Integrin-Mediated Cell Adhesion Mechanisms

Integrins are heterodimeric transmembrane receptors that mediate the dynamic attachment of eukaryotic cells to the extracellular matrix and to neighbouring cells. Each integrin consists of an α- and a β-subunit, the combination of which determines ligand specificity and signalling capacity. Integrin activation involves conformational shifts from a bent, low-affinity state to an extended, high-affinity state. Intracellular adaptor proteins such as talin and kindlin bind to β-tail cytoplasmic domains to induce inside-out activation, while extracellular ligand engagement triggers outside-in signalling cascades. These cascades regulate cytoskeletal organisation, mechanotransduction and gene expression, governing processes including cell migration, proliferation, survival and differentiation. Through the assembly of focal adhesions, integrins couple mechanical cues from the matrix with intracellular responses, enabling cells to sense stiffness, generate traction forces and remodel their microenvironment. Integrin-mediated adhesion is essential for embryogenesis, immune surveillance and tissue repair, and its dysregulation contributes to cancer metastasis, chronic inflammation and fibrosis. Recent advances have illuminated the allosteric interplay of cytoplasmic adaptors, the formation of multi-protein adhesion complexes and the integration of mechanical and metabolic signals, opening new avenues for therapeutic intervention and biomaterials design.

Research from Nature Portfolio

Recent studies have elucidated the molecular choreography of integrin activation by cytoskeletal adaptors. One investigation combined nuclear magnetic resonance, biochemical reconstitution and cell biology to reveal that talin and kindlin bind distinct sites on the β-integrin tail and engage in direct allosteric interplay. This cooperation produces a ternary complex that amplifies talin affinity and stabilises high-affinity integrin conformations, a mechanism essential for robust cell adhesion and motility. In parallel, work on kindlin-2 has uncovered its mechanoresponsive translocation to mitochondria where it partners with a proline-synthesising enzyme in response to extracellular matrix stiffening. This kindlin-2–enzyme complex elevates proline metabolism and drives cell proliferation, linking mechanical cues to metabolic reprogramming and revealing a potential axis for targeting tumour growth.

Integrin-Mediated Cell Adhesion Mechanisms publication trend

The graph below shows the total number of articles in integrin-mediated cell adhesion mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Integrin: A transmembrane receptor composed of α and β subunits that mediates cell–ECM and cell–cell adhesion.

Talin: A cytoskeletal adaptor that binds the β-integrin cytoplasmic tail to trigger inside-out activation.

Kindlin: A family of FERM-domain proteins that cooperatively bind β-integrin tails to stabilise high-affinity states and recruit signalling complexes.

Inside-out signalling: Intracellular events that induce integrin conformational changes to increase extracellular ligand affinity.

Outside-in signalling: Extracellular ligand engagement that initiates intracellular pathways controlling cytoskeletal dynamics and gene expression.

Focal adhesion: A multi-protein assembly that links integrins to the actin cytoskeleton and transduces mechanical signals.

Extracellular matrix (ECM): A complex network of proteins and polysaccharides providing structural support and signalling cues to cells.

References

1. Talin and kindlin use integrin tail allostery and direct binding to activate integrins. Nature Structural & Molecular Biology (2023).
2. Kindlin-2 links mechano-environment to proline synthesis and tumor growth. Nature Communications (2019).
3. Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression. Theranostics (2023).
4. LFA-1 knockout inhibited the tumor growth and is correlated with treg cells. Cell Communication and Signaling (2023).
5. Cell Adhesion Molecules and Their Roles and Regulation in the Immune and Tumor Microenvironment. Frontiers in Immunology (2019).