ORCID Profile
0000-0003-1837-3748
Current Organisations
Tokyo Medical and Dental University
,
University of Tokyo
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Publisher: Cold Spring Harbor Laboratory
Date: 15-04-1999
Abstract: Bone resorption and remodeling is an intricately controlled, physiological process that requires the function of osteoclasts. The processes governing both the differentiation and activation of osteoclasts involve signals induced by osteoprotegerin ligand (OPGL), a member of tumor necrosis factor (TNF) superfamily, and its cognate receptor RANK. The molecular mechanisms of the intracellular signal transduction remain to be elucidated. Here we report that mice deficient in TNF receptor-associated factor 6 (TRAF6) are osteopetrotic with defects in bone remodeling and tooth eruption due to impaired osteoclast function. Using in vitro assays, we demonstrate that TRAF6 is crucial not only in IL-1 and CD40 signaling but also, surprisingly, in LPS signaling. Furthermore, like TRAF2 and TRAF3, TRAF6 is essential for perinatal and postnatal survival. These findings establish unexpectedly erse and critical roles for TRAF6 in perinatal and postnatal survival, bone metabolism, LPS, and cytokine signaling.
Publisher: American Society of Hematology
Date: 15-12-2007
DOI: 10.1182/BLOOD-2007-02-073874
Abstract: Macrophages phagocytose particles to resolve infections and remove apoptotic cells. Phosphoinositide 3-kinase generates phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3] is restricted to the phagocytic cup, promoting phagocytosis. The PtdIns(3,4,5)P3 5-phosphatase (5-ptase) Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1) inhibits phagocytosis. We report here that another PtdIns(3,4,5)P3-5-ptase, the 72-kDa-5-phosphatase (72-5ptase), inhibits Fcγ receptor (FcγR)– but not complement receptor 3 (CR3)–mediated phagocytosis, affecting pseudopod extension and phagosome closure. In contrast, SHIP1 inhibited FcγR and CR3 phagocytosis with greater effects on CR3-stimulated phagocytosis. The 72-5ptase and SHIP1 were both dynamically recruited to FcγR-stimulated phagocytic cups, but only SHIP1 was recruited to CR3-stimulated phagocytic cups. To determine whether 5-ptases focally degrade PtdIns(3,4,5)P3 at the phagocytic cup after specific stimuli, time-lapse imaging of specific biosensors was performed. Transfection of dominant-negative 72-5ptase or 72-5ptase small interfering RNA (siRNA) resulted in lified and prolonged PtdIns(3,4,5)P3 at the phagocytic cup in response to FcγR- but not CR3-stimulation. In contrast, macrophages from Ship1−/−/AktPH-GFP transgenic mice exhibited increased and sustained PtdIns(3,4,5)P3 at the cup in response to CR3 activation, with minimal changes to FcγR activation. Therefore, 72-5ptase and SHIP1 exhibit specificity in regulating FcγR- versus CR3-stimulated phagocytosis by controlling the litude and duration of PtdIns(3,4,5)P3 at the phagocytic cup.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2015
DOI: 10.1158/2159-8290.CD-14-1347
Abstract: The phosphatases PTEN and INPP4B have been proposed to act as tumor suppressors by antagonizing PI3K–AKT signaling and are frequently dysregulated in human cancer. Although PTEN has been extensively studied, little is known about the underlying mechanisms by which INPP4B exerts its tumor-suppressive function and its role in tumorigenesis in vivo. Here, we show that a partial or complete loss of Inpp4b morphs benign thyroid adenoma lesions in Pten heterozygous mice into lethal and metastatic follicular-like thyroid cancer (FTC). Importantly, analyses of human thyroid cancer cell lines and specimens reveal INPP4B downregulation in FTC. Mechanistically, we find that INPP4B, but not PTEN, is enriched in the early endosomes of thyroid cancer cells, where it selectively inhibits AKT2 activation and in turn tumor proliferation and anchorage-independent growth. We therefore identify INPP4B as a novel tumor suppressor in FTC oncogenesis and metastasis through localized regulation of the PI3K–AKT pathway at the endosomes. Significance: Although both PTEN and INPP4B can inhibit PI3K–AKT signaling through their lipid phosphatase activities, here we demonstrate lack of an epistatic relationship between the two tumor suppressors. Instead, the qualitative regulation of PI3K–AKT2 signaling by INPP4B provides a mechanism for their cooperation in suppressing thyroid tumorigenesis and metastasis. Cancer Discov 5(7) 740–51. ©2015 AACR. See related commentary by Vo and Fruman, p. 697. See related article by Kofuji and colleagues, p. 730. This article is highlighted in the In This Issue feature, p. 681
Publisher: Public Library of Science (PLoS)
Date: 06-12-2012
Publisher: Springer Science and Business Media LLC
Date: 05-2010
DOI: 10.1038/NATURE09023
Abstract: Phosphorylated derivatives of phosphatidylinositol, collectively referred to as phosphoinositides, occur in the cytoplasmic leaflet of cellular membranes and regulate activities such as vesicle transport, cytoskeletal reorganization and signal transduction. Recent studies have indicated an important role for phosphoinositide metabolism in the aetiology of diseases such as cancer, diabetes, myopathy and inflammation. Although the biological functions of the phosphatases that regulate phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) have been well characterized, little is known about the functions of the phosphatases regulating the closely related molecule phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P(2)). Here we show that inositol polyphosphate phosphatase 4A (INPP4A), a PtdIns(3,4)P(2) phosphatase, is a suppressor of glutamate excitotoxicity in the central nervous system. Targeted disruption of the Inpp4a gene in mice leads to neurodegeneration in the striatum, the input nucleus of the basal ganglia that has a central role in motor and cognitive behaviours. Notably, Inpp4a(-/-) mice show severe involuntary movement disorders. In vitro, Inpp4a gene silencing via short hairpin RNA renders cultured primary striatal neurons vulnerable to cell death mediated by N-methyl-d-aspartate-type glutamate receptors (NMDARs). Mechanistically, INPP4A is found at the postsynaptic density and regulates synaptic NMDAR localization and NMDAR-mediated excitatory postsynaptic current. Thus, INPP4A protects neurons from excitotoxic cell death and thereby maintains the functional integrity of the brain. Our study demonstrates that PtdIns(3,4)P(2), PtdIns(3,4,5)P(3) and the phosphatases acting on them can have distinct regulatory roles, and provides insight into the unique aspects and physiological significance of PtdIns(3,4)P(2) metabolism. INPP4A represents, to our knowledge, the first signalling protein with a function in neurons to suppress excitotoxic cell death. The discovery of a direct link between PtdIns(3,4)P(2) metabolism and the regulation of neurodegeneration and involuntary movements may aid the development of new approaches for the treatment of neurodegenerative disorders.
No related grants have been discovered for Takehiko Sasaki.