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AMPK negatively regulates tensin-dependent integrin activity




TekijätGeorgiadou M, Lilja J, Jacquemet G, Guzman C, Rafaeva M, Alibert C, Yan Y, Sahgal P, Lerche M, Manneville JB, Makela TP, Ivaska J

KustantajaROCKEFELLER UNIV PRESS

Julkaisuvuosi2017

JournalJournal of Cell Biology

Tietokannassa oleva lehden nimiJOURNAL OF CELL BIOLOGY

Lehden akronyymiJ CELL BIOL

Vuosikerta216

Numero4

Aloitussivu1107

Lopetussivu1121

Sivujen määrä15

ISSN0021-9525

DOIhttps://doi.org/10.1083/jcb.201609066


Tiivistelmä
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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