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At least 1,009 records · Page 56Linked to original sources
PubMed2005

The role(s) of Src kinase and Cbl proteins in the regulation of osteoclast differentiation and function.

The osteoclast resorbs mineralized bone during bone development, homeostasis, and repair. The deletion of the gene encoding the nonreceptor tyrosine kinase c-Src produces an osteopetrotic skeletal phenotype that is the consequence of the inability of the mature osteoclast to efficiently resorb bone. Src-/- osteoclasts exhibit reduced motility and abnormal organization of the apical secretory domain (the ruffled border) and attachment-related cytoskeletal elements that are necessary for bone resorption. A key function of Src in osteoclasts is to promote the rapid assembly and disassembly of the podosomes, the specialized integrin-based attachment structures of osteoclasts and other highly motile cells. Once recruited to the activated integrins, especially alphavbeta3), by the adhesion tyrosine kinase Pyk2, Src binds and phosphorylates Cbl and Cbl-b, homologous multisite adapter proteins with ubiquitin ligase activity. The Cbl proteins in turn recruit and activate additional signaling effectors, including phosphatidylinositol 3-kinase and dynamin, which play key roles in the development of cell polarity and the regulation of cell attachment and motility. In addition, Src and the Cbl proteins contribute to signaling cascades that are activated by several important receptors, including receptor activator of nuclear factor kappaB and the macrophage colony-stimulating factor receptor, and also downregulate the signaling from many of these receptors.

Animals↗
PubMed2006

The C-terminus of alpha2-antiplasmin interacts with endothelial cells.

The serpin, alpha(2)-antiplasmin (alpha(2)AP), has an extended C-terminus relative to other inhibitors. This 51-residue region contains an RGD sequence; such sequences constitute a key recognition sequence for cell adhesion, mediated through integrins. In the present study, this sequence was expressed in Escherichia coli and its binding to endothelial cells and whether binding depends on the RGD sequence was investigated. Binding to the surface of human umbilical vein endothelial cells (HUVEC-C) was observed by flow cytometry and immunohistochemistry. Binding studies on immobilised cells showed specific and RGD-dependent binding of the peptides to HUVEC-C. The binding of the wild-type peptide to the HUVEC-C was significantly higher than that of a mutant peptide, in which RGD was replaced by SAA (P < 0.05, n = 4). Similarly, ethylenediaminetetraacetic acid decreased the binding of the wild-type peptide (P < 0.05, n = 4). The binding was competed out by full-length alpha(2)AP, fibronectin and anti-alpha(5)beta(1). This is the first evidence of binding of the C-terminus of alpha(2)AP to endothelial cells via its RGD sequence, with most but not all of the binding being integrin-mediated. We speculate that this interaction with alpha(2)AP may potentially play a role in the control of cellular fibrinolysis by regulating local plasmin activity on cell surfaces.

Binding, Competitive↗
PubMed2005

AMPA receptor stimulation increases alpha5beta1 integrin surface expression, adhesive function and signaling.

Integrin proteins are critical for stabilization of hippocampal long-term potentiation but the mechanisms by which integrin activities are involved in synaptic transmission are not known. The present study tested whether activation of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) class glutamate receptors increases surface expression of alpha5beta1 integrin implicated in synaptic potentiation. Surface protein biotinylation assays demonstrated that AMPA treatment of COS7 cells expressing GluR1 homomeric AMPA receptors increased membrane insertion and steady-state surface levels of alpha5 and beta1 subunits. Treated cells exhibited increased adhesion to fibronectin- and anti-alpha5-coated substrates and tyrosine kinase signaling elicited by fibronectin-substrate adhesion, as expected if new surface receptors are functional. Increased surface expression did not occur in calcium-free medium and was blocked by the protein kinase C inhibitor chelerythrine chloride and the exocytosis inhibitor brefeldin A. AMPA treatment similarly increased alpha5 and beta1 surface expression in dissociated neurons and cultured hippocampal slices. In both neuronal preparations AMPA-induced integrin trafficking was blocked by combined antagonism of NMDA receptor and L-type voltage-sensitive calcium channel activities but was not induced by NMDA treatment alone. These results provide the first evidence that glutamate receptor activation increases integrin surface expression and function, and suggest a novel mechanism by which synaptic activity can engage a volley of new integrin signaling in coordination with, and probably involved in, stabilization of synaptic potentiation.

Alkaloids↗
PubMed2005

Increased metastatic potential of tumor cells in von Willebrand factor-deficient mice.

BACKGROUND: The key role played by von Willebrand factor (VWF) in platelet adhesion suggests a potential implication in various pathologies, where this process is involved. In cancer metastasis development, tumor cells interact with platelets and the vessel wall to extravasate from the circulation. As a potential mediator of platelet-tumor cell interactions, VWF could influence this early step of tumor spread and therefore play a role in cancer metastasis. OBJECTIVES: To investigate whether VWF is involved in metastasis development. METHODS: In a first step, we characterized the interaction between murine melanoma cells B16-BL6 and VWF in vitro. In a second step, an experimental metastasis model was used to compare the formation of pulmonary metastatic foci in C57BL/6 wild-type and VWF-null mice following the injection of B16-BL6 cells or Lewis lung carcinoma cells. RESULTS: In vitro adhesion assays revealed that VWF is able to promote a dose-dependent adhesion of B16-BL6 cells via its Arg-Gly-Asp (RGD) sequence. In the experimental metastasis model, we found a significant increase in the number of pulmonary metastatic foci in VWF-null mice compared with the wild-type mice, a phenotype that could be corrected by restoring VWF plasma levels. We also showed that increased survival of the tumor cells in the lungs during the first 24 h in the absence of VWF was the cause of this increased metastasis. CONCLUSION: These findings suggest that VWF plays a protective role against tumor cell dissemination in vivo. Underlying mechanisms remain to be investigated.

Animals↗
PubMed2004

In vitro and in vivo metabolism of a potent and selective integrin alpha v beta 3 antagonist in rats, dogs, and monkeys.

Compound A (3-[2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyrindin-2-yl)propyl]-imidazolidin-1-yl]-3(S)-(6-methoxy-pyridin-3-yl)-propionic acid), a potent and selective antagonist of integrin alpha(v)beta(3) receptor, is under development for treatment of osteoporosis. This study describes metabolism and excretion of A in vivo in rats, dogs, and monkeys, and metabolism of A in vitro in primary hepatocytes from rats, dogs, monkeys, and humans. In all three animal species studied, A was primarily excreted as unchanged drug and, to a lesser degree, as phase I and phase II metabolites. Major biotransformation pathways of A included glucuronidation/glucosylation on the carboxylic group to form acyl-linked glucuronides/glucosides; and oxidation on the tetrahydronaphthyridine moiety to generate a carbinolamine and its further metabolized products. Minor pathways involved O-demethylation and hydroxylations on the alkyl chain. Only in rats, a glutathione adduct of A was also observed, and its formation is proposed to be via an iminium intermediate on the tetrahydronaphthyridine ring. Similar metabolic pathways were observed in the incubates of hepatocytes from the corresponding animals as well as from humans. CYP 3A and 2D subfamilies were capable of metabolizing A to its oxidative products. Overall, these in vitro and in vivo findings should provide useful insight on possible biotransformation pathways of A in humans.

Animals↗
PubMed2006

The microtubule binding drug laulimalide inhibits vascular endothelial growth factor-induced human endothelial cell migration and is synergistic when combined with docetaxel (taxotere).

Laulimalide, a natural product from marine sponges, is a microtubule-stabilizing agent that binds to tubulin at a site distinct from that of the taxoids. In the present study, we found that laulimalide inhibited human umbilical vein endothelial cell (HUVEC) tubule formation and vascular endothelial growth factor (VEGF)-induced HUVEC migration, key components of the angiogenic process. These occurred at concentrations substantially lower than that which inhibited HUVEC proliferation. When combined, laulimalide and docetaxel (Taxotere) synergistically inhibited migration and tubule formation, but their combined effect on proliferation was antagonistic. Possible mechanism(s) by which laulimalide inhibited VEGF-induced HUVEC migration were explored. Similar to docetaxel, laulimalide had no effect on the VEGF-induced tyrosine phosphorylation of the VEGF receptor Flk-1/KDR (VEGFR-2). Low concentrations of laulimalide substantially blocked subsequent VEGFR-2 downstream events, as did docetaxel, including the phosphorylation of the Tyr397 and Tyr407 residues of focal adhesion kinase (FAK), the association of VEGFR-2 with FAK and Hsp90, and the Tyr31 phosphorylation of paxillin. Laulimalide inhibited integrin activation; however, compared with docetaxel, it had a weaker inhibitory effect on the VEGF-induced association of VEGFR-2 with the alpha5beta1 integrin. Compared with docetaxel, laulimalide more potently caused a reduction in the constitutive levels (i.e., in the absence of VEGF) of phosphorylated paxillin and more potently inhibited the association of RhoA with the alpha5beta1 integrin. In conclusion, although both docetaxel and laulimalide inhibited integrin-associated signaling pathways that mediated VEGF-induced cell migration, their actions on the signaling cascade seemed not to be identical. These complementary actions could account for their synergistic effects on HUVEC.

Cell Movement↗
PubMed2002

Tumor regression by targeted gene delivery to the neovasculature.

Efforts to influence the biology of blood vessels by gene delivery have been hampered by a lack of targeting vectors specific for endothelial cells in diseased tissues. Here we show that a cationic nanoparticle (NP) coupled to an integrin alphavbeta3-targeting ligand can deliver genes selectively to angiogenic blood vessels in tumor-bearing mice. The therapeutic efficacy of this approach was tested by generating NPs conjugated to a mutant Raf gene, ATPmu-Raf, which blocks endothelial signaling and angiogenesis in response to multiple growth factors. Systemic injection of the NP into mice resulted in apoptosis of the tumor-associated endothelium, ultimately leading to tumor cell apoptosis and sustained regression of established primary and metastatic tumors.

Adenosine Triphosphate↗
PubMed2007

Differential transmission of actin motion within focal adhesions.

Cell migration requires the transmission of motion generated in the actin cytoskeleton to the extracellular environment through a complex assembly of proteins in focal adhesions. We developed correlational fluorescent speckle microscopy to measure the coupling of focal-adhesion proteins to actin filaments. Different classes of focal-adhesion structural and regulatory molecules exhibited varying degrees of correlated motions with actin filaments, indicating hierarchical transmission of actin motion through focal adhesions. Interactions between vinculin, talin, and actin filaments appear to constitute a slippage interface between the cytoskeleton and integrins, generating a molecular clutch that is regulated during the morphodynamic transitions of cell migration.

Actin Cytoskeleton↗
PubMed2002

Opsonophagocytosis-inhibiting mac protein of group a streptococcus: identification and characteristics of two genetic complexes.

Recently, it was reported that a streptococcal Mac protein (designated Mac(5005)) made by serotype M1 group A Streptococcus (GAS) is a homologue of human CD11b that inhibits opsonophagocytosis and killing of GAS by human polymorphonuclear leukocytes (PMNs) (B. Lei, F. R. DeLeo, N. P. Hoe, M. R. Graham, S. M. Mackie, R. L. Cole, M. Liu, H. R. Hill, D. E. Low, M. J. Federle, J. R. Scott, and J. M. Musser, Nat. Med. 7:1298-1305, 2001). To study mac variation and expression of the Mac protein, the gene in 67 GAS strains representing 36 distinct M protein serotypes was sequenced. Two distinct genetic complexes were identified, and they were designated complex I and complex II. Mac variants in each of the two complexes were closely related, but complex I and complex II variants differed on average at 50.66 +/- 5.8 amino acid residues, most of which were located in the middle one-third of the protein. Complex I Mac variants have greater homology with CD11b than complex II variants. GAS strains belonging to serotypes M1 and M3, the most abundant M protein serotypes responsible for human infections in many case series, have complex I Mac variants. The mac gene was cloned from representative strains assigned to complexes I and II, and the Mac proteins were purified to apparent homogeneity. Both Mac variants had immunoglobulin G (IgG)-endopeptidase activity. In contrast to Mac(5005) (complex I), Mac(8345) (complex II) underwent autooxidation of its cysteine residues, resulting in the loss of IgG-endopeptidase activity. A Mac(5005) Cys94Ala site-specific mutant protein was unable to cleave IgG but retained the ability to inhibit IgG-mediated phagocytosis by human PMNs. Thus, the IgG-endopeptidase activity was not essential for the key biological function of Mac(5005). Although Mac(5005) and Mac(8345) each have an Arg-Gly-Asp (RGD) motif, the proteins differed in their interactions with human integrins alpha(v)beta(3) and alpha(IIb)beta(3). Binding of Mac(5005) to integrins alpha(v)beta(3) and alpha(IIb)beta(3) was mediated primarily by the RGD motif in Mac(5005), whereas binding of Mac(8345) involved the RGD motif and a region in the middle one-third of the molecule whose sequence is different in Mac(8345) and Mac(5005). Taken together, the data add to the emerging theme in GAS pathogenesis that allelic variation in virulence genes contributes to fundamental differences in host-pathogen interactions among strains.

Amino Acid Sequence↗
PubMed2004

Protein kinase B/Akt acts via glycogen synthase kinase 3 to regulate recycling of alpha v beta 3 and alpha 5 beta 1 integrins.

Protein kinase B (PKB)/Akt is known to promote cell migration, and this may contribute to the enhanced invasiveness of malignant cells. To elucidate potential mechanisms by which PKB/Akt promotes the migration phenotype, we have investigated its role in the endosomal transport and recycling of integrins. Whereas the internalization of alpha v beta 3 and alpha 5 beta 1 integrins and their transport to the recycling compartment were independent of PKB/Akt, the return of these integrins (but not internalized transferrin) to the plasma membrane was regulated by phosphatidylinositol 3-kinases and PKB/Akt. The blockade of integrin recycling and cell spreading on integrin ligands effected by inhibition of PKB/Akt was reversed by inhibition of glycogen synthase kinase 3 (GSK-3). Moreover, expression of nonphosphorylatable active GSK-3 beta mutant GSK-3 beta-A9 suppressed recycling of alpha 5 beta 1 and alpha v beta 3 and reduced cell spreading on ligands for these integrins, indicating that PKB/Akt promotes integrin recycling by phosphorylating and inactivating GSK-3. We propose that the ability of PKB/Akt to act via GSK-3 to promote the recycling of matrix receptors represents a key mechanism whereby integrin function and cell migration can be regulated by growth factors.

Animals↗
PubMed2004

Acquired expression of periostin by human breast cancers promotes tumor angiogenesis through up-regulation of vascular endothelial growth factor receptor 2 expression.

The late stages of human breast cancer development are poorly understood complex processes associated with the expression of genes by cancers that promote specific tumorigenic activities, such as angiogenesis. Here, we describe the identification of periostin as a mesenchyme-specific gene whose acquired expression by human breast cancers leads to a significant enhancement in tumor progression and angiogenesis. Undetectable in normal human breast tissues, periostin was found to be overexpressed by the vast majority of human primary breast cancers examined. Tumor cell lines engineered to overexpress periostin showed a phenotype of accelerated growth and angiogenesis as xenografts in immunocompromised animals. The underlying mechanism of periostin-mediated induction of angiogenesis was found to derive in part from the up-regulation of the vascular endothelial growth factor receptor Flk-1/KDR by endothelial cells through an integrin alpha(v)beta(3)-focal adhesion kinase-mediated signaling pathway. These findings demonstrate the presence of a novel mechanism by which tumor angiogenesis is acquired with the expression of a mesenchyme-specific gene as a crucial step in late stages of tumorigenesis.

Animals↗
PubMed2002

Integrin alpha V beta 3 as a target for treatment of rheumatoid arthritis and related rheumatic diseases.

