SGK3 Mediates INPP4B-dependent PI3K Signaling in Breast Cancer

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2014 Dec 3

PMID 25458846

Citations 91

Authors

Jessica A Gasser

Hiroyuki Inuzuka

Alan W Lau

Wenyi Wei

Rameen Beroukhim

Alex Toker

Affiliations

Soon will be listed here.

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.

Citing Articles

Association of Computed Tomography Scan-Assessed Body Composition with Immune and PI3K/AKT Pathway Proteins in Distinct Breast Cancer Tumor Components.

Cheng T, Fu D, Falzarano S, Zhang R, Datta S, Zhang W Int J Mol Sci. 2025; 25(24.

PMID: 39769193 PMC: 11676426. DOI: 10.3390/ijms252413428.

Novel determinants of NOTCH1 trafficking and signaling in breast epithelial cells.

Kobia F, Castro E Almeida L, Paganoni A, Carminati F, Andronache A, Lavezzari F Life Sci Alliance. 2024; 8(3).

PMID: 39663000 PMC: 11633778. DOI: 10.26508/lsa.202403122.

CD97 maintains tumorigenicity of glioblastoma stem cells via mTORC2 signaling and is targeted by CAR Th9 cells.

Zhou S, Lin W, Jin X, Niu R, Yuan Z, Chai T Cell Rep Med. 2024; 5(12):101844.

PMID: 39637858 PMC: 11722114. DOI: 10.1016/j.xcrm.2024.101844.

INPP4B promotes PDAC aggressiveness via PIKfyve and TRPML-1-mediated lysosomal exocytosis.

Saffi G, To L, Kleine N, Melo C, Chen K, Genc G J Cell Biol. 2024; 223(11).

PMID: 39120584 PMC: 11317760. DOI: 10.1083/jcb.202401012.

PIK3CA mutations enhance the adipogenesis of ADSCs in facial infiltrating lipomatosis through TRPV1.

Chen H, Sun B, Gao W, Qiu Y, Wei W, Li Y iScience. 2024; 27(8):110467.

PMID: 39104411 PMC: 11298645. DOI: 10.1016/j.isci.2024.110467.

References

Kobayashi T, Deak M, Morrice N, Cohen P . Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase. Biochem J. 1999; 344 Pt 1:189-97. PMC: 1220630. View

Lai C, Srivastava A, Pilling C, Chase A, Falke J, Voth G . Molecular mechanism of membrane binding of the GRP1 PH domain. J Mol Biol. 2013; 425(17):3073-90. PMC: 4265004. DOI: 10.1016/j.jmb.2013.05.026. View

Xu J, Liu D, Gill G, Songyang Z . Regulation of cytokine-independent survival kinase (CISK) by the Phox homology domain and phosphoinositides. J Cell Biol. 2001; 154(4):699-705. PMC: 2196448. DOI: 10.1083/jcb.200105089. View

Sorlie T, Perou C, Tibshirani R, Aas T, Geisler S, Johnsen H . Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001; 98(19):10869-74. PMC: 58566. DOI: 10.1073/pnas.191367098. View

Scheid M, Huber M, Damen J, Hughes M, Kang V, Neilsen P . Phosphatidylinositol (3,4,5)P3 is essential but not sufficient for protein kinase B (PKB) activation; phosphatidylinositol (3,4)P2 is required for PKB phosphorylation at Ser-473: studies using cells from SH2-containing inositol-5-phosphatase.... J Biol Chem. 2002; 277(11):9027-35. DOI: 10.1074/jbc.M106755200. View

Choi Y, Zhang J, Murga C, Yu H, Koller E, Monia B . PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells. Oncogene. 2002; 21(34):5289-300. DOI: 10.1038/sj.onc.1205650. View

Firestone G, Giampaolo J, OKeeffe B . Stimulus-dependent regulation of serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity. Cell Physiol Biochem. 2003; 13(1):1-12. DOI: 10.1159/000070244. View

Debnath J, Muthuswamy S, Brugge J . Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods. 2003; 30(3):256-68. DOI: 10.1016/s1046-2023(03)00032-x. View

Luo J, Manning B, Cantley L . Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell. 2003; 4(4):257-62. DOI: 10.1016/s1535-6108(03)00248-4. View

10.

Rajagopalan H, Jallepalli P, Rago C, Velculescu V, Kinzler K, Vogelstein B . Inactivation of hCDC4 can cause chromosomal instability. Nature. 2004; 428(6978):77-81. DOI: 10.1038/nature02313. View

11.

Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S . High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004; 304(5670):554. DOI: 10.1126/science.1096502. View

12.

Mora A, Komander D, van Aalten D, Alessi D . PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol. 2004; 15(2):161-70. DOI: 10.1016/j.semcdb.2003.12.022. View

13.

Norris F, MAJERUS P . Hydrolysis of phosphatidylinositol 3,4-bisphosphate by inositol polyphosphate 4-phosphatase isolated by affinity elution chromatography. J Biol Chem. 1994; 269(12):8716-20. View

14.

Franke T, Kaplan D, Cantley L, Toker A . Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science. 1997; 275(5300):665-8. DOI: 10.1126/science.275.5300.665. View

15.

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S . PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997; 275(5308):1943-7. DOI: 10.1126/science.275.5308.1943. View

16.

Norris F, Atkins R, MAJERUS P . The cDNA cloning and characterization of inositol polyphosphate 4-phosphatase type II. Evidence for conserved alternative splicing in the 4-phosphatase family. J Biol Chem. 1997; 272(38):23859-64. DOI: 10.1074/jbc.272.38.23859. View

17.

Maehama T, Dixon J . The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998; 273(22):13375-8. DOI: 10.1074/jbc.273.22.13375. View

18.

Kobayashi T, Cohen P . Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem J. 1999; 339 ( Pt 2):319-28. PMC: 1220160. View

19.

Murray J, Campbell D, Morrice N, Auld G, Shpiro N, Marquez R . Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3. Biochem J. 2004; 384(Pt 3):477-88. PMC: 1134133. DOI: 10.1042/BJ20041057. View

20.

Lee J, Soung Y, Kim S, Lee H, Park W, Nam S . PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene. 2004; 24(8):1477-80. DOI: 10.1038/sj.onc.1208304. View