Early embryonic lethality in mice deficient in the p110β catalytic subunit of PI 3-kinase

Bi, Lei; Okabe, Ichiro; Bernard, David; Nussbaum, Robert L.

doi:10.1007/bf02684023

Cited by 175 publications

(144 citation statements)

References 22 publications

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“…Although a previous report has suggested that p110b is expressed in heart, liver, kidney, and testis in adult mice, and from embryonic day 7 (E7) to E11 during embryonic development, (50) the GeneAtlas GNF1M mouse gene expression profile (http://biogps.org/) shows that p110b is most highly expressed in blastocysts at the development stage, which is consistent with the observation that p110b-deficient mice die at around E3.5. (50) The expression profile also indicates that, in normal adult mice, p110b is selectively expressed in osteoclasts and their precursor cells, macrophages, among all tissues and cells. Thus, the selective inhibitor for p110b such as TGX-221 (51) may be able to target class IA PI3K in osteoclasts with minimal side effects.…”

Section: Discussionsupporting

confidence: 82%

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: Discussionsupporting

confidence: 82%

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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“…28 Deficiency of p110 is also very severe, and mice lacking p110␣ or p110␤ die in utero. 29,30 The role of p110 has been described in B-cell development and function 31,32 and in B-and T-cell receptor signaling 33 as part of the PI-3K pathway. 34 In contrast, Gab2 recruits negative regulators of PI-3K signaling downstream of the T-cell receptor.…”

Section: Discussionmentioning

confidence: 99%

Abnormal hematopoiesis in Gab2 mutant mice

Zhang

Díaz-Flores

et al. 2007

Blood

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Gab2 is an important adapter molecule for cytokine signaling. Despite its major role in signaling by receptors associated with hematopoiesis, the role of Gab2 in hematopoiesis has not been addressed. We report that despite normal numbers of peripheral blood cells, bone marrow cells, and c-Kit ؉ Lin ؊ Sca-1 ؉ (KLS) cells, Gab2-deficient hematopoietic cells are deficient in cytokine responsiveness. Significant reductions in the number of colonyforming units in culture (CFU-C) in the presence of limiting cytokine concentrations were observed, and these defects could be completely corrected by retroviral complementation. In earlier hematopoiesis, Gab2-deficient KLS cells isolated in vitro responded poorly to hematopoietic growth factors, resulting in an up to 11-fold reduction in response to a cocktail of stem cell factor, flt3 ligand, and thrombopoietin. Gab2-deficient c-Kit ؉ Lin ؊ cells also demonstrate impaired activation of extracellular signal-regulated kinase (ERK) and S6 in response to IL-3, which supports defects in activating the phosphatidylinositol-3 kinase (PI-3K) and mitogen-associated protein kinase (MAPK) IntroductionOne of the most prominent motifs in signaling molecules is the Src homology-2 (SH2) domain found in JAKs, signal transducers and activators of transcription (STATs), Grb2, p85, Shc, and others. These SH2 domains are able to bind and "dock" with the phosphorylated tyrosine residues that are common in signal transduction pathways. Multiple protein-binding motifs are present in many of the adapter molecules, leading to multimeric complexes that may also include CrkL, PLC, SHIP, and SHP-2. The Grb2-associated binding protein (Gab) family of adapter proteins (Gab1, Gab2, Gab3) include a family of scaffolding/docking/adapter molecules involved in multiple signaling pathways, including the phosphatidylinositol-3 kinase (PI-3K) and mitogen-associated protein kinase (MAPK) pathways, and include multiple proteinbinding sites. [1][2][3] These proteins are tyrosine phosphorylated following cytokine stimulation and are able to interact with a large number of partners. The mechanisms that confer specificity in directing which interactions occur in any particular cell type upon cytokine stimulation remain to be determined. Gab1 deficiency results in embryonic lethality, and conditional deletion of Gab1 shows a role for Gab1 in promoting extracellular signal-regulated kinase (ERK) activation in hepatic function. 4,5 Gab1 acts as an adapter protein to link gp130 signaling to the ERK pathway. 6 In contrast, Gab3 knockout mice do not show major phenotypes. 2 Gab2 is tyrosine phosphorylated by several early-acting cytokine receptors such as flt3, c-Kit, IL-3R, and c-Mpl, and contains proline-rich and pleckstrin homology (PH) domains that promote binding to signaling molecules. 1,7,8 This cytokine activation profile is very similar to STAT5. Gab2 activates the PI-3K and MAPK pathways and can regulate hematopoietic cell migration functions. 9 Gab proteins also contain a large number of consensus serine/...

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“…Alternatively, a lower threshold for total PI3K signaling may be required for presentation function in the MLR vs BCRmediated presentation, the latter of which may be more sensitive to partial reductions in 3-phosphoinositide production. Given the lethality of p110␣ or p110␤ deletion (48,49), future studies using other isoform-specific inhibitors and/or cell-specific gene disruption using cre-loxP system will be needed to study the function of these isoforms in Ag presentation.…”

Section: Discussionmentioning

confidence: 99%

Requirement for Phosphoinositide 3-Kinase p110δ Signaling in B Cell Antigen Receptor-Mediated Antigen Presentation

Al‐Alwan

Okkenhaug

Vanhaesebroeck

et al. 2007

The Journal of Immunology

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The BCR serves to both signal cellular activation and enhance uptake and presentation of Ags by B cells; however, the intracellular signaling mechanisms linking the BCR to Ag presentation functions have been controversial. PI3Ks are critical signaling enzymes controlling many cellular processes, with the p110δ isoform playing a critical role in BCR signaling. In this study, we used pharmacological and genetic approaches to evaluate the role of p110δ signaling in Ag presentation by primary B lymphocytes. It was found that activation of allogeneic T cells is significantly reduced when B cells are pretreated with global PI3K inhibitors, but was intact when p110δ signaling was specifically inactivated. In contrast, inactivation of p110δ significantly impaired the ability of B cells to activate T cells in a BCR-mediated Ag uptake and presentation model. Prestimulation of p110δ-inactivated B cells with anti-CD40 or LPS could not rescue their BCR-mediated Ag presentation ability to normal levels. p110δ signaling was required for efficient presentation of either anti-Ig or protein Ag via a lysozyme-specific BCR. p110δ-inactivated B cells were able to internalize Ag normally, and no defects in association of Ag with lysosome-associated membrane protein 1+ late endosomes were observed; however, these cells were less effective in forming polarized conjugates with Ag-specific T cells. Our data demonstrate a role for p110δ signaling in B cell Ag presentation function, implicating 3-phosphoinositides and their targets in the latter stages of this process.

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Early embryonic lethality in mice deficient in the p110β catalytic subunit of PI 3-kinase

Cited by 175 publications

References 22 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

Abnormal hematopoiesis in Gab2 mutant mice

Requirement for Phosphoinositide 3-Kinase p110δ Signaling in B Cell Antigen Receptor-Mediated Antigen Presentation

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