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Expert Reviews in Molecular Medicine Jan 2010Within the integrin family of cell adhesion receptors, integrins alpha3beta1, alpha6beta1, alpha6beta4 and alpha7beta1 make up a laminin-binding subfamily. The... (Review)
Review
Within the integrin family of cell adhesion receptors, integrins alpha3beta1, alpha6beta1, alpha6beta4 and alpha7beta1 make up a laminin-binding subfamily. The literature is divided on the role of these laminin-binding integrins in metastasis, with different studies indicating either pro- or antimetastatic functions. The opposing roles of the laminin-binding integrins in different settings might derive in part from their unusually robust associations with tetraspanin proteins. Tetraspanins organise integrins into multiprotein complexes within discrete plasma membrane domains termed tetraspanin-enriched microdomains (TEMs). TEM association is crucial to the strikingly rapid cell migration mediated by some of the laminin-binding integrins. However, emerging data suggest that laminin-binding integrins also promote the stability of E-cadherin-based cell-cell junctions, and that tetraspanins are essential for this function as well. Thus, TEM association endows the laminin-binding integrins with both pro-invasive functions (rapid migration) and anti-invasive functions (stable cell junctions), and the composition of TEMs in different cell types might help determine the balance between these opposing activities. Unravelling the tetraspanin control mechanisms that regulate laminin-binding integrins will help to define the settings where inhibiting the function of these integrins would be helpful rather than harmful, and may create opportunities to modulate integrin activity in more sophisticated ways than simple functional blockade.
Topics: Animals; Humans; Integrins; Laminin; Neoplasm Metastasis; Protein Binding
PubMed: 20078909
DOI: 10.1017/S1462399409001355 -
JCI Insight Apr 2023Fibroblastic reticular cells (FRCs) play important roles in tolerance by producing laminin α4 (Lama4) and altering lymph node (LN) structure and function. The present...
Fibroblastic reticular cells (FRCs) play important roles in tolerance by producing laminin α4 (Lama4) and altering lymph node (LN) structure and function. The present study revealed the specific roles of extracellular matrix Lama4 in regulating LN conduits using FRC-specific KO mouse strains. FRC-derived Lama4 maintained conduit fiber integrity, as its depletion altered conduit morphology and structure and reduced homeostatic conduit flow. Lama4 regulated the lymphotoxin β receptor (LTβR) pathway, which is critical for conduit and LN integrity. Depleting LTβR in FRCs further reduced conduits and impaired reticular fibers. Lama4 was indispensable for FRC generation and survival, as FRCs lacking Lama4 displayed reduced proliferation but upregulated senescence and apoptosis. During acute immunization, FRC Lama4 deficiency increased antigen flow through conduits. Importantly, adoptive transfer of WT FRCs to FRC Lama4-deficient mice rescued conduit structure, ameliorated Treg and chemokine distribution, and restored transplant allograft acceptance, which were all impaired by FRC Lama4 depletion. Single-cell RNA sequencing analysis of LN stromal cells indicated that the laminin and collagen signaling pathways linked crosstalk among FRC subsets and endothelial cells. This study demonstrated that FRC Lama4 is responsible for maintaining conduits by FRCs and can be harnessed to potentiate FRC-based immunomodulation.
Topics: Mice; Animals; Laminin; Endothelial Cells; Lymph Nodes; Signal Transduction; Chemokines
PubMed: 37092548
DOI: 10.1172/jci.insight.167816 -
FEBS Letters Nov 2015Muscle regeneration is essentially due to activation of satellite cells, which can be isolated and amplified ex vivo, thus representing good candidates for cell therapy.... (Review)
Review
Muscle regeneration is essentially due to activation of satellite cells, which can be isolated and amplified ex vivo, thus representing good candidates for cell therapy. Accumulating data show that the local microenvironment plays a major role during muscle regeneration. In the satellite cell niche, a major extracellular matrix protein is laminin. Human myoblasts transplanted into immunodeficient mice are preferentially located in laminin-enriched areas. Additionally, laminin-111 enhances myoblast proliferation in vitro and increases expression of the α7β1 integrin-type laminin receptor. Intramuscular injection of laminin-111 ameliorates muscular pathology in mdx mice, protecting muscle fibers from damage. Moreover, transplantation of human myoblasts with laminin-111 into Rag/mdx immunodeficient recipients improved efficacy of myoblast transplantation, increasing the number of human dystrophin-positive myofibres. Taken together, these data strongly indicate that exogenous laminin can ameliorate the regeneration process in different models of muscular dystrophies and can be instrumental for improving cell therapy aiming at repairing the degeneration/regeneration process in skeletal muscle.
