title: SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer.
abstract: Oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), occur with high frequency in breast cancer. The protein kinase Akt is considered to be the primary effector of PIK3CA, although mechanisms by which PI3K mediates Akt-independent tumorigenic signals remain obscure. We show that serum and glucocorticoid-regulated kinase 3 (SGK3) is amplified in breast cancer and activated downstream of PIK3CA in a manner dependent on the phosphoinositide phosphatase INPP4B. Expression of INPP4B leads to enhanced SGK3 activation and suppression of Akt phosphorylation. Activation of SGK3 downstream of PIK3CA and INPP4B is required for 3D proliferation, invasive migration, and tumorigenesis in vivo. We further show that SGK3 targets the metastasis suppressor NDRG1 for degradation by Fbw7. We propose a model in which breast cancers harboring oncogenic PIK3CA activate SGK3 signaling while suppressing Akt, indicative of oncogenic functions for both INPP4B and SGK3 in these tumors.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Gasser
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Alan W
authors.initials: AW
authors.lastname: Lau
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
authors.affiliation: Cancer Program and Medical and Population Genetics Group, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Departments of Medical Oncology, Pediatric Oncology, and Cancer Biology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Departments of Medicine and Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Departments of Medicine, Pathology, Pediatrics, and Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: atoker@bidmc.harvard.edu.
authors.forename: Alex
authors.initials: A
authors.lastname: Toker
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D058534:Class I Phosphatidylinositol 3-Kinases; D004789:Enzyme Activation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D059748:Proteolysis; D015398:Signal Transduction; D000099259:N-myc Downstream-Regulated Gene 1 Protein; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D018797:Cell Cycle Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C484760:PIK3CA protein, human; C403243:SGK3 protein, human; D000099184:Serum-Glucocorticoid Regulated Kinases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase