Key Points
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The integrin adhesome consists of molecules that are associated with the structure and signalling activity of integrin-mediated adhesions. The analysis of adhesome components shows that their mutation or dysregulation is often associated with human disease.
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Searching databases for monogenic diseases that display Mendelian inheritance revealed over 50 genes, which primarily encode adhesome signalling proteins, that are involved in human diseases (predominately cancer).
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An additional set of 138 adhesome genes was shown to be genetically associated with disease. These diseases are caused by dysregulation of multiple genes, some of which, such as adhesion receptors, are related to the integrin adhesome.
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The current approaches that are used for associating particular genes with specific diseases include in silico analysis, cell culture studies and animal experiments.
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The development of mammalian disease models by genetic manipulation has demonstrated the relevance of specific groups of genes in human diseases, including haematological and blistering disorders (among others).
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The combined data derived from different mammalian disease models reveal that the integrin adhesome has a major role in regulating tissue homeostasis and cellular interactions, and that aberrant expression and gene mutations in its diverse constituents can lead to major pathological states.
Abstract
The adhesive interactions of cells with their environment through the integrin family of transmembrane receptors have key roles in regulating multiple aspects of cellular physiology, including cell proliferation, viability, differentiation and migration. Consequently, failure to establish functional cell adhesions, and thus the assembly of associated cytoplasmic scaffolding and signalling networks, can have severe pathological effects. The roles of specific constituents of integrin-mediated adhesions, which are collectively known as the 'integrin adhesome', in diverse pathological states are becoming clear. Indeed, the prominence of mutations in specific adhesome molecules in various human diseases is now appreciated, and experimental as well as in silico approaches provide insights into the molecular mechanisms underlying these pathological conditions.
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Acknowledgements
The authors thank R. Zaidel-Bar for providing an updated version of the integrin adhesome. The authors also thank I. Sabanay, M. Bokstad and V. Small for providing the images for Fig. 1. The authors are grateful for the support of the European Research Council (ERC) under the European Community's Seventh Framework Programme (FP7/2007-2013), Advanced ERC Grant (ERC Grant Agreement no. 294852 to B.G. and ERC Grant Agreement no. 322652 to R.F.). They thank A. Pozzi for helpful discussions and to B. Morgenstern for expert editorial assistance.
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Supplementary information
Supplementary information S1 (table)
The adhesome. (XLSX 27 kb)
Supplementary information S2 (table)
List of adhesome genes that lead to Mendelian hereditary disease (OMIM), and their corresponding disease and disease type. (XLSX 31 kb)
Supplementary information S3 (table)
List of adhesome genes associated with disease (GAD), and their corresponding diseases and disease type. (XLSX 42 kb)
Supplementary information S4 (figure)
Graphs of OMIM and GAD adhesome diseases. (PDF 400 kb)
Supplementary information S5 (table)
Virus interactions with integrins (PDF 145 kb)
Supplementary information S6 (table)
Bacterial interactions with integrins (PDF 134 kb)
Glossary
- Integrins
-
A family of cell adhesion receptors that mediate either cell–cell interactions or cell–extracellular matrix interactions. Integrins are heterodimers with two distinct subunits, the α-subunit and the β-subunit.
- Focal adhesions
-
Stable integrin-mediated, cell–substrate adhesion structures that anchor the termini of actin filaments (stress fibres) and mediate strong attachments to substrates. They also function as integrin signalling platforms.
- Focal complexes
-
Small dot-like adhesions (∼1 μm in width) that are mainly found in lamellipodia. They are transient adhesion sites during cell migration and can mature into more stable focal adhesions.
- Fibrillar adhesion
-
A form of integrin-mediated adhesion, which is typically associated with fibronectin fibres and has high levels of tensin and low levels of phosphorylated Tyr residues. These adhesions are less mechanosensitive than focal adhesions.
- Podosomes
-
Adhesive, ring-like, actin-rich structures that are formed on the ventral surface of cells, such as monocytes, osteoclasts and smooth muscle cells.
- Invadopodia
-
Extracellular matrix (ECM) contacts that are different from focal complexes and focal adhesions but similar to podosomes, which are associated with the invasion of cells into the ECM. Invadopodia can extend up to several micrometres, associate with ECM-degrading enzymes and are seen in transformed fibroblasts or malignant cells.
- Mendelian genetic disorders
-
Inherited genetic diseases that are caused by mutations in one gene.
- Multigenic diseases
-
Diseases that are caused by mutations or alterations in more than one gene.
- Glanzmann's thrombasthenia
-
A bleeding disorder that arises from mutations in genes either encoding αIIb integrin or β3 integrin, which together form the fibrinogen receptor on platelets.
- Leukocyte adhesion deficiency type III
-
(LAD-III). An autosomal recessive immunodeficiency disorder that is caused by mutations in the gene encoding kindlin 3, which reduces the activation of most integrins.
- Leukocyte adhesion deficiency type I
-
(LAD-I). An autosomal recessive immunodeficiency disorder resulting from mutations in the gene encoding β2 integrin, which is expressed on several cells of the immune system.
- Myotendinous junction
-
A specialized region located at the muscle–tendon interface that represents the primary site of force transmission.
- Intercalated discs
-
Specialized cardiac muscle structures that join adjacent cardiomyocytes, mainly through adherens-type junctions.
- Z-line
-
A region at the boundaries of muscle sarcomeres in which the actin filaments are anchored. It appears as a dark transverse line in electron micrographs.
- Intermediate filaments
-
Cytoplasmic and nuclear proteins that polymerize into stable filaments of ∼10 nm in diameter. Their ability to form very stable filaments enables them to confer mechanical strength to the cytoskeleton.
- Focal segmental glomerulosclerosis
-
(FSGS). A kidney disease that is characterized by gradual disintegration of the glomerular filtration units as a result of a loss of attachment between podocytes and the glomerular basement membrane.
- Podocytes
-
Cells in the kidney that have a crucial function in the filtration of solutes in the blood to form urine.
- Fab fragment
-
(Fragment antigen-binding). The antigen-binding portion of an antibody, which consists of the light chain and the heavy chain before the hinge region.
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Winograd-Katz, S., Fässler, R., Geiger, B. et al. The integrin adhesome: from genes and proteins to human disease. Nat Rev Mol Cell Biol 15, 273–288 (2014). https://doi.org/10.1038/nrm3769
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DOI: https://doi.org/10.1038/nrm3769