Topics: Animals; Cell Transplantation; Cell- and Tissue-Based Therapy; Humans; Laminin; Muscles; Myoblasts; Regeneration
PubMed: 26459029
DOI: 10.1016/j.febslet.2015.10.004 -
Redox Biology Jan 2019Basement membranes are specialized extracellular matrices that underlie arterial wall endothelial cells, with laminin being a key structural and biologically-active...
Basement membranes are specialized extracellular matrices that underlie arterial wall endothelial cells, with laminin being a key structural and biologically-active component. Hypochlorous acid (HOCl), a potent oxidizing and chlorinating agent, is formed in vivo at sites of inflammation via the enzymatic action of myeloperoxidase (MPO), released by activated leukocytes. Considerable data supports a role for MPO-derived oxidants in cardiovascular disease and particularly atherosclerosis. These effects may be mediated via extracellular matrix damage to which MPO binds. Herein we detect and quantify sites of oxidation and chlorination on isolated laminin-111, and laminin in basement membrane extracts (BME), by use of mass spectrometry. Increased modification was detected with increasing oxidant exposure. Mass mapping indicated selectivity in the sites and extent of damage; Met residues were most heavily modified. Fewer modifications were detected with BME, possibly due to the shielding effects. HOCl oxidised 30 (of 56 total) Met and 7 (of 24) Trp residues, and chlorinated 33 (of 99) Tyr residues; 3 Tyr were dichlorinated. An additional 8 Met and 10 Trp oxidations, 14 chlorinations, and 18 dichlorinations were detected with the MPO/HO/Cl system when compared to reagent HOCl. Interestingly, chlorination was detected at Tyr in the integrin-binding region; this may decrease cellular adhesion. Co-localization of MPO-damaged epitopes and laminin was detected in human atherosclerotic lesions. These data indicate that laminin is extensively modified by MPO-derived oxidants, with structural and functional changes. These modifications, and compromised cell-matrix interactions, may promote endothelial cell dysfunction, weaken the structure of atherosclerotic lesions, and enhance lesion rupture.
Topics: Amino Acids; Amino Acids, Diamino; Animals; Basement Membrane; Chlorine; Extracellular Matrix Proteins; Humans; Hydrogen Peroxide; Hypochlorous Acid; Laminin; Mice; Oxidation-Reduction; Peroxidase
PubMed: 30476874
DOI: 10.1016/j.redox.2018.10.022 -
The International Journal of... 2011The interaction of endothelial cells and pericytes with their microenvironment, in particular with the basement membrane, plays a crucial role during vasculogenesis and... (Review)
Review
The interaction of endothelial cells and pericytes with their microenvironment, in particular with the basement membrane, plays a crucial role during vasculogenesis and angiogenesis. In this review, we focus on laminins, a major family of extracellular matrix molecules present in basement membranes. Laminins interact with cell surface receptors to trigger intracellular signalling that shapes cell behaviour. Each laminin exerts a distinct effect on endothelial cells and pericytes which largely depends on the adhesion receptor profile expressed on the cell surface. Moreover, proteolytic cleavage of laminins may affect their role in angiogenesis. We report in vitro and in vivo data on laminin-111, -411, -511 and -332 and their associated signalling that regulates cell behaviour and angiogenesis under normal and pathological conditions. We also discuss how tissue-specific deletion of laminin genes affects the behaviour of endothelial cells and pericytes and thus angiogenesis. Finally, we examine how coculture systems with defined laminin expression contribute to our understanding of the roles of laminins in normal and pathological vasculogenesis and angiogenesis.
