefore this is regulated by fibrinolysis, tertiary hemostasis. Tissue-type plasminogen activator synthesised by the endothelium, converts plasminogen to plasmin, the clot lysis enzyme. Plasmin clears the blood vessels by degrading fibrin. Fibrinolysis is controlled by plasminogen activators inhibitor (PAI-1), alpha2-antiplasmin and alpha2-macroglobulin, and thrombin-activatable fibrinolysis inhibitor (TAFI).

Antifibrinolytic Agents↗

PubMed2003

Expression of mouse agrin in normal, denervated and dystrophic muscle.

Agrin is a heparan sulfate proteoglycan that is required for the development of postsynaptic specializations at the neuromuscular junction. An alternatively spliced isoform of agrin that lacks this activity is found in basement membranes of several tissues including embryonic muscle. Overexpression of a miniaturized form of this agrin isoform ameliorates the severe muscle dystrophy of laminin alpha2-deficient mice, a mouse model for merosin-deficient congenital muscle dystrophy. Several lines of evidence indicate that this amelioration is based on the high-affinity binding of the mini-agrin to the laminins and to alpha-dystroglycan. Here, we used antibodies raised against mouse agrin to evaluate protein expression in adult muscle of normal and dystrophic mice. We find that expression of agrin in non-synaptic region varies greatly between different muscles in wild-type mice and that its levels are altered in dystrophic muscle.

Agrin↗

PubMed2005

Lower serum zinc in Chronic Fatigue Syndrome (CFS): relationships to immune dysfunctions and relevance for the oxidative stress status in CFS.

The present study examines serum zinc concentrations in patients with chronic fatigue syndrome (CFS) versus normal volunteers. Serum zinc levels were determined by means of an atomic absorption method. We found that serum zinc was significantly lower in the CFS patients than in the normal controls. There was a trend toward a significant negative correlation between serum zinc and the severity of CFS and there was a significant and negative correlation between serum zinc and the subjective experience of infection. We found that serum zinc was significantly and negatively correlated to the increase in the alpha2 protein fraction and positively correlated to decreases in the expression of mitogen-induced CD69+ (a T cell activation marker) on CD3+ as well as CD3+CD8+ T cells. These results show that CFS is accompanied by a low serum zinc status and that the latter is related to signs of inflammation and defects in early T cell activation pathways. Since zinc is a strong anti-oxidant, the present results further support the findings that CFS is accompanied by increased oxidative stress. The results of these reports suggest that some patients with CFS should be treated with specific antioxidants, including zinc supplements.

Adult↗

PubMed2003

Extracellular matrix and nuclear abnormalities in skeletal muscle of a patient with Walker-Warburg syndrome caused by POMT1 mutation.

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder characterized by congenital muscular dystrophy, structural eye abnormalities and severe brain malformations. We performed an immunohistochemical and electron microscopy study of a muscle biopsy from a patient affected by WWS carrying a homozygous frameshift mutation in O-mannosyltransferase 1 gene (POMT1). alpha-Dystroglycan glycosylated epitope was not detected in muscle fibers and intramuscular peripheral nerves. Laminin alpha2 chain and perlecan were reduced in muscle fibers and well preserved in intramuscular peripheral nerves. The basal lamina in several muscle fibers showed discontinuities and detachment from the plasmalemma. Most nuclei, including myonuclei and satellite cell nuclei, showed detachment or complete absence of peripheral heterochromatin from the nuclear envelope. Apoptotic changes were detected in 3% of muscle fibers. The particular combination of basal lamina and nuclear changes may suggest that a complex pathogenetic mechanism, affecting several subcellular compartments, underlies the degenerative process in WWS muscle.

Antigens, CD↗

PubMed2001

Transactivation of core binding factor alpha1 as a basic mechanism to trigger parathyroid hormone-induced osteogenesis.

