Laminin N-terminus (LaNt) proteins, laminins and basement membrane regulation (original) (raw)
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The role of laminins in basement membrane function
Journal of Anatomy, 1998
Laminins are a family of multifunctional macromolecules, ubiquitous in basement membranes, and represent the most abundant structural noncollagenous glycoproteins of these highly specialised extracellular matrices. Their discovery started with the difficult task of isolating molecules produced by cultivated cells or extracted from tissues. The development of molecular biology techniques has facilitated and accelerated the identification and the characterisation of new laminin variants making it feasible to identify full-length polypeptides which have not been purified. Further, genetically engineered laminin fragments can be generated for studies of their structure-function relationship, permitting the demonstration that laminins are involved in multiple interactions with themselves, with other components of the basal lamina, and with cells. It endows laminins with a central role in the formation, the architecture, and the stability of basement membranes. In addition, laminins may both separate and connect different tissues, i.e. the parenchymal and the interstitial connective tissues. Laminins also provide adjacent cells with a mechanical scaffold and biological information either directly by interacting with cell surface components, or indirectly by trapping growth factors. In doing so they trigger and control cellular functions. Recently, the structural and biological diversity of the laminins has started to be elucidated by gene targeting and by the identification of laminin defects in acquired or inherited human diseases. The consequent phenotypes highlight the pivotal role of laminins in determining heterogeneity in basement membrane functions.
Assembly and tissue functions of early embryonic laminins and netrins
Current Opinion in Cell Biology, 2004
Vertebrate laminins and netrins share N-terminal domain structure, but appear to be only distantly related. Both families can be divided into different subfamilies on the basis of structural considerations. Recent observations suggest that specific laminin and netrin members have developmental functions that are highly conserved across species. Vertebrate laminin-1 (a1b1g1) and laminin-10 (a5b1g1), like the two Caenorhabditis elegans laminins, are embryonically expressed and are essential for basement membrane assembly. Basement membrane assembly is a cooperative process in which laminins polymerize through their LN domains and anchor to the cell surface through their G domains; this leads to cell signaling through integrins and dystroglycan (and possibly other receptors) recruited to the adherent laminin. Netrins may associate with this network through heterotypic LN domain interactions. Vertebrate netrin-1, like invertebrate UNC-6/ netrins, is well known as an extracellular guidance cue that directs axon migration towards or away from the ventral midline. It also regulates cell adhesions and migrations, probably as a basement membrane component. Although sharing structural features, these two vertebrate protein families are quite distinct, having both retained members that mediate the ancestral developmental functions.
The Journal of Cell Biology, 1999
Laminins are heterotrimeric molecules composed of an α, a β, and a γ chain; they have broad functional roles in development and in stabilizing epithelial structures. Here, we identified a novel laminin, composed of known α and β chains but containing a novel γ chain, γ3. We have cloned gene encoding this chain, LAMC3, which maps to chromosome 9 at q31-34. Protein and cDNA analyses demonstrate that γ3 contains all the expected domains of a γ chain, including two consensus glycosylation sites and a putative nidogen-binding site. This suggests that γ3-containing laminins are likely to exist in a stable matrix. Studies of the tissue distribution of γ3 chain show that it is broadly expressed in: skin, heart, lung, and the reproductive tracts. In skin, γ3 protein is seen within the basement membrane of the dermal-epidermal junction at points of nerve penetration. The γ3 chain is also a prominent element of the apical surface of ciliated epithelial cells of: lung, oviduct, epididymis, duct...
Laminin isoforms in development and disease
The members of the laminin family of hetero-trimers are major constituents of all basement membranes, sheet-like extracellular structures, present in almost all organs. The laminins bind to cell surface receptors and thereby tightly connect the basement membrane to the adjacent cell layer. This provides for the specific basement membrane functions to stabilize cellular structures, to serve as effective physical barriers, and furthermore, to govern cell fate by inducing intracellular signalling cascades. Many different types of diseases involve basement membranes and laminins. Metastasizing solid tumors must pass through basement membranes to reach the vascular system, and various microbes and viruses enter the cells through direct interaction with laminins. Furthermore, whereas mutations in one specific laminin chain lead to a muscular disorder, mutations of other laminin chains cause skin blistering and kidney defects, respectively. This review summarizes recent progress concerning the molecular mechanisms of laminins in development and disease. The current knowledge may lead to clinical treatment of lamininopathies and may include stem-cell approaches as well as gene therapy.
