Threonine 34 phosphorylation by phosphoinositide-dependent protein kinase 1 facilitates dissociation of Akt from the plasma membrane |
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| Institution: | 1. The Central Laboratory of Sanming First Hospital Affiliated to Fujian Medical University, Sanming City, 365000, China;2. Department of Clinical Medical Oncology, Qingyuan People''s Hospital, The Six Affiliated Hosptial of Guangzhou Medical University, Qingyuan City, 511518, China;3. Department of Gastrointestinal Surgery, Qingyuan People''s Hospital, The Six Affiliated Hosptial of Guangzhou Medical University, Qingyuan City, 511518, China;1. Medical University Vienna, Institute of Cancer Research, Comprehensive Cancer, Vienna, Austria;2. Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain;3. CIBERONC, Madrid, Spain;4. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain;1. Department of Integrative Oncology, BC Cancer Research Centre, BC Cancer Agency, Vancouver, BC, Canada;2. Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital, Vancouver, BC, Canada;3. Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada;4. Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada;1. Department of Neurology, University of California, San Francisco, San Francisco;2. Department of Psychology, University of California, Berkeley, Berkeley;3. Laboratory for Computational Neurochemistry and Drug Discovery and Department of Veterans Affairs Medical Center, University of California, San Francisco, San Francisco;4. Department of Neurology and Neurological Sciences (FML), Stanford University School of Medicine, Stanford, California;1. UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1 V 9EL, UK;2. Randall Division of Cell & Molecular Biophysics, New Hunt''s House, Guy''s Campus, Kings College London, London SE11UL, UK |
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| Abstract: | Akt is a key mediator of cell proliferation, survival and metabolism. After translocation to the membrane and phosphorylation at T308 and S473, the activated Akt dissociates from the plasma membrane to cytoplasm, which is an important step to phosphorylate its downstream targets. In addition to its central role in regulating the kinase activity, phosphorylation of T308 in the kinase loop has been reported to be necessary for this dissociation process. However, it is not clear whether the membrane detachment requires further mechanisms. In the present report, we demonstrate that membrane dissociation of Akt requires phosphoinositide-dependent protein kinase 1 (PDK1) which directly phosphorylates not only T308 but also T34 in the pleckstrin homology (PH) domain. Like T308, T34 was phosphorylated in a phosphatidylinositol 3,4,5-trisphosphate- and phosphatidylserine-dependent manner. Phosphorylation of T34 also occurred in cells following growth factor stimulation, concurrently with T308 phosphorylation. Moreover, when T34 was mutated to aspartic acid (T34D) to mimic its phosphorylation, Akt-membrane association assessed by surface plasmon resonance spectroscopy was significantly reduced. In cells, this mutation impaired the IGF-induced Akt membrane translocation and subsequent phosphorylation at T308 and S473. Taken together, our results demonstrate that T34 phosphorylation by PDK1 promotes the membrane dissociation of activated Akt for its downstream action through attenuating membrane binding affinity. This membrane dissociation mechanism offers a new insight for Akt activation process and provides a potential new target for controlling the Akt-dependent cellular processes. |
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| Keywords: | Protein kinase B Threonine 34 Membrane translocation Akt activation PDK1 |
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