During 28-day culture of bone marrow- and calvaria-derived osteoblasts, the constant presence of parathyroid hormone (PTH)(1-34) retarded differentiation and nodule formation (NF) in a dose-dependent fashion (C-phase). In contrast, addition of PTH(1-34) in late stage cultures (from day 10 to 21) accelerated NF (A-phase). The stable production of such an A-phase allowed us to study the mechanism of bone anabolic action of PTH(1-34). Subcellular localization studies of core binding factor alpha1 (Cbfa1) and reporter assays provided the results indicating that in the A-phase, PTH(1-34) triggers its bone anabolic action via enhancement of Cbfa1 transactivation. RT-PCR and Northern blot analyses revealed that alkaline phosphatase, osteocalcin and bone sialoprotein expression decreased in the C-phase and increased in the A-phase; however, expression of other bone proteins (Cbfa1, PTH/PTH-related peptide-receptor, osteopontin, collagen I alpha1, collagen I alpha2, vitamin K-dependent gamma-glutamyl carboxylase) did not change in a phase transition-related manner. Ovariectomized osteopenic mice, treated with PTH(1-34) (4 and 40 microg/kg, s.c., every other day, 4 or 6 weeks), recovered lost bone, displayed elevated nuclear localization of Cbfal in tibiae without alteration of its cytosolic level and exhibited upregulation of expressions of the same set of proteins (alkaline phosphatase, osteocalcin and bone sialoprotein) in femora. These results obtained by a concerted study in vitro and in vivo suggest that PTH triggers its osteogenic action via promotion of the transactivation of Cbfa1.

Alkaline Phosphatase↗

PubMed2005

Type IV collagen induces down-regulation of steroidogenic response to gonadotropins in adult rat Leydig cells involving mitogen-activated protein kinase.

We have previously shown that type IV collagen (alpha1 (IV) and alpha2 (IV) collagen chains) (Col-IV) inhibits testosterone (T) production by Leydig cells (LC). The aim of this study was to analyze mechanism/s by which Col-IV exerts this effect. No significant differences in the specific binding of hCG to LH/hCG receptors in LC cultured on uncoated or Col-IV coated plates were observed. An inhibition of cAMP production in hCG-stimulated LC cultured on Col-IV was detected. The inhibition exerted by Col-IV on T production in response to hCG was also observed when cells were stimulated with 8Bromo-cAMP. In addition, conversion of steroid precursors to T in LC cultured on uncoated and Col-IV coated plates was similar. On the other hand, we detected an increase of ERK1/2 phosphorylation in hCG-stimulated LC cultured on Col-IV. Genistein added to LC cultures reduced the ability of Col-IV to increase ERK1/2 phosphorylation and reverted the inhibitory effect of Col-IV on T production. An inhibitor of MEK, PD98059 added to LC cultures also reverted the inhibitory effect of Col-IV on T production. A decrease of steroidogenic acute regulatory protein (StAR) expression in hCG-stimulated LC cultured on Col-IV coated plates that could be reverted by addition of PD98059 to the cultures was also demonstrated. All together these results suggest that Col-IV inhibits T production in LC by binding to integrins, activating ERK1/2, decreasing cAMP production and decreasing StAR expression.

Aging↗

PubMed2000

Interaction of merosin (laminin 2) with very late activation antigen-6 is necessary for the survival of CD4+ CD8+ immature thymocytes.

The laminin alpha2-chain is a component of merosin, a member of the laminin family molecules, which is mainly expressed in the basement membranes of striated muscle. It is known that laminin alpha2 gene (lama2) null mutant mice (dy3k/dy3k) exhibit congenital muscular dystrophy (CMD). Because the laminin alpha2-chain is also expressed in the thymus, the role of merosin in the thymus was examined. In association with the onset of muscular dystrophy, CD4+ CD8+ double-positive (DP) thymocytes disappear by apoptotic cell death, while CD4+ CD8- or CD4- CD8+ thymocytes remain. In order to study the mechanisms leading to the selective death of DP cells in the absence of merosin, the role of the interaction between very late activation antigen-6 (VLA-6), a candidate merosin ligand in the thymus, and merosin was examined. The in vitro survival of thymocytes from normal mice was maintained by the addition of either anti-VLA-6 monoclonal antibodies (mAbs) or merosin. Furthermore, when the normal thymocytes were cultured on thymic epithelial cell lines, viable DP cell recoveries on wild-type epithelial cells were better than on cells from null mutant mice. The results suggest that DP cells are more sensitive to an uncharacterized apoptotic death signal, and that survival is supported by the interaction between VLA-6 and merosin.

