Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling.
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)P(2)) with no effect on phosphatidylinositol-3.4.5-triphosphate (PI(3,4,5)P(3)), suggesting that PI(3,4)P(2) and PI(3,4,5)P(3) 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.
Gewinner
Christina
C
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Wang
Zhigang C
ZC
Richardson
Andrea
A
Teruya-Feldstein
Julie
J
Etemadmoghadam
Dariush
D
Bowtell
David
D
Barretina
Jordi
J
Lin
William M
WM
Rameh
Lucia
L
Salmena
Leonardo
L
Pandolfi
Pier Paolo
PP
Cantley
Lewis C
LC
D001943:Breast Neoplasms / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D019656:Loss of Heterozygosity; D010051:Ovarian Neoplasms / Q000235:genetics / Q000401:mortality; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D007328:Insulin; D025521:Tumor Suppressor Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human