Talin-bound NPLY motif recruits integrin-signaling adapters to regulate cell spreading and mechanosensing.
Integrin-dependent cell adhesion and spreading are critical for morphogenesis, tissue regeneration, and immune defense but also tumor growth. However, the mechanisms that induce integrin-mediated cell spreading and provide mechanosensing on different extracellular matrix conditions are not fully understood. By expressing β3-GFP-integrins with enhanced talin-binding affinity, we experimentally uncoupled integrin activation, clustering, and substrate binding from its function in cell spreading. Mutational analysis revealed Tyr747, located in the first cytoplasmic NPLY(747) motif, to induce spreading and paxillin adapter recruitment to substrate- and talin-bound integrins. In addition, integrin-mediated spreading, but not focal adhesion localization, was affected by mutating adjacent sequence motifs known to be involved in kindlin binding. On soft, spreading-repellent fibronectin substrates, high-affinity talin-binding integrins formed adhesions, but normal spreading was only possible with integrins competent to recruit the signaling adapter protein paxillin. This proposes that integrin-dependent cell-matrix adhesion and cell spreading are independently controlled, offering new therapeutic strategies to modify cell behavior in normal and pathological conditions.
Department of Cell Physiology and Metabolism, University Medical Center, University of Geneva, 1211 Geneva, Switzerland.
Perrine
P
Pinon
Jenita
J
Pärssinen
Patricia
P
Vazquez
Michael
M
Bachmann
Rolle
R
Rahikainen
Marie-Claude
MC
Jacquier
Latifeh
L
Azizi
Juha A
JA
Määttä
Martin
M
Bastmeyer
Vesa P
VP
Hytönen
Bernhard
B
Wehrle-Haller
D020816:Amino Acid Motifs; D000818:Animals; D019556:COS Cells; D002448:Cell Adhesion / Q000502:physiology; D002522:Chlorocebus aethiops; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D041681:NIH 3T3 Cells; D051419:Paxillin / Q000235:genetics / Q000378:metabolism; D016608:Talin / Q000235:genetics / Q000378:metabolism*
D039661:Integrin beta3; D051419:Paxillin; C496062:Pxn protein, mouse; D016608:Talin