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.

https://anatomypubs.onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291097-0177%28200006%29218%3A2%3C213%3A%3AAID-DVDY1%3E3.0.CO%3B2-R

Form and function: the laminin family of heterotrimers.

Integrins are heterodimeric cell adhesion molecules that link the extracellular matrix to the cytoskeleton. The integrin family in man comprises 24 members, which are the result of different combinations of 1 of 18 alpha- and 1 of 8 beta-subunits. Alternative splicing of mRNA of some alpha- and beta-subunits and postranslational modifications of integrin subunits further increase the diversity of the integrin family. In their capacity as adhesion receptors that organize the cytoskeleton, integrins play an important role in controlling various steps in the signaling pathways that regulate processes as diverse as proliferation, differentiation, apoptosis, and cell migration. The intracellular signals that lead to these effects may be transduced via cytoplasmic components, which have been identified as integrin-binding proteins in yeast two-hybrid screens and which could mediate the coupling of integrins to intracellular signaling pathways. In this review an overview is given of the function and ligand-binding properties of integrins as well as of proteins that associate with integrins and may play a role in their signaling function.

Function and interactions of integrins.

Blood vessels promote tumour growth, and both blood and lymphatic vessels facilitate tumour metastasis by serving as conduits for the transport of tumour cells to new sites. Angiogenesis and lymphangiogenesis are regulated by integrins, which are members of a family of cell surface receptors whose ligands are extracellular matrix proteins and immunoglobulin superfamily molecules. Select integrins promote endothelial cell migration and survival during angiogenesis and lymphangiogenesis, whereas other integrins promote pro-angiogenic macrophage trafficking to tumours. Several integrin-targeted therapeutic agents are currently in clinical trials for cancer therapy. Here, we review the evidence implicating integrins as a family of fundamental regulators of angiogenesis and lymphangiogenesis.

Integrins in angiogenesis and lymphangiogenesis

Basement membranes are widely distributed extracellular matrices that coat the basal aspect of epithelial and endothelial cells and surround muscle, fat, and Schwann cells. These extracellular matrices, first expressed in early embryogenesis, are self-assembled on competent cell surfaces through binding interactions among laminins, type IV collagens, nidogens, and proteoglycans. They form stabilizing extensions of the plasma membrane that provide cell adhesion and that act as solid-phase agonists. Basement membranes play a role in tissue and organ morphogenesis and help maintain function in the adult. Mutations adversely affecting expression of the different structural components are associated with developmental arrest at different stages as well as postnatal diseases of muscle, nerve, brain, eye, skin, vasculature, and kidney.

/pdf/basement-membranes-cell-scaffoldings-and-signaling-platforms-v4a8ao6lzy.pdf

Basement Membranes: Cell Scaffoldings and Signaling Platforms

At the surface of the skin, the epidermis serves as the armour for the body. Scientists are now closer than ever to understanding how the epidermis accomplishes this extraordinary feat, and is able to survive and replenish itself under the harshest conditions that face any tissue. By combining genetic engineering with cell-biological studies and with human genome data analyses, skin biologists are discovering the mechanisms that underlie the development and differentiation of the epidermis and hair follicles of the skin. This explosion of knowledge paves the way for new discoveries into the genetic bases of human skin disorders and for developing new therapeutics.

Getting under the skin of epidermal morphogenesis.

Cell-extracellular matrix interactions have important roles in many biological processes, including embryonic development, growth control and differentiation. Integrins are the principal receptors for extracellular matrix1. They are composed of non-covalently associated α and β chains1. Integrin oc6 can associate with either β1 or β4 (refs 2,3). Both integrin complexes are receptors for laminins, major components of basement membranes2,3. The distribution of α6 (refs 4–10) as well as studies using function-blocking antibodies have suggested an essential role for this laminin receptor during embryogenesis, in processes such as endoderm migration4,5 or kidney tubule formation9. Here we report that, surprisingly, mice lacking the α6 integrin chain develop to birth. However, they die at birth with severe blistering of the skin and other epithelia, a phenotype reminiscent of the human disorder epidermolysis bullosa11. Hemidesmo-somes are absent in mutant tissue. This absence is likely to result from the lack of α6/β4, the only integrin in hemidesmosomes of stratified squamous and transitional epithelia12–14. Mutations in the genes encoding integrin β4 and chains of laminin-5 have been implicated in junctional epidermolysis bullosa15–18. Our study provides evidence that some forms of epidermolysis bullosa may originate from defects of the α6 gene.

Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice.

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Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice.