INPP4B Is a PtdIns(3,4,5)P3 Phosphatase That Can Act as a Tumor Suppressor.

Abstract

UNLABELLED:

Inositol polyphosphate 4-phosphatase B (INPP4B) has been identified as a tumor suppressor mutated in human breast, ovary, and prostate cancers. The molecular mechanism underlying INPP4B's tumor-suppressive role is currently unknown. Here, we demonstrate that INPP4B restrains tumor development by dephosphorylating the PtdIns(3,4,5)P3 that accumulates in situations of PTEN deficiency. In vitro, INPP4B directly dephosphorylates PtdIns(3,4,5)P3. In vivo, neither inactivation of Inpp4b (Inpp4b(Δ/Δ)) nor heterozygous deletion of Pten (Pten(+/-)) in mice causes thyroid abnormalities, but a combination of these mutations induces malignant thyroid cancers with lung metastases. At the molecular level, simultaneous deletion of Inpp4b and Pten synergistically increases PtdIns(3,4,5)P3 levels and activates AKT downstream signaling proteins in thyroid cells. We propose that the PtdIns(3,4,5)P3 phosphatase activity of INPP4B can function as a "back-up" mechanism when PTEN is deficient, making INPP4B a potential novel therapeutic target for PTEN-deficient or PIK3CA-activated cancers.

SIGNIFICANCE:

Although INPP4B expression is reduced in several types of human cancers, our work on Inpp4B-deficient mice provides the first evidence that INPP4B is a bona fide tumor suppressor whose function is particularly important in situations of PTEN deficiency. Our biochemical data demonstrate that INPP4B directly dephosphorylates PtdIns(3,4,5)P3.

• Authors: Satoshi Kofuji, Hirotaka Kimura, Hiroki Nakanishi, Hiroshi Nanjo, Shunsuke Takasuga, Hui Liu, Satoshi Eguchi, Ryotaro Nakamura, Reietsu Itoh, Noriko Ueno, Ken Asanuma, Mingguo Huang, Atsushi Koizumi, Tomonori Habuchi, Masakazu Yamazaki, Akira Suzuki, Junko Sasaki, Takehiko Sasaki
• Journal: Cancer discovery (Cancer Discov) Vol. 5 Issue 7 Pg. 730-9 (Jul 2015) ISSN: 2159-8290 [Electronic] United States
• PMID: 25883023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Phosphatidylinositol Phosphates
• phosphatidylinositol 3,4,5-triphosphate
• Phosphoric Monoester Hydrolases
• phosphatidylinositol-3,4-bisphosphate 4-phosphatase
• PTEN Phosphohydrolase

Topics

• Animals
• Cells, Cultured
• Female
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Humans
• Lung Neoplasms (genetics, metabolism, pathology)
• Male
• Mice
• Mouse Embryonic Stem Cells
• PTEN Phosphohydrolase (deficiency)
• Phosphatidylinositol Phosphates (metabolism)
• Phosphoric Monoester Hydrolases (genetics, metabolism)
• Thyroid Neoplasms (genetics, metabolism, pathology)