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Cold Spring Harbor Perspectives in... Oct 2017Laminin, a basement membrane protein discovered in 1979, was shortly thereafter implicated in the polarization of epithelial cells in both mammals and a variety of lower... (Review)
Review
Laminin, a basement membrane protein discovered in 1979, was shortly thereafter implicated in the polarization of epithelial cells in both mammals and a variety of lower organisms. To transduce a spatial cue to the intrinsic polarization machinery, laminin must polymerize into a dense network that forms the foundation of the basement membrane. Evidence suggests that activation of the small GTPase Rac1 by β1-integrins mobilizes laminin-binding integrins and dystroglycan to consolidate formation of the laminin network and initiate rearrangements of both the actin and microtubule cytoskeleton to help establish the apicobasal axis. A key coordinator of spatial signals from laminin is the serine-threonine kinase Par-1, which is known to affect dystroglycan availability, microtubule and actin organization, and lumen formation. The signaling protein integrin-linked kinase (ILK) may also play a role. Despite significant advances, knowledge of the mechanism by which assembled laminin produces a spatial signal remains fragmentary, and much more research into the complex functions of laminin in polarization and other cellular processes is needed.
Topics: Animals; Cell Polarity; Epithelial Cells; Laminin
PubMed: 28159878
DOI: 10.1101/cshperspect.a027920 -
Cell Adhesion & Migration 2013The heterotrimeric laminins are a defining component of all basement membranes and self-assemble into a cell-associated network. The three short arms of the cross-shaped... (Review)
Review
The heterotrimeric laminins are a defining component of all basement membranes and self-assemble into a cell-associated network. The three short arms of the cross-shaped laminin molecule form the network nodes, with a strict requirement for one α, one β and one γ arm. The globular domain at the end of the long arm binds to cellular receptors, including integrins, α-dystroglycan, heparan sulfates and sulfated glycolipids. Collateral anchorage of the laminin network is provided by the proteoglycans perlecan and agrin. A second network is then formed by type IV collagen, which interacts with the laminin network through the heparan sulfate chains of perlecan and agrin and additional linkage by nidogen. This maturation of basement membranes becomes essential at later stages of embryo development.
Topics: Agrin; Animals; Basement Membrane; Collagen Type IV; Cytoskeleton; Dystroglycans; Extracellular Matrix; Heparan Sulfate Proteoglycans; Humans; Integrin alpha Chains; Laminin; Polymerization; Protein Binding; Protein Interaction Mapping; Protein Structure, Tertiary
PubMed: 23076216
DOI: 10.4161/cam.21831 -
Developmental Dynamics : An Official... Jun 2000The laminins are a family of glycoproteins that provide an integral part of the structural scaffolding of basement membranes in almost every animal tissue. Each laminin... (Review)
Review
The laminins are a family of glycoproteins that provide an integral part of the structural scaffolding of basement membranes in almost every animal tissue. Each laminin is a heterotrimer assembled from alpha, beta, and gamma chain subunits, secreted and incorporated into cell-associated extracellular matrices. The laminins can self-assemble, bind to other matrix macromolecules, and have unique and shared cell interactions mediated by integrins, dystroglycan, and other receptors. Through these interactions, laminins critically contribute to cell differentiation, cell shape and movement, maintenance of tissue phenotypes, and promotion of tissue survival. Recent advances in the characterization of genetic disruptions in humans, mice, nematodes and flies have revealed developmental roles for the different laminin subunits in diverse cell types, affecting differentiation from blastocyst formation to the post-natal period. These genetic defects have challenged some of the previous concepts about basement membranes and have shed new light on the diversity and complexity of laminin functions as well as established the molecular basis of several human diseases.
Topics: Animals; Brain; Cell Adhesion Molecules; Humans; Invertebrates; Kidney; Laminin; Mice; Muscle, Skeletal; Peripheral Nerves; Polymers; Receptors, Laminin; Kalinin
PubMed: 10842354
DOI: 10.1002/(SICI)1097-0177(200006)218:2<213::AID-DVDY1>3.0.CO;2-R -
Matrix Biology : Journal of the... Apr 2023Null mutations of the Lama2-gene cause a severe congenital muscular dystrophy and associated neuropathy. In the absence of laminin-α2 (Lmα2) there is a compensatory...
Null mutations of the Lama2-gene cause a severe congenital muscular dystrophy and associated neuropathy. In the absence of laminin-α2 (Lmα2) there is a compensatory replacement by Lmα4, a subunit that lacks the polymerization and α-dystroglycan (αDG)-binding properties of Lmα2. The dystrophic phenotype in the dy/dy Lama2 mouse were evaluated with transgenes driving expression of two synthetic laminin-binding linker proteins. Transgenic muscle-specific expression of αLNNd, a chimeric protein that enables α4-laminin polymerization, and miniagrin (mag), a protein that increases laminin binding to the receptor αDG, separately improved median mouse survival two-fold. The double transgenes (DT) improved mean survival three-fold with increases in overall body weight, muscle size, and grip strength, but, given absence of neuronal expression, did not prevent hindlimb paresis. Muscle improvements included increased myofiber size and number and reduced fibrosis. Myofiber hypertrophy with increased mTOR and Akt phosphorylation were characteristics of mag-dy/dy and DT-dy/dy muscle. Elevations of matrix-bound α4-, β1 and γ1 laminin subunits were detected in muscle extracts and immunostained sections in response to DT expression. Collectively, these findings reveal a complimentary polymerization and αDG-binding benefit to Lama2 mouse muscle largely mediated through modified laminin-411.
