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: Jessica A Gasser, Hiroyuki Inuzuka, Alan W Lau, Wenyi Wei, Rameen Beroukhim, Alex Toker
• Journal: Molecular cell (Mol Cell) Vol. 56 Issue 4 Pg. 595-607 (Nov 20 2014) ISSN: 1097-4164 [Electronic] United States
• PMID: 25458846 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

• Animals
• Breast Neoplasms (enzymology, genetics, 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, physiology)
• Phosphoric Monoester Hydrolases (metabolism)
• Protein Processing, Post-Translational
• Protein Serine-Threonine Kinases (physiology)
• Proteolysis
• Signal Transduction