title: pVHL suppresses kinase activity of Akt in a proline-hydroxylation-dependent manner.
abstract: Activation of the serine-threonine kinase Akt promotes the survival and proliferation of various cancers. Hypoxia promotes the resistance of tumor cells to specific therapies. We therefore explored a possible link between hypoxia and Akt activity. We found that Akt was prolyl-hydroxylated by the oxygen-dependent hydroxylase EglN1. The von Hippel-Lindau protein (pVHL) bound directly to hydroxylated Akt and inhibited Akt activity. In cells lacking oxygen or functional pVHL, Akt was activated to promote cell survival and tumorigenesis. We also identified cancer-associated Akt mutations that impair Akt hydroxylation and subsequent recognition by pVHL, thus leading to Akt hyperactivation. Our results show that microenvironmental changes, such as hypoxia, can affect tumor behaviors by altering Akt activation, which has a critical role in tumor growth and therapeutic resistance.
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Jianping
authors: J
authors: Guo
authors: Department of Medicine, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Abhishek A
authors: AA
authors: Chakraborty
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Pengda
authors: P
authors: Liu
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Wenjian
authors: W
authors: Gan
authors: Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors: Xingnan
authors: X
authors: Zheng
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Hiroyuki
authors: H
authors: Inuzuka
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Bin
authors: B
authors: Wang
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Jinfang
authors: J
authors: Zhang
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Linli
authors: L
authors: Zhang
authors: Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: Min
authors: M
authors: Yuan
authors: Department of Pathology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Jesse
authors: J
authors: Novak
authors: Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Jin Q
authors: JQ
authors: Cheng
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Alex
authors: A
authors: Toker
authors: Department of Pathology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Sabina
authors: S
authors: Signoretti
authors: Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors: Qing
authors: Q
authors: Zhang
authors: Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: John M
authors: JM
authors: Asara
authors: Department of Medicine, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors: William G
authors: WG
authors: Kaelin
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. wwei2@bidmc.harvard.edu.
authors: Wenyi
authors: W
authors: Wei
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D006900:Hydroxylation; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology*; D010766:Phosphorylation; D011392:Proline / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: D011392:Proline; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051057:Proto-Oncogene Proteins c-akt