SUMOylation regulates AKT1 activity.
Serine threonine kinase AKT has a central role in the cell, controlling survival, proliferation, metabolism and angiogenesis. Deregulation of its activity underlies a wide range of pathological situations, including cancer. Here we show that AKT is post-translationally modified by the small ubiquitin-like modifier (SUMO) protein. Interestingly, neither SUMO conjugation nor activation of SUMOylated AKT is regulated by the classical AKT targeting to the cell membrane or by the phosphoinositide 3-kinase pathway. We demonstrate that SUMO induces the activation of AKT, whereas, conversely, down-modulation of the SUMO machinery diminishes AKT activation and cell proliferation. Furthermore, an AKT SUMOylation mutant shows reduced activation, and decreased anti-apoptotic and pro-tumoral activities in comparison with the wild-type protein. These results identify SUMO as a novel key regulator of AKT phosphorylation and activity.
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología-CSIC, Madrid, Spain.
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de la Cruz-Herrera
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología-CSIC, Madrid, Spain.
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Campagna
Ubiquitylation and Cancer Molecular Biology laboratory, Inbiomed, San Sebastian-Donostia, Gipuzkoa, Spain.
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Lang
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología-CSIC, Madrid, Spain.
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del Carmen González-Santamaría
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología-CSIC, Madrid, Spain.
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Marcos-Villar
Ubiquitylation and Cancer Molecular Biology laboratory, Inbiomed, San Sebastian-Donostia, Gipuzkoa, Spain.
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Rodríguez
Departamento de Fisioloxía and Centro de Investigación en Medicina Molecular (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain.
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Vidal
Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Santiago de Compostela, Spain.
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Collado
1] Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología-CSIC, Madrid, Spain [2] Centro de Investigación en Medicina Molecular (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain.
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Rivas
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D058207:Sumoylation / Q000235:genetics / Q000502:physiology*; D014452:Ubiquitins / Q000378:metabolism
D000081082:Phosphoinositide-3 Kinase Inhibitors; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; C117909:SUMO2 protein, human; C492189:SUMO3 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D014452:Ubiquitins; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt