Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1

Nishio, Makoto; Watanabe, Kenichi; Sasaki, Junko; Taya, Choji; Takasuga, Shunsuke; Iizuka, Ryota; Balla, Tamás; Yamazaki, Masakazu; Watanabe, Hiroshi; Itoh, Reietsu; Kuroda, Seika; Horie, Yasuo; Förster, Irmgard; Mak, Tak W.; Yonekawa, Hiromichi; Penninger, Josef; Kanaho, Yasunori; Suzuki, Akira; Sasaki, Takehiko

doi:10.1038/ncb1515

Cited by 266 publications

(270 citation statements)

References 43 publications

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“…We then analyzed the localization of PI-3,4,5-P 3 in osteoclasts using AktPH-GFP transgenic mice. (28) The transgenic mice express a GFP-fused PH domain derived from Akt, which preferentially binds to PI-3,4,5-P 3 , thus enabling the visualization of PI-3,4,5-P 3 localization in the cells. In mature osteoclasts cultured on dentin, GFP signals were detected in the area just inside the sealing zone and at the cell periphery (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mice and the in vivo analysis of bone tissues Pik3r1 F/F , (25) Pik3r2 À/À , (26) CtsKCre transgenic, (27) and Akt pleckstrin homology domain-green fluorescent protein (AktPH-GFP) transgenic mice (28) were previously generated and are described elsewhere. Because a small population of osteoclasts from CtsKCrePik3r1 F/F mice still expressed p85a, CtsKCrePik3r1 F/F we mated mice to Pik3r1 þ/À mice to generate CtsKCrePik3r1 F/À (Pik3r1 Doc/À ) mice.…”

Section: Methodsmentioning

confidence: 99%

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Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Shirakawa

Nakamura

Masuda

et al. 2012

Journal of Bone and Mineral Research

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Class IA phosphatidylinositol 3-kinases (PI3Ks) are activated by growth factor receptors and regulate a wide range of cellular processes. In osteoclasts, they are activated downstream of a v b 3 integrin and colony-stimulating factor-1 receptor (c-Fms), which are involved in the regulation of bone-resorbing activity. The physiological relevance of the in vitro studies using PI3K inhibitors has been of limited value, because they inhibit all classes of PI3K. Here, we show that the osteoclast-specific deletion of the p85 genes encoding the regulatory subunit of the class IA PI3K results in an osteopetrotic phenotype caused by a defect in the bone-resorbing activity of osteoclasts. Class IA PI3K is required for the ruffled border formation and vesicular transport, but not for the formation of the sealing zone. p85a/b doubly deficient osteoclasts had a defect in macrophage colony-stimulating factor (M-CSF)-induced protein kinase B (Akt) activation and the introduction of constitutively active Akt recovered the bone-resorbing activity. Thus, the class IA PI3K-Akt pathway regulates the cellular machinery crucial for osteoclastic bone resorption, and may provide a molecular basis for therapeutic strategies against bone diseases. ß

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Shirakawa

Nakamura

Masuda

et al. 2012

Journal of Bone and Mineral Research

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“…This mechanism of modulating cell migration is different from that used by other known regulators. For example, the phosphatases PTEN and SHIP impinge on directional sensing and motility of cells by dephosphorylating PIP 3 (Franca-Koh et al, 2007;Nishio et al, 2007). Moreover, they are essential for the establishment of internal gradient of signaling molecules and directional sensing of Dictyostelium and neutrophils (Funamoto et al, 2002;Iijima and Devreotes, 2002;Li et al, 2005;Nishio et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

RACK1 Regulates Directional Cell Migration by Acting on Gβγ at the Interface with Its Effectors PLCβ and PI3Kγ

Chen

Lin

Shin

et al. 2008

MBoC

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Migration of cells up the chemoattractant gradients is mediated by the binding of chemoattractants to G protein-coupled receptors and activation of a network of coordinated excitatory and inhibitory signals. Although the excitatory process has been well studied, the molecular nature of the inhibitory signals remains largely elusive. Here we report that the receptor for activated C kinase 1 (RACK1), a novel binding protein of heterotrimeric G protein ␤␥ (G␤␥) subunits, acts as a negative regulator of directed cell migration. After chemoattractant-induced polarization of Jurkat and neutrophil-like differentiated HL60 (dHL60) cells, RACK1 interacts with G␤␥ and is recruited to the leading edge. Down-regulation of RACK1 dramatically enhances chemotaxis of cells, whereas overexpression of RACK1 or a fragment of RACK1 that retains G␤␥-binding capacity inhibits cell migration. Further studies reveal that RACK1 does not modulate cell migration through binding to other known interacting proteins such as PKC␤ and Src. Rather, RACK1 selectively inhibits G␤␥-stimulated phosphatidylinositol 3-kinase ␥ (PI3K␥) and phospholipase C (PLC) ␤ activity, due to the competitive binding of RACK1, PI3K␥, and PLC␤ to G␤␥. Taken together, these findings provide a novel mechanism of regulating cell migration, i.e., RACK1-mediated interference with G␤␥-dependent activation of key effectors critical for chemotaxis.

