Humphries, J. D., Byron, A. & Humphries, M. J. Integrin ligands at a glance. J. Cell Sci. 119, 3901–3903 (2006).

Article  CAS  PubMed  Google Scholar 

Hynes, R. O. Integrins. Cell 110, 673–687 (2002).

Article  CAS  PubMed  Google Scholar 

Ivaska, J. & Heino, J. Cooperation between integrins and growth factor receptors in signaling and endocytosis. Annu. Rev. Cell Dev. Biol. 27, 291–320 (2011).

Article  CAS  PubMed  Google Scholar 

Stanislovas, J. & Kermorgant, S. c-Met-integrin cooperation: mechanisms, tumorigenic effects, and therapeutic relevance. Front. Cell Dev. Biol. 10, 994528 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Hamidi, H. & Ivaska, J. Every step of the way: integrins in cancer progression and metastasis. Nat. Rev. Cancer 18, 533–548 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yamada, K. M. & Sixt, M. Mechanisms of 3D cell migration. Nat. Rev. Mol. Cell Biol. 20, 738–752 (2019).

Article  CAS  PubMed  Google Scholar 

SenGupta, S., Parent, C. A. & Bear, J. E. The principles of directed cell migration. Nat. Rev. Mol. Cell Biol. 22, 529–547 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Green, H. J. & Brown, N. H. Integrin intracellular machinery in action. Exp. Cell Res. 378, 226–231 (2019).

Article  CAS  PubMed  Google Scholar 

Orré, T., Rossier, O. & Giannone, G. The inner life of integrin adhesion sites: from single molecules to functional macromolecular complexes. Exp. Cell Res. 379, 235–244 (2019).

Article  PubMed  Google Scholar 

Saraswathibhatla, A., Indana, D. & Chaudhuri, O. Cell–extracellular matrix mechanotransduction in 3D HHS Public Access. Nat. Rev. Mol. Cell Biol. 24, 495–516 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kanchanawong, P. & Calderwood, D. A. Organization, dynamics and mechanoregulation of integrin-mediated cell–ECM adhesions. Nat. Rev. Mol. Cell Biol. 24, 142–161 (2023).

Article  CAS  PubMed  Google Scholar 

Kechagia, J. Z., Ivaska, J. & Roca-Cusachs, P. Integrins as biomechanical sensors of the microenvironment. Nat. Rev. Mol. Cell Biol. 20, 457–473 (2019).

Article  CAS  PubMed  Google Scholar 

Luo, B.-H., Carman, C. V. & Springer, T. A. Structural basis of integrin regulation and signaling. Annu. Rev. Immunol. 25, 619–647 (2007).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Anderson, J. M., Li, J. & Springer, T. A. Regulation of integrin α5β1 conformational states and intrinsic affinities by metal ions and the ADMIDAS. Mol. Biol. Cell 33, ar56 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang, K. & Chen, J. The regulation of integrin function by divalent cations. Cell Adh. Migr. 6, 20–29 (2012).

Article  PubMed  PubMed Central  Google Scholar 

Takagi, J., Petre, B. M., Walz, T. & Springer, T. A. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 110, 599–611 (2002).

Article  CAS  PubMed  Google Scholar 

Campbell, I. D. & Humphries, M. J. Integrin structure, activation, and interactions. Cold Spring Harb. Perspect. Biol. 3, a004994 (2011).

Article  PubMed  PubMed Central  Google Scholar 

Kolasangiani, R., Bidone, T. C. & Schwartz, M. A. Integrin conformational dynamics and mechanotransduction. Cells 11, 3584 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vinogradova, O. et al. A structural mechanism of integrin αIIbβ3 “inside-out” activation as regulated by its cytoplasmic face. Cell 110, 587–597 (2002). This study provides a structural mechanism by which a handshake between the α-subunit and the β-subunit cytoplasmic integrin tails restrains the integrin in a resting state and finds that unclasping of this interaction triggers the inside-out conformational signal that leads to receptor activation.

Article  CAS  PubMed  Google Scholar 

Shafaq-Zadah, M. et al. Spatial N-glycan rearrangement on α5β1 integrin nucleates galectin-3 oligomers to determine endocytic fate. Preprint at bioRxiv https://doi.org/10.1101/2023.10.27.564026 (2023).

Cormier, A. et al. Cryo-EM structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension. Nat. Struct. Mol. Biol. 25, 698–704 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schumacher, S. et al. Structural insights into integrin α5β1 opening by fibronectin ligand. Sci. Adv. 7, eabe9716 (2021). This study reports cryo electron microscopy structures of human α5β1 integrin in its extended fibronectin-bound state and in its resting state in a half-bent conformation, and shows that affinity of α5β1 integrin for fibronectin is increased with manganese ions (Mn2+) while adopting the half-bent conformation, indicating that ligand-binding affinity is independent of conformation, and showing that α5β1 integrin opening is induced by ligand-binding.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Li, J. et al. Ligand binding initiates single-molecule integrin conformational activation. Cell 187, 2990–3005.e17 (2024). This study uses fluorescence resonance energy transfer to investigate conformational regulation of α5β1 integrin, finding that ligand binding to bent integrin triggers rapid receptor extension and activation.

Article  CAS  PubMed  Google Scholar 

Askari, J. A. et al. Focal adhesions are sites of integrin extension. J. Cell Biol. 188, 891–903 (2010). This study uses fluorescence resonance energy transfer to demonstrate that integrin α5β1 is found in the extended conformation inside IACs.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Adair, B. D., Xiong, J.-P., Yeager, M. & Arnaout, M. A. Cryo-EM structures of full-length integrin αIIbβ3 in native lipids. Nat. Commun. 14, 4168 (2023). This work reports cryo electron microscopy structures of full-length αIIbβ3 integrin in its apo state in native cell membrane-based nanoparticles, showing that this integrin adopts the bent inactive state but with a fully accessible ligand-binding site. This finding challenges the model that this site is occluded by the plasma membrane.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Calderwood, D. A. et al. The talin head domain binds to integrin β subunit cytoplasmic tails and regulates integrin activation. J. Biol. Chem. 274, 28071–28074 (1999).

Article  CAS  PubMed  Google Scholar 

Haydari, Z., Shams, H., Jahed, Z. & Mofrad, M. R. K. Kindlin assists talin to promote integrin activation. Biophys. J. 118, 1977–1991 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tiwari, S., Askari, J. A., Humphries, M. J. & Bulleid, N. J. Divalent cations regulate the folding and activation status of integrins during their intracellular trafficking. J. Cell Sci. 124, 1672–1680 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Grzesiak, J. J. & Pierschbacher, M. D. Shifts in the concentrations of magnesium and calcium in early porcine and rat wound fluids activate the cell migratory response. J. Clin. Invest. 95, 227–233 (1995).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kong, F., García, A. J., Mould, A. P., Humphries, M. J. & Zhu, C. Demonstration of catch bonds between an integrin and its ligand. J. Cell Biol. 185, 1275–1284 (2009). Using atomic force microscopy, this study observes triphasic force-dependent bond lifetimes that deviate from the Bell model, demonstrating fibronectin–α5β1 integrin catch bonds which provide a physical mechanism for integrin-mediated force sensing.

Article  CAS  PubMed  PubMed Central