Animals↗

PubMed2006

Three complement-like repeats compose the complete alpha2-macroglobulin binding site in the second ligand binding cluster of the low density lipoprotein receptor-related protein.

Given the importance of the low density lipoprotein receptor-related protein (LRP) as an essential endocytosis and signaling receptor for many protein ligands, and of alpha2-macroglobulin (alpha2M)-proteinase complexes as one such set of ligands, an understanding of the specificity of their interaction with LRP is an important goal. A starting point is the known role of the 138-residue receptor binding domain (RBD) in binding to LRP. Previous studies have localized high affinity alpha2M binding to the eight complement repeat (CR)-containing cluster 2 of LRP. In the present study we have identified the minimum CR domains that constitute the full binding site for RBD and, hence, for alpha2M on LRP. We report on the ability of the triple construct of CR3-4-5 to bind RBD with an affinity (Kd = 130 nM) the same as for isolated RBD to intact LRP. This Kd is 30-fold smaller than for RBD to CR5-6-7, demonstrating the specificity of the interaction with CR3-4-5. Binding requires previously identified critical lysine residues but is almost pH-independent within the range of pH values encountered between extracellular and internal compartments, consistent with an earlier proposed model of intracellular ligand displacement by intramolecular YWTD domains. The present findings suggest a model to explain the ability of LRP to bind a wide range of structurally unrelated ligands in which a nonspecific ligand interaction with the acidic region present in most CR domains is augmented by interactions with other CR surface residues that are unique to a particular CR cluster.

Binding Sites↗

PubMed2004

Marked reduction of focal adhesion kinase, serum response factor and myocyte enhancer factor 2C, but increase in RhoA and myostatin in the hindlimb dy mouse muscles.

Laminin alpha2 (merosin)-deficient congenital muscular dystrophy (CMD) patients show progressive muscle fiber necrosis and ineffective muscle regeneration. This is probably due to decreased formation of multi nucleated myotubes resulting from a myoblast fusion defect. When receiving a mechanical signal from muscle membranes, a cascade of RhoA, focal adhesion kinase (FAK), and serum response factor (SRF) positively regulates myogenesis and muscle hypertrophy associated with functional overload. In contrast, myostatin, a potent negative regulator of skeletal muscle hypertrophy, appears to be up-regulated in the muscles of mdx mice, an animal model for Duchenne muscular dystrophy. Using Western blot and immunohistochemical analyses, we investigated the levels of RhoA, FAK, SRF, and myostatin in the skeletal muscles of dy mice. The amount of RhoA protein was increased in the hindlimb muscles of dy mice aged 12 weeks. At 12 weeks, FAK immunoreactivity was observed in the myonuclei and/or satellite cells of normal mice, but not of dy mice. SRF protein levels decreased markedly in the gastrocnemius and rectus femoris muscles of dy mice at 2 and 12 weeks. Several muscle fibers in normal mice possessed uniform SRF immunoreactivity in the cytoplasm. An SRF immunostaining pattern in muscle was not detected in dy mice. Western blot and the densitometric analysis showed a decreased amount of myocyte enhancer factor 2C (MEF2C) in hindlimb muscles of dy mice. Although slight myostatin immunoreactivity was observed in the nuclei of some normal mice, marked myostatin immunoreactivity was observed in the cytoplasm of mature dy mice myonuclei and/or satellite cells. A low expression of FAK, SRF and MEF2C in muscles of dy mice may inhibit postnatal muscle hypertrophy by fusing satellite cells with existing fibers. Enhancing myostatin protein would result in further atrophy and degeneration of muscle fiber in dy mice.

Animals↗