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“…To determine whether a lack of Pten leads to hyperactivation of PI3K in Leishmania-infected macrophages, we examined levels of the PI3K product PIP 3 using the fusion bioprobe AktPH-GFP [48]. We crossed mice expressing AktPH-GFP with Pten flox/flox or LysMCrePten flox/flox mice to generate AktPH-GFP;Pten flox/flox and AktPH-GFP;LysMCrePten flox/flox mice.…”

Section: Effect Of Leishmania Infection On Pi3k Activation In the Prementioning

confidence: 99%

“…LysMCrePten +/+ and Pten flox/flox mice were indistinguishable in pilot experiments examining cytokine production and macrophage killing ability (data not shown), so that Pten flox/flox and LysMCrePten flox/flox offspring mice were used as representative WT controls and homozygous mutant mice, respectively. For the PIP 3 detection experiments, Pten flox/flox and LysMCrePten flox/flox mice were crossed with AktPH-GFP Tg mice [48] to generate offspring of the WT or LysMCrePten flox/flox background that expressed the AktPH-GFP bioprobe binding to PIP 3 . The Institutional Review Board of the Akita University School of Medicine approved all animal experiments.…”

Section: Generation Of Lysmcrepten Flox/flox Micementioning

confidence: 99%

Effective clearance of intracellular Leishmania majorin vivo requires Pten in macrophages

et al. 2008

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Leishmaniases are a major international public health problem, and macrophages are crucial for host resistance to this parasite. To determine if phosphatase and tensin homologue deleted on chromosome ten (Pten), a negative regulator of the PI3K pathway, plays a role in macrophage-mediated resistance to Leishmania, we generated C57BL/6 mice lacking Pten specifically in macrophages (LysMCrePten flox/flox mice). Examination of lesions resulting from Leishmania major infection showed that LysMCrePten flox/flox mice were more susceptible to the parasite than wild-type (WT) mice in the early phase of the infection, but were eventually able to eliminate the pathogen. In vitro Pten-deficient macrophages showed a reduced ability to kill parasites in response to IFN-c treatment, possibly because the mutant cells exhibited decreased TNF secretion that correlated with reductions in inducible nitric oxide synthase expression and nitric oxide production. In response to various TLR ligands, Pten-deficient macrophages produced less TNF and IL-12 but more IL-10 than WT cells. However, analysis of cells in the lymph nodes draining L. major inoculation sites indicated that both LysMCrePten flox/flox and WT mice developed normal Th1 responses following L. major infection, in line with the ability of LysMCrePten flox/flox mice to eventually eliminate the parasite. Our results indicate that the efficient clearance of intracellular parasites requires Pten in macrophages.Key words: Leishmania Á Macrophage Á Pten IntroductionIn humans, Leishmania infections are classified as self-healing, cutaneous, mucocutaneous or visceral [1]. These clinical manifestations of the disease reflect differences among infecting parasite species as well as the efficiency of the host's immune response to a given species. Many of the clinical manifestations of human leishmaniasis are mimicked in inbred mice, and experimental infection of various mouse strains with Leishmania major is widely used to study resistance and susceptibility to leishmaniasis. These studies have shown that intact phagocyte function is essential for recovery from Leishmania infections. In an attempt to thwart this means of host defense, Leishmania disrupt numerous Eur. J. Immunol. 2008. 38: 1331-1340 Immunity to infection , and this TNF synergizes with IFN-c to promote parasite killing [4, 5]. Mice resistant to infection with L. major have elevated levels of TNF in their draining lymph nodes (LN) during the course of the infection, whereas no TNF is detectable in susceptible animals [6]. In addition, C57BL/6 mice, which are resistant to L. major infection, become susceptible if they transgenically express high levels of the competitive inhibitor soluble hTNFRp55 fusion protein [7]. Knockout mice lacking TNFRp55 or TNF are also susceptible to this parasite [8][9][10].Signaling through both FccR [11] and TLR (especially TLR2 [12] and TLR4 [13, 14]) is known to be important for macrophagemediated defense against Leishmania. However, how these receptors are linked to TNF production is ...

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Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1

Cited by 266 publications

References 43 publications

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

RACK1 Regulates Directional Cell Migration by Acting on Gβγ at the Interface with Its Effectors PLCβ and PI3Kγ

Effective clearance of intracellular Leishmania majorin vivo requires Pten in macrophages

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