The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours. The importance of integrins in several cell types that affect tumour progression has made them an appealing target for cancer therapy. Integrin antagonists, including the alphavbeta3 and alphavbeta5 inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clinical developments emphasize the need to identify how integrin antagonists influence the tumour and its microenvironment.

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Integrins in cancer: biological implications and therapeutic opportunities

The extracellular matrix (ECM) and ECM proteins are important in phenomena as diverse as developmental patterning, stem cell niches, cancer, and genetic diseases. The ECM has many effects beyond providing structural support. ECM proteins typically include multiple, independently folded domains whose sequences and arrangement are highly conserved. Some of these domains bind adhesion receptors such as integrins that mediate cell-matrix adhesion and also transduce signals into cells. However, ECM proteins also bind soluble growth factors and regulate their distribution, activation, and presentation to cells. As organized, solid-phase ligands, ECM proteins can integrate complex, multivalent signals to cells in a spatially patterned and regulated fashion. These properties need to be incorporated into considerations of the functions of the ECM.

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The Extracellular Matrix: Not Just Pretty Fibrils

Recent progress in the design and application of artificial cellular microenvironments and nanoenvironments has revealed the extraordinary ability of cells to adjust their cytoskeletal organization, and hence their shape and motility, to minute changes in their immediate surroundings. Integrin-based adhesion complexes, which are tightly associated with the actin cytoskeleton, comprise the cellular machinery that recognizes not only the biochemical diversity of the extracellular neighbourhood, but also its physical and topographical characteristics, such as pliability, dimensionality and ligand spacing. Here, we discuss the mechanisms of such environmental sensing, based on the finely tuned crosstalk between the assembly of one type of integrin-based adhesion complex, namely focal adhesions, and the forces that are at work in the associated cytoskeletal network owing to actin polymerization and actomyosin contraction.

Environmental sensing through focal adhesions

Cell migration affects all morphogenetic processes and contributes to numerous diseases, including cancer and cardiovascular disease. For most cells in most environments, movement begins with protrusion of the cell membrane followed by the formation of new adhesions at the cell front that link the actin cytoskeleton to the substratum, generation of traction forces that move the cell forwards and disassembly of adhesions at the cell rear. Adhesion formation and disassembly drive the migration cycle by activating Rho GTPases, which in turn regulate actin polymerization and myosin II activity, and therefore adhesion dynamics.

Cell adhesion: integrating cytoskeletal dynamics and cellular tension

The metastatic process, i.e. the dissemination of cancer cells throughout the body to seed secondary tumors at distant sites, requires cancer cells to leave the primary tumor and to acquire migratory and invasive capabilities. In a process of epithelial-mesenchymal transition (EMT), besides changing their adhesive repertoire, cancer cells employ developmental processes to gain migratory and invasive properties that involve a dramatic reorganization of the actin cytoskeleton and the concomitant formation of membrane protrusions required for invasive growth. The molecular processes underlying such cellular changes are still only poorly understood, and the various migratory organelles, including lamellipodia, filopodia, invadopodia and podosomes, still require a better functional and molecular characterization. Notably, direct experimental evidence linking the formation of migratory membrane protrusions and the process of EMT and tumor metastasis is still lacking. In this review, we have summarized recent novel insights into the molecular processes and players underlying EMT on one side and the formation of invasive membrane protrusions on the other side.

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EMT, the cytoskeleton, and cancer cell invasion

Integrins are transmembrane cell-adhesion molecules that carry signals from the outside to the inside of the cell and vice versa. Like other cell surface receptors, integrins signal in response to ligand binding; however, events within the cell can also regulate the affinity of integrins for ligands. This feature is important in physiological situations such as those in blood, in which cells are always in close proximity to their ligands, yet cell-ligand interactions occur only after integrin activation in response to specific external cues. This review focuses on the mechanisms whereby two key proteins, talin and the kindlins, regulate integrin activation by binding the tails of integrin-beta subunits.

https://science.sciencemag.org/content/sci/324/5929/895.full.pdf

The Tail of Integrins, Talin, and Kindlins

Integrins are cell surface transmembrane receptors that recognize and bind to extracellular matrix proteins and counter receptors. Binding of activated integrins to their ligands induces a vast number of structural and signaling changes within the cell. Large, multimolecular complexes assemble onto the cytoplasmic tails of activated integrins to engage and organize the cytoskeleton, and activate signaling pathways that ultimately lead to changes in gene expression. Additionally, integrin-mediated signaling intersects with growth factor-mediated signaling through various levels of cross-talk. This review discusses recent work that has tremendously broadened our understanding of the complexity of integrin-mediated signaling.

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Genetic and cell biological analysis of integrin outside-in signaling.

The ternary complex of integrin-linked kinase (ILK), PINCH and parvin functions as a signalling platform for integrins by interfacing with the actin cytoskeleton and many diverse signalling pathways. All these proteins have synergistic functions at focal adhesions, but recent work has indicated that these proteins might also have separate roles within a cell. They function as regulators of gene transcription or cell-cell adhesion.

/pdf/ilk-pinch-and-parvin-the-tipp-of-integrin-signalling-34u61z98wa.pdf

ILK, PINCH and parvin: the tIPP of integrin signalling.

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.

The integrin adhesome: from genes and proteins to human disease.

Cells recognize and respond to their extracellular environment through transmembrane receptors such as integrins, which physically connect the extracellular matrix to the cytoskeleton. Integrins provide the basis for the assembly of intracellular signaling platforms that link to the cytoskeleton and influence nearly every aspect of cell physiology; however, integrins possess no enzymatic or actin-binding activity of their own and thus rely on adaptor molecules, which bind to the short cytoplasmic tails of integrins, to mediate and regulate these functions. Many adaptors compete for relatively few binding sites on integrin tails, so regulatory mechanisms have evolved to reversibly control the spatial and temporal binding of specific adaptors. This Commentary discusses the adaptor proteins that bind directly to the tails of beta integrins and, using talin, tensin, filamin, 14-3-3 and integrin-linked kinase (ILK) as examples, describes the ways in which their binding is regulated.

/pdf/mechanisms-that-regulate-adaptor-binding-to-beta-integrin-1v5qpw7nuu.pdf

Kyle R. Legate

Papers

The Tail of Integrins, Talin, and Kindlins

Genetic and cell biological analysis of integrin outside-in signaling.

ILK, PINCH and parvin: the tIPP of integrin signalling.

The integrin adhesome: from genes and proteins to human disease.

Mechanisms that regulate adaptor binding to beta-integrin cytoplasmic tails.