Phosphatidylinositol 3-Kinase C2α Contains a Nuclear Localization Sequence and Associates with Nuclear Speckles

Didichenko, Svetlana A.; Thelen, Marcus

doi:10.1074/jbc.m104610200

Cited by 94 publications

(75 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The significance of nuclear PI3 kinases was highlighted by a report that linked nuclear PI3 kinase activity to cyclin D1 expression (51). Other studies have shown that nuclear PI3 kinases localize with subnuclear structures known as nuclear speckles, which contain elements of both transcriptional and pre-mRNA processing machinery (50,52,53). One could speculate that PI3 kinase and its phosphoinositide products may be involved in the arrangement of ordered nuclear structures that facilitate RNA pol II binding to promoters, as shown here, as well as subsequent RNA pol II complex formation, transcriptional elongation, and RNA splicing.…”

Section: Discussionmentioning

confidence: 96%

A Permissive Role for Phosphatidylinositol 3-Kinase in the Stat5- mediated Expression of Cyclin D2 by the Interleukin-2 Receptor

Moon

Rubio

Martino

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

The interleukin-2 (IL-2) receptor promotes T cell proliferation in part by inducing the expression of D-type cyclins, which enable cells to progress from the G 1 to S phase of the cell cycle. We previously showed that the IL-2 receptor induces expression of cyclin D2 by activating the transcription factor Stat5, which binds directly and immediately to a site upstream of the cyclin D2 promoter. We show here that subsequent transcription of the cyclin D2 gene occurs by a delayed, cycloheximide-sensitive mechanism, which implies the involvement of additional regulatory mechanisms. The transcription factor c-Myc is induced by Stat5 and is reported to bind to two E box motifs in the cyclin D2 promoter. However, in IL-2-stimulated T cells, c-Myc does not appear to be involved in cyclin D2 induction, since we found that these two E boxes are preferentially bound by USF-1 and USF-2 and, moreover, are dispensable for cyclin D2 promoter activity. Instead, we found that Stat5 activates the phosphatidylinositol 3-kinase (PI3 kinase) pathway by a delayed, cycloheximide-sensitive mechanism and that PI3 kinase activity is essential for the induction of cyclin D2 by Stat5. Chromatin immunoprecipitation experiments revealed that PI3 kinase is required for the optimal binding of RNA polymerase II to the promoters of cyclin D2 as well as other genes. Our results reveal a novel link between PI3 kinase and RNA polymerase II promoter binding activity and demonstrate discrete, coordinated roles for the PI3 kinase and Stat5 pathways in cyclin D2 transcription.

show abstract

Section: Discussionmentioning

confidence: 96%

A Permissive Role for Phosphatidylinositol 3-Kinase in the Stat5- mediated Expression of Cyclin D2 by the Interleukin-2 Receptor

Moon

Rubio

Martino

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…These interchromatin granule clusters contain factors involved in the transcription and processing of pre-mRNA, including RNA polymerase II and splicing factors, and some elements of the PI cycle. PtdIns(4,5)P 2 , PtdIns(4)P 5-kinases (I␣ and II␣), and class II PI3K C2␣ were shown to be associated with nuclear speckles (23,43,44). These results are very intriguing, because class II PI3K is unable to phosphorylate PtdIns(4,5)P 2 whereas active SHIP-2 dephosphorylates PtdIns(3,4,5)P 3 .…”

Section: Discussionmentioning

confidence: 99%

SHIP-2 and PTEN Are Expressed and Active in Vascular Smooth Muscle Cell Nuclei, but Only SHIP-2 Is Associated with Nuclear Speckles

