Evidence that Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor that Inhibits PI3K Signaling

Christina Gewinner, Zhigang C. Wang, Andrea Richardson, Julie Teruya-Feldstein, Dariush Etemadmoghadam, David Bowtell, Jordi Barretina, William M. Lin, Lucia Rameh, Leonardo Salmena, Pier Paolo Pandolfi, Lewis C. Cantley

Research output: Contribution to journalArticle

Abstract

We report that knocking down the expression of inositol polyphosphate 4-phosphatase type II (INPP4B) in human epithelial cells, like knockdown of PTEN, resulted in enhanced Akt activation and anchorage-independent growth and enhanced overall motility. In xenograft experiments, overexpression of INPP4B resulted in reduced tumor growth. INPP4B preferentially hydrolyzes phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) with no effect on phosphatidylinositol-3.4.5-triphosphate (PI(3,4,5)P3), suggesting that PI(3,4)P2 and PI(3,4,5)P3 may cooperate in Akt activation and cell transformation. Dual knockdown of INPP4B and PTEN resulted in cellular senescence. Finally, we found loss of heterozygosity (LOH) at the INPP4B locus in a majority of basal-like breast cancers, as well as in a significant fraction of ovarian cancers, which correlated with lower overall patient survival, suggesting that INPP4B is a tumor suppressor.

Original languageEnglish (US)
Pages (from-to)115-125
Number of pages11
JournalCancer Cell
Volume16
Issue number2
DOIs
StatePublished - Aug 4 2009
Externally publishedYes

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Phosphatidylinositol 3-Kinases
Cell Aging
Loss of Heterozygosity
Growth
Phosphatidylinositols
Heterografts
Ovarian Neoplasms
Neoplasms
Epithelial Cells
Breast Neoplasms
Survival
phosphoinositide-3,4-bisphosphate
phosphatidylinositol-3,4-bisphosphate 4-phosphatase
phosphoinositide-3,4,5-triphosphate
triphosphoric acid
phosphatidylinositol 3,4-diphosphate

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Gewinner, C., Wang, Z. C., Richardson, A., Teruya-Feldstein, J., Etemadmoghadam, D., Bowtell, D., ... Cantley, L. C. (2009). Evidence that Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor that Inhibits PI3K Signaling. Cancer Cell, 16(2), 115-125. https://doi.org/10.1016/j.ccr.2009.06.006

Evidence that Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor that Inhibits PI3K Signaling. / Gewinner, Christina; Wang, Zhigang C.; Richardson, Andrea; Teruya-Feldstein, Julie; Etemadmoghadam, Dariush; Bowtell, David; Barretina, Jordi; Lin, William M.; Rameh, Lucia; Salmena, Leonardo; Pandolfi, Pier Paolo; Cantley, Lewis C.

In: Cancer Cell, Vol. 16, No. 2, 04.08.2009, p. 115-125.

Research output: Contribution to journalArticle

Gewinner, C, Wang, ZC, Richardson, A, Teruya-Feldstein, J, Etemadmoghadam, D, Bowtell, D, Barretina, J, Lin, WM, Rameh, L, Salmena, L, Pandolfi, PP & Cantley, LC 2009, 'Evidence that Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor that Inhibits PI3K Signaling', Cancer Cell, vol. 16, no. 2, pp. 115-125. https://doi.org/10.1016/j.ccr.2009.06.006
Gewinner, Christina ; Wang, Zhigang C. ; Richardson, Andrea ; Teruya-Feldstein, Julie ; Etemadmoghadam, Dariush ; Bowtell, David ; Barretina, Jordi ; Lin, William M. ; Rameh, Lucia ; Salmena, Leonardo ; Pandolfi, Pier Paolo ; Cantley, Lewis C. / Evidence that Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor that Inhibits PI3K Signaling. In: Cancer Cell. 2009 ; Vol. 16, No. 2. pp. 115-125.
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