Topics: Animals; Basement Membrane; Cell Adhesion; Coculture Techniques; Endothelial Cells; Humans; Laminin; Models, Biological; Neovascularization, Pathologic; Neovascularization, Physiologic; Pericytes; Protein Processing, Post-Translational; Signal Transduction
PubMed: 21858771
DOI: 10.1387/ijdb.103223ps -
International Journal of Cancer Dec 2001The basement membrane (BM) separates epithelial elements from the surrounding stroma. BM is dynamic in regulation of epithelial cells differentiation as well as their... (Review)
Review
The basement membrane (BM) separates epithelial elements from the surrounding stroma. BM is dynamic in regulation of epithelial cells differentiation as well as their organization into 3-dimensional tissues. In these functions, among the molecules of the BM, laminins are especially dynamic. Laminins are distributed in a spatially and temporally regulated manner in various epithelial tissues. Various changes in the laminin distribution accompany the malignant transformation of epithelia. The role of the BM and laminins in the progression of carcinomas is not well understood. The BM has been suggested to act as a mechanical barrier against carcinoma cell invasion. BM laminins may play an active role in regulating the migration and proliferation of the carcinoma cells. Laminin isoform laminin-5 expression is typical for some invasive carcinomas and it may act as a ligand for invading carcinoma cells. Neoexpression of laminin-5 has also been associated to proliferative activity of the carcinoma cells. Integrins alpha(3)beta(1) and alpha(6)beta(4) are probable cell surface receptors acting with laminin-5 in the regulation of carcoma cell invasion and proliferation.
Topics: Basement Membrane; Cell Adhesion Molecules; Cell Division; Humans; Integrins; Neoplasm Invasiveness; Neoplasms; Kalinin
PubMed: 11745475
DOI: 10.1002/ijc.1539 -
Matrix Biology : Journal of the... Jul 2010Laminin-121, previously referred as to laminin-3, was expressed recombinantly in human embryonic kidney (HEK) 293 cells by triple transfection of full-length cDNAs... (Comparative Study)
Comparative Study
Laminin-121, previously referred as to laminin-3, was expressed recombinantly in human embryonic kidney (HEK) 293 cells by triple transfection of full-length cDNAs encoding mouse laminin α1, β2 and γ1 chains. The recombinant laminin-121 was purified using Heparin-Sepharose followed by molecular sieve chromatography and shown to be correctly folded by electron microscopy and circular dichroism (CD). The CD spectra of recombinant laminin-121 were very similar to those of laminin-111 isolated from Engelbreth-Holm-Swarm tumor (EHS-laminin) but its T(m) value was smaller than EHS-laminin and recombinant lamnin-111 suggesting that the replacement of the β chain reduced the stability of the coiled-coil structure of laminin-121. Its binding to integrins was compared with EHS-laminin, laminin-3A32 purified from murine epidermal cell line and recombinantly expressed laminins-111, -211 and -221. Laminin-121 showed the highest affinity to α6β1 and α7β1 integrins and furthermore, laminin-121 most effectively supported neurite outgrowth. Together, this suggests that the β2 laminins have higher affinity for integrins than the β1 laminins.
Topics: Animals; Cell Line; Chromatography, Gel; Circular Dichroism; HEK293 Cells; Humans; In Vitro Techniques; Integrins; Kidney; Laminin; Mice; Recombinant Proteins; Sepharose; Transfection
PubMed: 20566382
DOI: 10.1016/j.matbio.2010.05.004 -
Redox Biology Jun 2019Laminin is a major protein of the basement membrane (BM), a specialized extracellular matrix (ECM) of the artery wall. The potent oxidizing and nitrating agent...