Topics: Mice; Animals; Muscle, Skeletal; Laminin; Mice, Transgenic; Muscular Dystrophies; Transgenes
PubMed: 36878377
DOI: 10.1016/j.matbio.2023.03.001 -
Atherosclerosis Apr 2023Laminins are essential components of the endothelial basement membrane, which predominantly contains LN421 and LN521 isoforms. Regulation of laminin expression under...
BACKGROUND AND AIMS
Laminins are essential components of the endothelial basement membrane, which predominantly contains LN421 and LN521 isoforms. Regulation of laminin expression under pathophysiological conditions is largely unknown. In this study, we aimed to investigate the role of IL-6 in regulating endothelial laminin profile and characterize the impact of altered laminin composition on the phenotype, inflammatory response, and function of endothelial cells (ECs).
METHODS
HUVECs and HAECs were used for in vitro experiments. Trans-well migration experiments were performed using leukocytes isolated from peripheral blood of healthy donors. The BiKE cohort was used to assess expression of laminins in atherosclerotic plaques and healthy vessels. Gene and protein expression was analyzed using Microarray/qPCR and proximity extension assay, ELISA, immunostaining or immunoblotting techniques, respectively.
RESULTS
Stimulation of ECs with IL-6+sIL-6R, but not IL-6 alone, reduces expression of laminin α4 (LAMA4) and increases laminin α5 (LAMA5) expression at the mRNA and protein levels. In addition, IL-6+sIL-6R stimulation of ECs differentially regulates the release of several proteins including CXCL8 and CXCL10, which collectively were predicted to inhibit granulocyte transmigration. Experimentally, we demonstrated that granulocyte migration is inhibited across ECs pre-treated with IL-6+sIL-6R. In addition, granulocyte migration across ECs cultured on LN521 was significantly lower compared to LN421. In human atherosclerotic plaques, expression of endothelial LAMA4 and LAMA5 is significantly lower compared to control vessels. Moreover, LAMA5-to-LAMA4 expression ratio was negatively correlated with granulocytic cell markers (CD177 and myeloperoxidase (MPO)) and positively correlated with T-lymphocyte marker CD3.
CONCLUSIONS
We showed that expression of endothelial laminin alpha chains is regulated by IL-6 trans-signaling and contributes to inhibition of trans-endothelial migration of granulocytic cells. Further, expression of laminin alpha chains is altered in human atherosclerotic plaques and is related to intra-plaque abundance of leukocyte subpopulations.
Topics: Humans; Laminin; Interleukin-6; Endothelial Cells; Plaque, Atherosclerotic; Granulocytes
PubMed: 36996622
DOI: 10.1016/j.atherosclerosis.2023.03.010 -
Current Opinion in Structural Biology Jun 2019A unique O-mannose-linked glycan on the transmembrane protein dystroglycan binds a number of extracellular matrix proteins containing laminin G-like (LG) domains. The... (Review)
Review
A unique O-mannose-linked glycan on the transmembrane protein dystroglycan binds a number of extracellular matrix proteins containing laminin G-like (LG) domains. The dystroglycan-matrix interaction is essential for muscle function: disrupted biosynthesis of the matrix-binding modification causes several forms of muscular dystrophy. The complete chemical structure of this modification has been deciphered in the past few years. We now know that LG domains bind to a glycosaminoglycan-like polysaccharide of [-3GlcAβ1,3Xylα1-] units, termed matriglycan, that is attached to a highly unusual heptasaccharide linker. X-ray crystallography has revealed the principles of Ca-dependent matriglycan binding by LG domains. In this review, the new structural insights are applied to the growing number of LG domain-containing proteins that bind dystroglycan. It is proposed that LG domains be recognised as 'D-type' lectins to indicate their conserved function in dystroglycan binding.
Topics: Amino Acid Sequence; Animals; Dystroglycans; Humans; Laminin; Lectins; Protein Domains
PubMed: 30530204
DOI: 10.1016/j.sbi.2018.11.007 -
Cell Adhesion & Migration 2013Laminins (LM) are extracellular matrix molecules that contribute to and are required for the formation of basement membranes. They participate in the modulation of... (Review)
Review
Laminins (LM) are extracellular matrix molecules that contribute to and are required for the formation of basement membranes. They participate in the modulation of epithelial/mesenchymal interactions and are implicated in organogenesis and maintenance of organ homeostasis. Among the LM molecules, the LM α5 chain (LMα5) is one of the most widely distributed LM in the developing and mature organism. Its presence in some basement membranes during embryogenesis is absolutely required for maintenance of basement membrane integrity and thus for proper organogenesis. LMα5 also regulates the expression of genes important for major biological processes, in part by repressing or activating signaling pathways, depending upon the physiological context.