A substantial and persuasive body of data now exists that supports the view that integrin alpha V beta 3 plays a critical part in activated macrophage dependent inflammation, osteoclast development, migration, and bone resorption, and inflammatory angiogenesis. All of these processes play an important part in the pathogenesis of rheumatoid arthritis (RA) and related arthropathies. Animal arthritis model data further support these concepts and also suggest that therapeutic antagonism of integrin alpha V beta 3 is worthy of further investigation in RA and related arthropathies. To this end, Vitaxin, also known as MEDI-522, has been developed. Vitaxin is a humanised monoclonal IgG1 antibody that specifically binds a conformational epitope formed by both the integrin alpha V and beta 3 subunits. It blocks the interaction of alpha V beta 3 with various ligands such as osteopontin and vitronectin. Clinical trials with Vitaxin in patients with RA are in progress.

Antibodies, Monoclonal↗
PubMed2005

Hypoxia of endothelial cells leads to MMP-2-dependent survival and death.

Exposure of endothelial cells (ECs) to hypoxia has separately been shown to induce their angiogenesis or death. Matrix metalloproteinase (MMP)-2 is associated with EC angiogenesis, although recent studies also implicate this molecule in EC death. We studied the effect of hypoxia in the absence or presence of TNF-alpha (characteristic of the inflammatory microenvironment accompanying hypoxia) on MMP-2 expression and its role in angiogenesis (proliferation, migration, and tube formation) and in the death of primary human umbilical vein endothelial cells (HUVECs). Hypoxia alone (24-48 h in 0.3% O(2) in the hypoxic chamber) and furthermore, when combined with TNF-alpha, significantly enhanced MMP-2 expression and activity. Hypoxia also led to a reduction in membrane type 1 MMP (MT1-MMP) and tissue inhibitor of metalloproteinase-2 mRNA and protein while enhancing the expression of alpha(v)beta(3) integrin and the cytoskeletal protein phosphopaxillin. Moreover, hypoxia led to colocalization of alpha(v)beta(3) and MMP-2, but not MT1-MMP, with phosphopaxillin in ECs. These results suggest MT1-MMP-independent activation of MMP-2 during hypoxia and support interactions between the ECM, integrins, and the cytoskeleton in hypoxia-induced MMP-2-related functions. Hypoxia enhanced EC migration in an MMP-2-dependent manner while leading to a reduction of cell number via their apoptosis, which was also dependent on MMP-2. In addition, hypoxia caused an aberrant tubelike formation on Matrigel that appeared to be unaffected by MMP-2. The hypoxia-induced, MMP-2-dependent migration of ECs is in accordance with the proangiogenic role ascribed to MMP-2, while the involvement of this protease in the hypoxia-related death of ECs supports an additional apoptotic role for this protease. Hence, in the hypoxic microenvironment, MMP-2 appears to have a dual autocrine role in determining the fate of ECs.

Cell Death↗
PubMed2006

Mobility and invasiveness of metastatic esophageal cancer are potentiated by shear stress in a ROCK- and Ras-dependent manner.

To metastasize, tumor cells must adopt different morphological responses to resist shear forces encountered in circulating blood and invade through basement membranes. The Rho and Ras GTPases play a critical role in regulating this dynamic behavior. Recently, we demonstrated shear-induced activation of adherent esophageal metastatic cells, characterized by formation of dynamic membrane blebs. Although membrane blebbing has only recently been characterized as a rounded mode of cellular invasion promoted through Rho kinase (ROCK), the role of shear forces in modulating membrane blebbing activity is unknown. To further characterize membrane blebbing in esophageal metastatic cells (OC-1 cell line), we investigated the role of shear in cytoskeletal remodeling and signaling through ROCK and Ras. Our results show that actin and tubulin colocalize to the cortical ring of the OC-1 cell under static conditions. However, under shear, actin acquires a punctuate distribution and tubulin localizes to the leading edge of the OC-1 cell. We show for the first time that dynamic bleb formation is induced by shear alone independent of integrin-mediated adhesion (P < 0.001, compared with OC-1 cells). Y-27632, a specific inhibitor of ROCK, causes a significant reduction in shear-induced bleb formation and inhibits integrin alpha(v)beta(3)-Ras colocalization at the leading edge of the cell. Direct measurement of Ras activation shows that the level of GTP-bound Ras is elevated in sheared OC-1 cells and that the shear-induced increase in Ras activity is inhibited by Y-27632. Finally, we show that shear stress significantly increases OC-1 cell invasion (P < 0.007), an effect negated by the presence of Y-27632. Together our findings suggest a novel physiological role for ROCK and Ras in metastatic cell behavior.