Laminin is a major protein of the basement membrane (BM), a specialized extracellular matrix (ECM) of the artery wall. The potent oxidizing and nitrating agent peroxynitrous acid (ONOOH) is formed at sites of inflammation, and data implicate ONOOH in ECM damage and cardiovascular disease. Co-localization of 3-nitrotyrosine, a product of ONOOH-mediated tyrosine (Tyr) modification, and laminin has been reported in human atherosclerotic lesions. The sites and consequences of 3-nitrotyrosine (and related nitrated tryptophan) formation on laminin, it's self-assembly and cell interactions are poorly understood. In this study murine laminin-111 was exposed to ONOOH (1-500-fold molar excess). Nitration sites were mapped and quantified using LC-MS/MS. Mono-nitration was detected at 148 sites (126 Tyr, 22 Trp), and di-nitration at 14 sites. Label-free quantification showed enhanced nitration with increasing oxidant doses. Tyr nitration was ∼10-fold greater than at Trp. CO modulated damage in a site-specific manner, with most sites less extensively nitrated. 119 mono-nitration sites were identified with CO present, and no unique sites were detected. 23 di-nitration sites were detected, with 15 unique to the presence of CO. Extensive modification was detected at sites involved in cell adhesion, protein-protein interactions and self-polymerization. Tyr-145 on the γ1 chain was extensively nitrated, and endothelial cells exhibited decreased adhesion to a nitrated peptide modelling this site. Modification of residues involved in self-polymerization interfered with the formation of ordered polymers as detected by scanning electron microscopy. These laminin modifications may contribute to endothelial cell dysfunction and modulate ECM structure and assembly, and thereby contribute to atherogenesis.
Topics: Carbon Dioxide; Chromatography, Liquid; Computational Biology; Extracellular Matrix; Humans; Laminin; Models, Molecular; Molecular Structure; Nitrates; Oxidation-Reduction; Protein Conformation; Protein Multimerization; Protein Processing, Post-Translational; Structure-Activity Relationship; Tandem Mass Spectrometry
PubMed: 31154162
DOI: 10.1016/j.redox.2019.101226 -
Human Mutation Sep 2010Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities,... (Review)
Review
Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin beta2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin beta2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.
Topics: Genetic Association Studies; Genetic Predisposition to Disease; Haplotypes; Humans; Laminin; Mutation; Phenotype
PubMed: 20556798
DOI: 10.1002/humu.21304 -
Fluids and Barriers of the CNS Dec 2022Unlike other proteins that exhibit a diffusion pattern after intracerebral injection, laminin displays a vascular pattern. It remains unclear if this unique vascular...
BACKGROUND
Unlike other proteins that exhibit a diffusion pattern after intracerebral injection, laminin displays a vascular pattern. It remains unclear if this unique vascular pattern is caused by laminin-receptor interaction or laminin self-assembly.
METHODS
We compared the distribution of various wild-type laminin isoforms in the brain after intracerebral injection. To determine what causes the unique vascular pattern of laminin in the brain, laminin mutants with impaired receptor-binding and/or self-assembly activities and function-blocking antibodies to laminin receptors were used. In addition, the dynamics of laminin distribution and elimination were examined at multiple time points after intracerebral injection.
RESULTS
We found that β2-containing laminins had higher affinity for the vessels compared to β1-containing laminins. In addition, laminin mutants lacking receptor-binding domains but not that lacking self-assembly capability showed substantially reduced vascular pattern. Consistent with this finding, dystroglycan (DAG1) function-blocking antibody significantly reduced the vascular pattern of wild-type laminin-111. Although failed to affect the vascular pattern when used alone, integrin-β1 function-blocking antibody further decreased the vascular pattern when combined with DAG1 antibody. EDTA, which impaired laminini-DAG1 interaction by chelating Ca, also attenuated the vascular pattern. Immunohistochemistry revealed that laminins were predominantly located in the perivascular space in capillaries and venules/veins but not arterioles/arteries. The time-course study showed that laminin mutants with impaired receptor-engaging activity were more efficiently eliminated from the brain compared to their wild-type counterparts. Concordantly, significantly higher levels of mutant laminins were detected in the cerebral-spinal fluid (CSF).
CONCLUSIONS
These findings suggest that intracerebrally injected laminins are enriched in the perivascular space in a receptor (DAG1/integrin)-dependent rather than self-assembly-dependent manner and eliminated from the brain mainly via the perivascular clearance system.
Topics: Dystroglycans; Laminin; Integrins; Brain; Veins
PubMed: 36463265
DOI: 10.1186/s12987-022-00396-y