Topics: Animals; Basement Membrane; Binding Sites; Body Patterning; Cell Differentiation; Cell Movement; Extracellular Matrix; Gene Expression Regulation, Developmental; Laminin; Mice; Organogenesis; Protein Binding; Stem Cells; Syndecan-4; Wnt Signaling Pathway
PubMed: 23076210
DOI: 10.4161/cam.22236 -
Matrix Biology : Journal of the... Apr 2021Laminin polymerization is a key step of basement membrane assembly that depends on the binding of α, β and γ N-terminal LN domains to form a polymer node. Nodal...
Laminin polymerization is a key step of basement membrane assembly that depends on the binding of α, β and γ N-terminal LN domains to form a polymer node. Nodal assembly can be divided into two steps consisting of β- and γ-LN dimerization followed by calcium-dependent addition of the α-LN domain. The assembly and structural organization of laminin-111 LN-LEa segments was examined by size-exclusion chromatography (SEC) and electron microscopy. Triskelion-like structures were observed in negatively-stained images of purified α1/β1/γ1 LN-LEa trimers. Image averaging of these revealed a heel-to-toe organization of the LN domains with angled outward projections of the LEa stem-like domains. A series of single-amino acid substitutions was introduced into the polymerization faces of the α1, β1 and γ1 LN domains followed by SEC analysis to distinguish between loss of β-γ mediated dimerization and loss of α-dependent trimerization (with intact β-γ dimers). Dimer-blocking mutations were confined to the γ1-toe and the β1-heel, whereas the trimer-only-blocking mutations mapped to the γ1-heel, β1-toe and the α1-toe and heel. Thus, in the polymer node the γ1-toe pairs with the β1-heel, the β1-toe pairs with the α1-heel, and the α1-toe pairs with the γ1-heel.
Topics: Laminin; Morphogenesis; Mutation; Polymers
PubMed: 34029691
DOI: 10.1016/j.matbio.2021.05.004 -
Cell Adhesion & Migration 2013A chain is no stronger than its weakest link is an old idiom that holds true for muscle biology. As the name implies, skeletal muscle's main function is to move the... (Review)
Review
A chain is no stronger than its weakest link is an old idiom that holds true for muscle biology. As the name implies, skeletal muscle's main function is to move the bones. However, for a muscle to transmit force and withstand the stress that contractions give rise to, it relies on a chain of proteins attaching the cytoskeleton of the muscle fiber to the surrounding extracellular matrix. The importance of this attachment is illustrated by a large number of muscular dystrophies caused by interruption of the cytoskeletal-extracellular matrix interaction. One of the major components of the extracellular matrix is laminin, a heterotrimeric glycoprotein and a major constituent of the basement membrane. It has become increasingly apparent that laminins are involved in a multitude of biological functions, including cell adhesion, differentiation, proliferation, migration and survival. This review will focus on the importance of laminin-211 for normal skeletal muscle function.
Topics: Animals; Basement Membrane; Cell Survival; Dystroglycans; Extracellular Matrix; Humans; Laminin; Mice; Muscle Contraction; Muscle Development; Muscle, Skeletal; Muscular Dystrophies; Mutation; Protein Binding; Sarcolemma; Signal Transduction
PubMed: 23154401
DOI: 10.4161/cam.22618 -
Advanced Healthcare Materials Jun 2022Laminins (LNs) are key components in the extracellular matrix of neuronal tissues in the developing brain and neural stem cell niches. LN-presenting hydrogels can...
Laminins (LNs) are key components in the extracellular matrix of neuronal tissues in the developing brain and neural stem cell niches. LN-presenting hydrogels can provide a biologically relevant matrix for the 3D culture of neurons toward development of advanced tissue models and cell-based therapies for the treatment of neurological disorders. Biologically derived hydrogels are rich in fragmented LN and are poorly defined concerning composition, which hampers clinical translation. Engineered hydrogels require elaborate and often cytotoxic chemistries for cross-linking and LN conjugation and provide limited possibilities to tailor the properties of the materials. Here a modular hydrogel system for neural 3D cell cultures, based on hyaluronan and poly(ethylene glycol), that is cross-linked and functionalized with human recombinant LN-521 using bioorthogonal copper-free click chemistry, is shown. Encapsulated human neuroblastoma cells demonstrate high viability and grow into spheroids. Long-term neuroepithelial stem cells (lt-NES) cultured in the hydrogels can undergo spontaneous differentiation to neural fate and demonstrate significantly higher viability than cells cultured without LN. The hydrogels further support the structural integrity of 3D bioprinted structures and maintain high viability of bioprinted and syringe extruded lt-NES, which can facilitate biofabrication and development of cell-based therapies.
Topics: Bioprinting; Cell Culture Techniques; Humans; Hyaluronic Acid; Hydrogels; Laminin; Neurons; Tissue Engineering
PubMed: 35114074
DOI: 10.1002/adhm.202102097