Déléris

Bacqueville

Gayral

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Recently, the control of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P 3 )-dependant signaling by phosphatases has emerged, but there is a shortage of information on intranuclear PtdIns(3,4,5)P 3 phosphatases. Therefore, we investigated the dephosphorylation of [ 32 P]PtdIns(3,4,5)P 3 specifically labeled on the D-3 position of the inositol ring in membrane-free nuclei isolated from pig aorta vascular smooth muscle cells (VSMCs). In vitro PtdIns(3,4,5)P 3 phosphatase assays revealed the production of both [ 32 P]PtdIns(3,4)P 2 and inorganic phosphate, demonstrating the presence of PtdIns(3,4,5)P 3 5-and 3-phosphatase activities inside the VSMC nucleus, respectively. Both activities presented the same potency in cellular lysates, whereas the nuclear PtdIns(3,4,5)P 3 5-phosphatase activity appeared to be the most efficient. Immunoblot experiments showed for the first time the expression of the 5-phosphatase SHIP-2 (src homology 2 domain-containing inositol phosphatase) as well as the 3-phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) in VSMC nuclei. In addition, immunoprecipitations from nuclear fractions indicated a [ 32 P]PtdIns(3,4,5)P 3 dephosphorylation by both SHIP-2 and PTEN. Moreover, confocal microscopy analyses demonstrated that SHIP-2 but not PTEN colocalized with a speckle-specific component, the SC35 splicing factor. These results suggest that SHIP-2 may be the primary enzyme for metabolizing PtdIns(3,4,5)P 3 into PtdIns(3,4)P 2 within the nucleus, thus producing another second messenger, whereas PTEN could down-regulate nuclear phosphoinositide 3-kinase signaling. Finally, intranuclear PtdIns(3,4,5)P 3 phosphatases might be involved in the control of VSMC proliferation and the pathogenesis of vascular proliferative disorders.Vascular smooth muscle cell (VSMC) 1 migration and proliferation are key factors in the development of atherosclerosis, post-angioplasty restenosis, and transplant vasculopathy (1, 2). We showed previously that phosphoinositide 3-kinase (PI3K) is essential for the VSMC cycle (3), and this enzyme was implicated recently in restenosis (4). PI3Ks make up a large family of lipid kinases, but class I PI3Ks are the most well known (5-7). They convey both growth and survival signals from activated receptors; class IA PI3K (␣, ␤, and ␦) is regulated by receptors with intrinsic or associated-tyrosine kinase activity, whereas the class IB or PI3K␥ is activated by G protein-coupled receptors. PI3Ks catalyze phosphorylation of phosphoinositides (PIs) at the D-3 position of the inositol ring to generate two potent second messengers, phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P 2 ) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ), which regulate downstream effectors such as the serine/threonine protein kinases PKB (also called Akt) and PKC , and control many cellular responses involved in neointimal hyperplasia and restenosis, including cell proliferation, migration, and survival (8, 9).Because 3-phosphoinositides (3-PIs) are not hydr...

show abstract

“…However, when fluorescent proteins that bind PtdIns(3)P are expressed in cells, they label endosomes and not the plasma membrane (32,92,318), suggesting that there is little free PtdIns(3)P at the cell surface. There is a recent report that PtdIns3KIIC2␣ localizes to the nucleus rather than the plasma membrane (77). More work is required to determine how PtdIns3KIIC2␣ functions in membrane traffic and to what extent PtdIns(3)P is involved in membrane traffic from the plasma membrane.…”

Section: Ptdins3kiic2␣mentioning

confidence: 99%

Phosphoinositides in Constitutive Membrane Traffic

Roth

2004

Physiological Reviews

267

View full text Add to dashboard Cite

Proteins that make, consume, and bind to phosphoinositides are important for constitutive membrane traffic. Different phosphoinositides are concentrated in different parts of the central vacuolar pathway, with phosphatidylinositol 4-phosphate predominate on Golgi, phosphatidylinositol 4,5-bisphosphate predominate at the plasma membrane, phosphatidylinositol 3-phosphate the major phosphoinositide on early endosomes, and phosphatidylinositol 3,5-bisphosphate found on late endocytic organelles. This spatial segregation may be the mechanism by which the direction of membrane traffic is controlled. Phosphoinositides increase the affinity of membranes for peripheral membrane proteins that function for sorting protein cargo or for the docking and fusion of transport vesicles. This implies that constitutive membrane traffic may be regulated by the mechanisms that control the activity of the enzymes that produce and consume phosphoinositides. Although the lipid kinases and phosphatases that function in constitutive membrane traffic are beginning to be identified, their regulation is poorly understood.

show abstract

Phosphatidylinositol 3-Kinase C2α Contains a Nuclear Localization Sequence and Associates with Nuclear Speckles

Cited by 94 publications

References 52 publications

A Permissive Role for Phosphatidylinositol 3-Kinase in the Stat5- mediated Expression of Cyclin D2 by the Interleukin-2 Receptor

A Permissive Role for Phosphatidylinositol 3-Kinase in the Stat5- mediated Expression of Cyclin D2 by the Interleukin-2 Receptor

SHIP-2 and PTEN Are Expressed and Active in Vascular Smooth Muscle Cell Nuclei, but Only SHIP-2 Is Associated with Nuclear Speckles

Phosphoinositides in Constitutive Membrane Traffic

Contact Info

Product

Resources

About