Journal
JOURNAL OF CELL BIOLOGY
Volume 216, Issue 4, Pages 1107-1121Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201609066
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Funding
- Academy of Finland
- Sigrid Juselius Foundation
- Cancer Society of Finland
- European Research Council Consolidator [615258]
- European Molecular Biology Organization Long-Term Fellowship
- University of Turku Doctoral Program of Molecular Medicine
- Doctoral Program in Biomedicine
- Finnish Cultural Foundation
- Universite Pierre et Marie Curie University Paris 6 (Program Doctoral Interfaces Pour le Vivant)
- Plan Cancer Institut National de la Sante et de la Recherche Medicale-Tecsan grant [PC201125]
- European Research Council (ERC) [615258] Funding Source: European Research Council (ERC)
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Tight regulation of integrin activity is paramount for dynamic cellular functions such as cell matrix adhesion and mechanotransduction. Integrin activation is achieved through intracellular interactions at the integrin cytoplasmic tails and through integrin-ligand binding. In this study, we identify the metabolic sensor AMP-activated protein kinase (AMPK) as a beta 1-integrin inhibitor in fibroblasts. Loss of AMPK promotes beta 1-integrin activity, the formation of centrally located active beta 1-integrin- and tensin-rich mature fibrillar adhesions, and cell spreading. Moreover, in the absence of AMPK, cells generate more mechanical stress and increase fibronectin fibrillogenesis. Mechanistically, we show that AMPK negatively regulates the expression of the integrin-binding proteins tensin1 and tensin3. Transient expression of tensins increases beta 1-integrin activity, whereas tensin silencing reduces integrin activity in fibroblasts lacking AMPK. Accordingly, tensin silencing in AMPK-depleted fibroblasts impedes enhanced cell spreading, traction stress, and fibronectin fiber formation. Collectively, we show that the loss of AMPK up-regulates tensins, which bind beta 1-integrins, supporting their activity and promoting fibrillar adhesion formation and integrin-dependent processes.
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