SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer

Jessica A Gasser; Hiroyuki Inuzuka; Alan W Lau; Wenyi Wei; Rameen Beroukhim; Alex Toker

doi:10.1016/j.molcel.2014.09.023

SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer

Mol Cell. 2014 Nov 20;56(4):595-607. doi: 10.1016/j.molcel.2014.09.023. Epub 2014 Oct 30.

Authors

Jessica A Gasser¹, Hiroyuki Inuzuka¹, Alan W Lau¹, Wenyi Wei¹, Rameen Beroukhim², Alex Toker³

Affiliations

¹ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
² 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.
³ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: atoker@bidmc.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Breast Neoplasms / enzymology*
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Movement
Cell Proliferation
Class I Phosphatidylinositol 3-Kinases
Enzyme Activation
Female
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins / metabolism
Mice
Mice, Nude
Mutation
NIH 3T3 Cells
Neoplasm Invasiveness
Neoplasm Transplantation
Phosphatidylinositol 3-Kinases / genetics*
Phosphatidylinositol 3-Kinases / physiology
Phosphoric Monoester Hydrolases / metabolism*
Protein Processing, Post-Translational
Protein Serine-Threonine Kinases / physiology*
Proteolysis
Signal Transduction

Substances

Cell Cycle Proteins
Intracellular Signaling Peptides and Proteins
N-myc downstream-regulated gene 1 protein
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
Protein Serine-Threonine Kinases
SGK3 protein, human
Phosphoric Monoester Hydrolases
phosphatidylinositol-3,4-bisphosphate 4-phosphatase

Abstract

Publication types

MeSH terms

Substances

Grants and funding