The final steps of integrin activation: the end game

By S. Shattil, Chungho Kim, M. Ginsberg. Nature reviews. Molecular cell biology, 2010

1,072 citations recorded by the source corpus.

Cell-directed changes in the ligand-binding affinity ('activation') of integrins regulate cell adhesion and migration, extracellular matrix assembly and mechanotransduction, thereby contributing to embryonic development and diseases such as atherothrombosis and cancer. Integrin activation comprises triggering events, intermediate signalling events and, finally, the interaction of integrins with cytoplasmic regulators, which changes an integrin's affinity for its ligands. The first two events involve diverse interacting signalling pathways, whereas the final steps are immediately proximal to integrins, thus enabling integrin-focused therapeutic strategies. Recent progress provides insight into the structure of integrin transmembrane domains, and reveals how the final steps of integrin activation are mediated by integrin-binding proteins such as talins and kindlins.

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Citations in the corpus

• Contribution of platelets to tumour metastasis (2011, background): “Activated integrin αIIbβ3 can bind soluble fibrinogen, which then forms inter-platelet bridges and leads to thrombus formatio”
• Analysis of the myosinII-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation (2011, result): “Factors mediating integrin–actin linkage were also enriched in focal adhesions of control cells, compared with blebbistatin-treated cell”
• Cilengitide: The First Anti-Angiogenic Small Molecule Drug Candidate. Design, Synthesis and Clinical Evaluation (2010, background): “During “inside-out signaling” an intracellular activator binds to the -subunit, induces a conformational change leading to increased affinity for extracellular ligands [72].”
• Arterial thrombosis—insidious, unpredictable and deadly (2011, background): “Once platelets firmly adhere to the vessel wall or to the surface of a growing thrombus, they undergo a complex series of morphological and biochemical changes that lead to the release of the contents of the platelet granules and upregulation of the adhesive function of integrin α IIb β 3 (refs”
• New fundamentals in hemostasis. (2013, background): “Patients with a deleterious kindlin-3 mutation (leukocyte adhesion deficiency 3) thus have platelets that are defective in IIb 3 activation (26, 270).”
• Integrins and extracellular matrix in mechanotransduction. (2010, background): “Tyrosine phosphorylation in this region may reduce the affinity of interactions with talin-1.(54) Other mechanisms by which the interaction between β integrin tail and talin can be disrupted is through competition for binding which occurs with filamin A(55) or integrin cytoplasmic domain associated ”