title: AMPK negatively regulates tensin-dependent integrin activity.
abstract: 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 β1-integrin inhibitor in fibroblasts. Loss of AMPK promotes β1-integrin activity, the formation of centrally located active β1-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 β1-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 β1-integrins, supporting their activity and promoting fibrillar adhesion formation and integrin-dependent processes.
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FI-20520 Turku, Finland johanna.ivaska@utu.fi maria.georgiadou@utu.fi.
authors.forename: Maria
authors.identifier: 0000-0003-0948-6337
authors.initials: M
authors.lastname: Georgiadou
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FI-20520 Turku, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Lilja
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FI-20520 Turku, Finland.
authors.forename: Guillaume
authors.identifier: 0000-0002-9286-920X
authors.initials: G
authors.lastname: Jacquemet
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FI-20520 Turku, Finland.
authors.forename: Camilo
authors.initials: C
authors.lastname: Guzmán
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FI-20520 Turku, Finland.
authors.forename: Maria
authors.identifier: 0000-0002-7317-4058
authors.initials: M
authors.lastname: Rafaeva
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, Centre National de la Recherche Scientifique, UMR144, F-75005 Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Université Paris 06, Centre National de la Recherche Scientifique, UMR144, F-75005 Paris, France.
authors.forename: Charlotte
authors.identifier: 0000-0001-6113-3833
authors.initials: C
authors.lastname: Alibert
authors.affiliation: Research Programs Unit, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FI-20520 Turku, Finland.
authors.forename: Pranshu
authors.identifier: 0000-0002-9857-3987
authors.initials: P
authors.lastname: Sahgal
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FI-20520 Turku, Finland.
authors.forename: Martina
authors.initials: M
authors.lastname: Lerche
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, Centre National de la Recherche Scientifique, UMR144, F-75005 Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Université Paris 06, Centre National de la Recherche Scientifique, UMR144, F-75005 Paris, France.
authors.forename: Jean-Baptiste
authors.identifier: 0000-0002-8670-3940
authors.initials: JB
authors.lastname: Manneville
authors.affiliation: Research Programs Unit, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Tomi P
authors.initials: TP
authors.lastname: Mäkelä
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FI-20520 Turku, Finland.|Department of Biochemistry, University of Turku, FI-20520 Turku, Finland.
authors.forename: Johanna
authors.identifier: 0000-0002-6295-6556
authors.initials: J
authors.lastname: Ivaska
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology; D008840:Microfilament Proteins / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D000070876:Tensins / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D019012:Integrin beta1; D008840:Microfilament Proteins; D000070876:Tensins; D055372:AMP-Activated Protein Kinases