Functional Diversity of Laminins
Annual Review of Cell and Developmental Biology, 2012
Laminins are a large family of conserved, multidomain trimeric basement membrane proteins that contribute to the structure of extracellular matrix and influence the behavior of associated cells, such as adhesion, differentiation, migration, phenotype stability, and resistance to anoikis. In lower organisms such as Hydra there is only one isoform of laminin, but higher organisms have at least 16 trimeric isoforms with varying degrees of cell/tissue specificity. In vitro protein and cell culture studies, gene manipulation in animals, and laminin gene mutations in human diseases have provided insight into the specific functions of some laminins, but the biological roles of many isoforms are still largely unexplored, mainly owing to difficulties in isolating them in pure form from tissues or cells. In this review, we elucidate the evolution of laminins, describe their molecular complexity, and explore the current knowledge of their diversity and functional aspects, including laminin-mediated signaling via membrane receptors, in vitro cell biology, and involvement in various tissues gained from animal model and human disease studies. The potential use of laminins in cell biology research and biotechnology is discussed. 523 Annu. Rev. Cell Dev. Biol. 2012.28:523-553. Downloaded from www.annualreviews.org by KAROLINSKA INSTITUTET UNIVERSITY LIBRARY on 10/13/12. For personal use only.
Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes
Nature Communications, 2016
Netrins, a family of laminin-related molecules, have been proposed to act as guidance cues either during nervous system development or the establishment of the vascular system. This was clearly demonstrated for netrin-1 via its interaction with the receptors DCC and UNC5s. However, mainly based on shared homologies with netrin-1, netrin-4 was also proposed to play a role in neuronal outgrowth and developmental/pathological angiogenesis via interactions with netrin-1 receptors. Here, we present the high-resolution structure of netrin-4, which shows unique features in comparison with netrin-1, and show that it does not bind directly to any of the known netrin-1 receptors. We show that netrin-4 disrupts laminin networks and basement membranes (BMs) through high-affinity binding to the laminin g1 chain. We hypothesize that this laminin-related function is essential for the previously described effects on axon growth promotion and angiogenesis. Our study unveils netrin-4 as a non-enzymatic extracellular matrix protein actively disrupting pre-existing BMs.
Transcriptional regulation of laminin gene expression
Microscopy Research and Technique, 2000
Laminins are the most abundant structural non-collagenous glycoproteins ubiquitously present in basement membranes. They are multidomain molecules consisting of of alpha, beta, and gamma chains. Although the precise functional differences between the laminin variants are not well understood, the diversity of laminin isoforms may reflect the formation of distinct basement membranes. The laminins display a remarkable restricted expression profile, suggesting a fine regulation of their genes. In this review, we focus on the most recent developments of laminin biology, centering on transcriptional and posttranscriptional controls. We discuss only those laminin chains whose gene organization and promoter elements have been characterized and proved to be functional. When possible, we correlate the effects of growth factors, cytokines, retinoids, and transcription factors on laminin gene expression with the identity of cis-acting elements in their genomic control regions.
A Novel Member of the Netrin Family, β-Netrin, Shares Homology with the β Chain of Laminin
The Journal of Cell Biology, 2000
The netrins are a family of laminin-related molecules. Here, we characterize a new member of the family, β-netrin. β-Netrin is homologous to the NH2 terminus of laminin chain short arms; it contains a laminin-like domain VI and 3.5 laminin EGF repeats and a netrin C domain. Unlike other netrins, this new netrin is more related to the laminin β chains, thus, its name β-netrin. An initial analysis of the tissue distribution revealed that kidney, heart, ovary, retina, and the olfactory bulb were tissues of high expression. We have expressed the molecule in a eukaryotic cell expression system and made antibodies to the expressed product. Both in situ hybridization and immunohistochemistry were used to describe the cellular source of β-netrin and where β-netrin is deposited. β-Netrin is a basement membrane component; it is present in the basement membranes of the vasculature, kidney, and ovaries. In addition, β-netrin is expressed in a limited set of fiber tracts within the brain, includ...