Integrins β1 and β3 exhibit distinct dynamic nanoscale organizations inside focal adhesions
Olivier RossierVivien OcteauJean‐Baptiste SibaritaCécile LeducBéatrice TessierDeepak NairVolker GatterdamOlivier DestaingCorinne Albigès‐RizoRobert TampéLaurent CognetDaniel ChoquetBrahim LounisGrégory Giannone
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Abstract Late passage fibroblasts show decreased cell‐substrate adhesion. We provide evidence that the reduced adhesion is due to a defect in the adhesive glycoprotein fibronectin. Late passage cells become more adhesive in culture media that has been conditioned by the growth of early passage cells. Analysis of fibronectins purified from early and late passage cell conditioned media indicates that there are striking differences in their abilities to promote cell adhesion. Young cell fibronectin supports the maximal adhesion of both young and old cells. However, old cells require quantitatively more fibronectin. In contrast, old cell fibronectin is less effective in supporting the adhesion of either cell type. In addition, neither cell type achieves a normal morphology in the presence of old cell fibronectin. The results support the conclusion that the fibronectin released by late passage cells is defective and does not support normal cell‐substrate interactions.
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We have examined the effect of cell attachment on fibronectin and asp1 integrin levels in three distinct anchorage-dependent fibroblast cell lines.Analysis of long-term biosynthetically labeled proteins from parallel cultures of adherent and nonadherent cells showed that the steady-state level of extracellular fibronectin is decreased upon loss of attachment.Pulse labeling studies and Northern blot analyses showed that the decrease occurs post-synthetically.A combined approach of surface radioiodination and biosynthetic labeling also demonstrated a selective post-synthetic decrease in cell-surface expression of the a6B1 integrin upon loss of cell attachment.Overall, we estimate that extracellular fibronectin and cell surface a6B1 integrin levels are reduced 6-7-fold in NIH-3T3, 16-20-fold in AKR-2B, and 60-fold in NRK fibroblasts.Finally, we find decreased total (serum-and cell-derived) fibronectin bound to the surface of nonadherent cells consistent with the reduced expression of a681 integrin.These results demonstrate a systematic down-regulation of fibronectin and its major receptor upon loss of attachment and suggest a potential mechanism involved in maintenance of the anchorage-dependent phenotype.The proliferation of nontransformed fibroblasts requires attachment to a solid surface, and this phenotype has been termed anchorage dependence (Stoker et al., 1968;Benecke et al., 1978).It is well established that cell/substratum attachment is mediated by the interaction between components of the extracellular matrix and specific cell surface integrins (Hynes, 1987;
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The properties of epithelial cells within tissues are regulated by their immediate microenvironment, which consists of neighboring cells and the extracellular matrix (ECM). Integrin heterodimers orchestrate dynamic assembly and disassembly of cell-ECM connections and thereby convey biochemical and mechanical information from the ECM into cells. However, the specific contributions and functional hierarchy between different integrin heterodimers in the regulation of focal adhesion dynamics in epithelial cells are incompletely understood. Here, we have studied the functions of RGD-binding αV-integrins in a Madin Darby Canine Kidney (MDCK) cell model and found that αV-integrins regulate the maturation of focal adhesions (FAs) and cell spreading. αV-integrin-deficient MDCK cells bound collagen I (Col I) substrate via α2β1-integrins but failed to efficiently recruit FA components such as talin, focal adhesion kinase (FAK), vinculin and integrin-linked kinase (ILK). The apparent inability to mature α2β1-integrin-mediated FAs and link them to cellular actin cytoskeleton led to disrupted mechanotransduction in αV-integrin deficient cells seeded onto Col I substrate.
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Vinculin
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In this issue, Lawson et al. provide new insight into the relationship between FAK and talin during assembly of integrin adhesions on fibronectin. They show that FAK is upstream of talin, and that talin is not required for FAK recruitment or for integrin activation at nascent adhesions. However, FAK-talin binding is required for adhesion turnover and cell motility. The findings question the view that talin is always upstream of focal adhesion protein recruitment to clustered integrin sites.
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