Actins↗
PubMed2005

Targeted measles virus vector displaying echistatin infects endothelial cells via alpha(v)beta3 and leads to tumor regression.

Targeting tumor-associated vascular endothelium by replication-competent viral vectors is a promising strategy for cancer gene therapy. Here we describe the development of a viral vector based on the Edmonston vaccine strain of measles virus targeted to integrin alpha(v)beta3, which is expressed abundantly on activated but not quiescent vascular endothelium. We displayed a disintegrin, M28L echistatin that binds with a high affinity to integrin alpha(v)beta3 on the COOH terminus of the viral attachment (H) protein and rescued the replication-competent recombinant virus by reverse genetics. The new targeted virus was named measles virus echistatin vector (MV-ERV). Its native binding to CD46 was purposefully retained to allow virus infection of tumor cells expressing this receptor. MV-ERV correctly displayed echistatin on the outer surface of its envelope and produced interesting ring formation phenomena due to cell detachment upon infection of susceptible Vero cells in vitro. MV-ERV grew to 10(6) plaque-forming units/mL, slightly lower than the parental Edmonston strain of measles virus (MV-Edm), but it selectively infected Chinese hamster ovary cells expressing integrin alpha(v)beta3. It also selectively infected both bovine and human endothelial cells on matrigels and unlike MV-Edm, MV-ERV infected newly formed blood vessels in chorioallantoic membrane assays. In animal models, MV-ERV but not the control MV-Edm caused the regression of s.c. xenografts of resistant multiple myeloma tumors (MM1) in severe combined immunodeficient mice. The tumors were either completely eradicated or their growth was significantly retarded. The specificity, potency, and feasibility of MV-ERV infection clearly show the potential use of MV-ERV in gene therapy for targeting tumor-associated vasculature for the treatment of solid tumors.

Amino Acid Sequence↗
PubMed2005

Dissecting the role of matrix metalloproteinases (MMP) and integrin alpha(v)beta3 in angiogenesis in vitro: absence of hemopexin C domain bioactivity, but membrane-Type 1-MMP and alpha(v)beta3 are critical.

Matrix metalloproteinase (MMP)-2 and its hemopexin C domain autolytic fragment (also called PEX) have been proposed to be crucial for angiogenesis. Here, we have investigated the dependency of in vitro angiogenesis on MMP-mediated extracellular proteolysis and integrin alpha(v)beta3-mediated cell adhesion in a three-dimensional collagen I model. The hydroxamate-based synthetic inhibitors BB94, CT1399, and CT1847 inhibited endothelial cell invasion, as did neutralizing anti-membrane-type 1-MMP (MT1-MMP) antibodies and tissue inhibitor of MMP (TIMP)-2 and TIMP-3 but not TIMP-1. This confirmed the pivotal importance of MT1-MMP over other MMPs in this model. Invasion was also inhibited by a nonpeptidic antagonist of integrin alpha(v)beta3, EMD 361276. Although PEX strongly inhibited pro-MMP-2 activation, when contaminating lipopolysaccharide was neutralized, PEX neither affected angiogenesis nor bound integrin alpha(v)beta(3). Moreover, no specific binding of pro-MMP-2 to integrin alpha(v)beta3 was found, whereas only one out of four independently prepared enzymatically active MMP-2 preparations could bind integrin alpha(v)beta3 , and this in a PEX-independent manner. Likewise, integrin alpha(v)beta3 -expressing cells did not bind MMP-2-coated surfaces. Hence, these findings show that endothelial cell invasion of collagen I gels is MT1-MMP and alpha(v)beta3 - dependent but MMP-2 independent and does not support a role for PEX in alpha(v)beta3 integrin binding or in modulating angiogenesis in this system.

Animals↗