A Novel Class II Phosphoinositide 3-Kinase Predominantly Expressed in the Liver and Its Enhanced Expression during Liver Regeneration (original) (raw)
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Activation of phosphoinositide 3-kinase C2β in the nuclear matrix during compensatory liver growth
Advances in Enzyme Regulation, 2006
In the nuclear matrix harvested 20 h after partial hepatectomy, an increase in immunoprecipitable PI3K-C2b activity is observed, which is sensitive to wortmannin (10 Mm) and shows strong preference for PtdIns over PtdIns(4)P as a substrate. On western blots PI3K-C2b revealed a single immunoreactive band of 180 kD, whereas 20 h after partial hepatectomy gel shift of 18 kDa was noticed in the nuclear matrix, suggesting that observed activation of enzyme is achieved by proteolysis. As it is know that PI3K-C2a is associated with nuclear speckles [Didichenko SA, Thelen M. Phosphatidylinositol 3-kinase C2a contains a nuclear localization sequence and associates with nuclear speckles. J Biol Chem 2001;276:48135-42.], the data presented in this report show that in the nuclear matrix PI3K-C2b is activated during the compensatory liver growth, which clearly demonstrates that different class II PI3K enzymes have different subnuclear localization and therefore might have different intranuclear functions. r
1998 Phosphoinositide 3-Kinase in Rat Liver Nuclei
Biochemical and immunochemical data from the present investigation reveal the existence of a p85/p110 phosphoinositide 3-kinase (PI 3-kinase) in rat liver nuclei. 32 P-Labeling of membrane phosphoinositides by incubating intact nuclei with [γ-32 P]ATP results in the formation of [ 32 P]phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P 3 ], accompanied by small quantities of [ 32 P]phosphatidylinositol 3-phosphate [PtdIns(3)P]. Studies with subnuclear fractions indicate that the PI 3-kinase is not confined to nuclear membranes. The nuclear soluble fraction also contains PI 3-kinase and an array of inositidemetabolizing enzymes, including phospholipase C (PLC), phosphoinositide phosphatase, and diacylglycerol (DAG) kinase. As a result, exposure of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P 2 ] to the nuclear extract in the presence of [γ-32 P]ATP generates a series of 32 P-labeled D-3 phosphoinositides and phosphatidic acid (PA) in an interdependent manner. On the basis of the immunological reactivity and kinetic behavior, the nuclear PI 3-kinase is analogous, if not identical, to PI 3-kinase R, and constitutes about 5% of the total PI 3-kinase in the cell. Moreover, we test the premise that nuclear PI 3-kinase may, in part, be regulated through the control of substrate availability by PtdIns(4,5)P 2 -binding proteins. Effect of CapG, a nuclear actin-regulatory protein, on PI 3-kinase activity is examined in view of its unique Ca 2+ -dependent PtdIns(4,5)P 2 -binding capability. In vitro data show that the CapG-mediated inhibition of nuclear PI 3-kinase is prompted by PKC phosphorylation of CapG and elevated [Ca 2+ ]. This CapGdependent regulation provides a plausible link between nuclear PLC and PI 3-kinase pathways for crosscommunications. Taken together, these findings provide definite data concerning the presence of an autonomous PI 3-kinase cycle in rat liver nuclei. The nuclear location of PI 3-kinase may lead to a better understanding regarding its functional role in transducing signals from the plasma membrane to the nucleus in response to diverse physiological stimuli.
PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy
American Journal of Physiology-gastrointestinal and Liver Physiology, 2008
Hepatic resection is associated with rapid proliferation and regeneration of the remnant liver. Phosphatidylinositol 3-kinase (PI3K), composed of a p85α regulatory and a p110α catalytic subunit, participates in multiple cellular processes, including cell growth and survival; however, the role of PI3K in liver regeneration has not been clearly delineated. In this study, we used the potent PI3K inhibitor, wortmannin, and small-interfering RNA (siRNA) targeting the p85α and p110α subunits to determine if total or selective PI3K inhibition would abrogate the proliferative response of the liver after partial hepatectomy in mice. Hepatic resection is associated with an induction in PI3K activity; total PI3K blockade with wortmannin, and selective inhibition of p85α or p110α with siRNA resulted in a significant decrease in hepatocyte proliferation, especially at the earliest timepoints. Fewer macrophages and Kupffer cells were present in the regenerating liver of mice treated with wortmannin or siRNA to p85α or p110α, as reflected by a paucity of F4/80-positive cells. Additionally, PI3K inhibition led to an aberrant architecture in the regenerating hepatocytes characterized by vacuolization, lipid deposition, and glycogen accumulation; these changes were not noted in the sham livers. Our data demonstrate that PI3K/Akt pathway activation plays a critical role in the early regenerative response of the liver after resection; inhibition of this pathway markedly abrogates the normal hepatic regenerative response, most likely by inhibiting macrophage infiltration and cytokine elaboration and thus hepatocyte priming for replication.
Biochemical and Biophysical Research Communications, 1992
We have examined the levels of gene expressions and activities of protein phosphatases,PPl and PP2A, in rat regenerating livers. PPI~ mRNA started to increase from 6 h after partial hepatectomy (PH) and showed two peaks at 12 and 48 h. PP2A mRNA level showed two peaks at 6 and 10~12 h. Protein phosphatase activities were determined both in non-nuclear fraction and in nuclei. While spontaneous PPI activity in non-nuclear fraction was nearly constant, potential PPI activity revealed by Co2+-trypsin treatment showed a small peak between 7 and 12 h. In nuclei, both spontaneous and potential PPI activity began to increase from 447 h after PH, reached a maximum (about 2.5-fold over control levels) at 12 h, the time which corresponds to the G1 to S transition in the cell cycle, and then declined back to control levels by 7 days. PP2A activity in non-nuclear fraction was nearly constant in both spontaneous and potential forms. PP2A activity in both forms in nuclei was very low throughout. These results suggest the possibility that PPI in nuclei plays some role in the G1 to S transition in the cell cycle of hepatocyte proliferation.
Biochemical and Biophysical Research Communications, 1996
Primary hepatocytes respond to the proliferating signals of Hepatocyte Growth Factor (HGF) through activation of the tyrosine kinase activity of the met (p 145) receptor. Addition of dHGF in hepatocyte cultures resulted in receptor phosphorylation which co-precipitated with a phosphorylated protein of 85 kDa. This protein was identified as the regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase). Co-precipitation of the PI 3-kinase regulatory subunit with the met receptor was observed only with the phosphorylated receptor. Wortmanin, which specifically inhibits PI 3-kinase, was found to abolish the hepatocyte DNA synthetic response due to stimulation with dHGF. It is suggested that the D-3-phosphorylated inositol phospholipids participate as major regulators in the growth and differentiation factor-initiated cascades, this not being restricted to primary hepatocytes.
The Role of Phosphoinositide 3-Kinase Signaling in
2012
The phosphatidylinositol 3-kinase signaling pathway plays a central role in regulating the host inflammatory response. The net effect can either be pro-or anti-inflammatory depending on the system and cellular context studied. This paper focuses on phosphatidylinositol 3-kinase signaling in innate and adaptive immune cells of the intestinal mucosa. The role of phosphatidylinositol 3kinase signaling in mouse models of inflammatory bowel disease is also discussed. With the development of new isoform specific inhibitors, we are beginning to understand the specific role of this complex pathway, in particular the role of the γ isoform in intestinal inflammation. Continued research on this complex pathway will enhance our understanding of its role and provide rationale for the design of new approaches to intervention in chronic inflammatory conditions such as inflammatory bowel disease.
PI3 kinase/Akt Pathways in a Murine Hepatocyte Cell Line
Abbreviations. LPA, Lysophosphatidic acid; S1P, sphingosine-1-phosphate; Erk1/Erk2, extracellular signal regulated kinases; MAP kinase, mitogen activated kinase; PI-3 kinase, phosphatidylinositol-3-phosphate kinase; Akt, protein kinase B, Edg, endothelial differentiation gene; TGF-α, transforming growth factor-α; TNF-α, tumor necrosis factor-α 3
The phosphoinositide (PI) 3-kinase family
Journal of Cell Science, 2003
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