Tyrosine-phosphorylation-dependent and Rho-protein-mediated control of cellular phosphatidylinositol 4,5-bisphosphate levels

Rümenapp, Ulrich; Schmidt, Martina; Olesch, Simone; Ott, Sabine; Eichel‐Streiber, Christoph von; Jakobs, Karl H.

doi:10.1042/bj3340625

Cited by 29 publications

(27 citation statements)

References 37 publications

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“…This effect could be explained by the ability of Src to modulate the amount of PLC substrate, PIP 2 . It has been previously reported that tyrosine kinase inhibition leads to a rapid decrease of cellular PIP 2 levels in HEK-293 cells (15). The resynthesis of PIP 2 occurs in a sustained fashion in nonstimulated cells and very rapidly after PLC hydrolysis (26).…”

Section: Discussionmentioning

confidence: 99%

“…Inositol phosphate production reflects PLC activity, which in turn depends on the availability of the substrate PIP 2 (5). Because tyrosine kinase inhibition may significantly reduce levels of PIP 2 (15), amounts of PIP 2 in control and PP1 (10 M)-treated cells were measured. No effect of PP1 was detected when the whole pool of phosphoinositides was assayed (data not shown).…”

Section: Src Activity Regulates 5-ht-induced Asm Cell Contractionmentioning

confidence: 99%

“…However, the majority of GPCRs are known to be linked to the ␤-isoform of PLC (PLC-␤), and activation of 5-HT receptors in rat tracheal smooth muscle cells, as well as of several types of GPCRs in A10 vascular smooth muscle cells, does not appear to result in PLC-␥ tyrosine phosphorylation despite the observed reductions in Ca 2ϩ signals after tyrosine kinase inhibition (6,24). Regardless of how and which PLC isoform is activated, the availability of its substrate phosphatidylinositol 4,5-bisphosphate (PIP 2 ) is an important determinant of inositol phosphate production (5,18), and it has been reported that PIP 2 levels may be controlled by tyrosine kinase activity (15). However, the kinase involved in this process was not identified, and the effects of lowering PIP 2 levels by tyrosine kinase inhibitors on Ca 2ϩ signaling were not studied.…”

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confidence: 99%

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Src modulates serotonin-induced calcium signaling by regulating phosphatidylinositol 4,5-bisphosphate

Tolloczko

Turkewitsch

Choudry

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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We tested the hypothesis that, in airway smooth muscle cells, stimulation of G-protein-coupled receptors by contractile agonists activates Src kinase and that this kinase modulates cell contractility and Ca2+ signaling by affecting the levels of the phospholipase C substrate phosphatidylinositol 4,5-bisphosphate (PIP2). Stimulation of cultured rat tracheal smooth muscle cells with serotonin (5-HT) induced an increase in Src activity, Ca2+ mobilization, and contraction (decrease in cell area). 5-HT-evoked cell contraction was reduced by a specific inhibitor of Src family kinases, 4-amino-5(4-methylphenyl)-7-( t-butyl)pyrazolo[3,4 -d]pyrimidine (PP1). Peak Ca2+ responses to 5-HT were attenuated by PP1 and an anti-Src-blocking antibody and augmented by expression of constitutively activated Y529F Src. Sustained phases of Ca2+ responses to 5-HT and Ca2+ influx resulting from emptying of Ca2+ stores in the endoplasmic reticulum by thapsigargin were also decreased after PP1 treatment. PP1 significantly reduced the turnover of inositol phosphates produced on 5-HT stimulation and the amount of PIP2 in the Triton X-100-insoluble lipid fraction. Overall, these data demonstrate that, in rat tracheal smooth muscle cells, Src kinase modulates 5-HT-evoked cell contractility and Ca2+ signaling by regulating PIP2 levels and Ca2+ influx.

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Section: Discussionmentioning

confidence: 99%

Section: Src Activity Regulates 5-ht-induced Asm Cell Contractionmentioning

confidence: 99%

mentioning

confidence: 99%

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Src modulates serotonin-induced calcium signaling by regulating phosphatidylinositol 4,5-bisphosphate

Tolloczko

Turkewitsch

Choudry

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Large clostridial toxins, such as Clostridium difficile toxin B and toxin A, also block PLD activity induced by PMA, or GTP [S] in vitro, probably by reducing PI4-P 5-kinase activity and decreasing PIP 2 level (Schmidt et al, 1996a;Rümenapp et al, 1998). Indeed, PLD, which contains a PH (pleckstrin homology) domain and a PX (Phox homology) domain, as well as binding sites for phospholipids, has been reported to anchor to PIP 2 where it is close to its substrates (Frohman and Morris, 1999).…”

Section: Toxins That Modulate Host Pld Activity Via Small Gtpasesmentioning

confidence: 99%

Bacterial protein toxins and lipids: role in toxin targeting and activity

Geny

Popoff

2006

Biology of the Cell

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All bacterial toxins, which globally are hydrophilic proteins, interact first with their target cells by recognizing a surface receptor, which is either a lipid or a lipid derivative, or another compound but in a lipid environment. Intracellular active toxins follow various trafficking pathways, the sorting of which is greatly dependent on the nature of the receptor, notably lipidic receptor or receptor embedded into a distinct environment such as lipid microdomains. Numerous other toxins act locally on cell membrane. Indeed, phospholipase activity is a common mechanism shared by several membrane‐damaging toxins. In addition, many toxins active intracellularly or on cell membrane modulate host cell phospholipid pathways. Unusually, a few bacterial toxins require a lipid post‐translational modification to be active. Thereby, lipids are obligate partners of bacterial toxins.

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“…PI(3,4,5)P 3 may affect Ca 2ϩ release by increasing activity of the gamma isoform of PLC (PLC␥) either directly through binding to the pleckstrin homology domain (Falasca et al, 1998) and the Src homology (SH2) domain (Rameh et al, 1998), or indirectly after activating Bruton's kinase Btk (Li et al, 1997). PI(3,4,5)P 3 has been also implicated in the activation of small GTPase proteins from the Rho family, which in turn stimulate production of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] through activation of PI(4)5-kinase (Smith and Chang, 1989;Hartwig et al, 1995;Tolias et al, 1995;Ren et al, 1996;Carpenter et al, 1997;Rumenapp et al, 1998). Because PI3K uses PI(4,5)P 2 as a substrate, activation of PI3K may potentially have two opposing effects: it may cause a decrease in PI(4,5)P 2 levels (by using it as a substrate) and increase in PI(4,5)P 2 levels by modulating the activity of PI(4)5-kinase.…”

mentioning

confidence: 99%

LY-294002 [2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] Affects Calcium Signaling in Airway Smooth Muscle Cells Independently of Phosphoinositide 3-Kinase Inhibition

Tolloczko

Turkewitsch²,

Al-Chalabi³

et al. 2004

J Pharmacol Exp Ther

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Phosphoinositide 3-kinase (PI3K) may potentially influence intracellular [Ca 2ϩ ] i concentration by several mechanisms. We have investigated the effects of phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and LY-294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] on Ca 2ϩ signaling in rat airway smooth muscle (ASM) cells using fura-2 and imaging methodology. Wortmannin (1 M) and LY-294002 (1 and 10 M) had opposite effects: wortmannin caused a small increase, whereas LY-294002 caused a significant decrease of peak Ca 2ϩ responses to serotonin (5-HT). LY-294002 (10 M) diminished 5-HT-induced ASM cell contraction, measured as a change in cell surface area, and inositol phosphate formation, measured by anion exchange chromatography. Thin layer chromatography revealed that the levels of phospholipase C (PLC) substrate phosphatidylinositol 4,5-bisphosphate were not affected. SDS polyacrylamide gel electrophoresis and Western blotting have shown that both wortmannin and LY-294002 inhibited plateletderived growth factor-induced PI3K activation. However, PI3K activation could not be detected after 5-HT stimulation. The specific casein kinase-2 (CK2) inhibitor 5,6-dichloro-1-␤-D-ribofuranosyl-benzimidazole (10 -40 M) reduced 5-HT-triggered responses to a similar extent as LY-294002. We conclude that LY-294002 modulates Ca 2ϩ signaling in rat ASM independently of its action on PI3K by acting on, or upstream of, PLC, possibly by inhibiting CK2.

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Tyrosine-phosphorylation-dependent and Rho-protein-mediated control of cellular phosphatidylinositol 4,5-bisphosphate levels

Cited by 29 publications

References 37 publications

Src modulates serotonin-induced calcium signaling by regulating phosphatidylinositol 4,5-bisphosphate

Src modulates serotonin-induced calcium signaling by regulating phosphatidylinositol 4,5-bisphosphate

Bacterial protein toxins and lipids: role in toxin targeting and activity

LY-294002 [2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] Affects Calcium Signaling in Airway Smooth Muscle Cells Independently of Phosphoinositide 3-Kinase Inhibition

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