Nuclear phospholipase C: Involvement in signal transduction (original) (raw)
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Regulation of nuclear phospholipase C activity
2004
A body of evidence, linking inositide-specific phospholipase C (PI-PLC) to the nucleus, is quite extensive. The main isoform in the nucleus is PI-PLCb1, whose activity is up-regulated in response to insulin-like growth factor-1 (IGF-1) or insulin stimulation. Whilst at the plasma membrane this PI-PLC is activated and regulated by Gaq/a 11 and Gbg subunits, there is yet no evidence that qa/a 11 is present within the nuclear compartment, neither GTP-g-S nor AlF4 can stimulate PI-PLCb1 activity in isolated nuclei. Here we review the evidence that upon occupancy of type 1 IGF receptor there is translocation to the nucleus of phosphorylated mitogen-activated protein kinase (MAPK) which phosphorylates nuclear PI-PLCb1 and triggers its signalling, hinting at a separate pathway of regulation depending on the subcellular location of PI-PLCb1. The difference in the regulation of the activity of PI-PLCb1mirrors the evidence that nuclear and cytoplasmatic inositides can differ markedly in their signalling capability. Indeed, we do know that agonists which affect nuclear inositol lipid cycle at the nucleus do not stimulate the one at the plasma membrane.
Nuclear Inositide Signaling Via Phospholipase C
Journal of Cellular Biochemistry, 2017
The existence of an independent nuclear inositide pathway distinct from the cytoplasmic one has been demonstrated in different physiological systems and in diseases. In this prospect we analyze the role of PI-PLCb1 nuclear isoform in relation to the cell cycle regulation, the cell differentiation, and different physiopathological pathways focusing on the importance of the nuclear localization from both molecular and clinical point of view. PI-PLCb1 is essential for G1/S transition through DAG and Cyclin D3 and plays also a central role in G2/M progression through Cyclin B1 and PKCa. In the differentiation process of C2C12 cells PI-PLCb1 increases in both myogenic differentiation and osteogenic differentiation. PI-PLCb1 and Cyclin D3 reduction has been observed in Myotonic Dystrophy (DM) suggesting a pivotal role of these enzymes in DM physiopathology. PI-PLCb1 is also involved in adipogenesis through a double phase mechanism. Moreover, PI-PLCb1 plays a key role in the normal hematopoietic differentiation where it seems to decrease in erythroid differentiation and increase in myeloid differentiation. In Myelodysplastic Syndromes (MDS) PI-PLCb1 has a genetic and epigenetic relevance and it is related to MDS patients' risk of Acute Myeloid Leukemia (AML) evolution. In MDS patients PI-PLCb1 seems to be also a therapeutic predictive outcome marker. In the central nervous system, PI-PLCb1 seems to be involved in different pathways in both brain cortex development and synaptic plasticity related to different diseases. Another PI-PLC isozyme that could be related to nuclear activities is PI-PLCz that is involved in infertility processes.
Physiology and pathology of nuclear phospholipase C β1
Advances in Enzyme Regulation, 2011
The existence and function of inositide signaling in the nucleus is well documented and we know that the existence of the inositide cycle inside the nucleus has a biological role. An autonomous lipid-dependent signaling system, independently regulated from its plasma membrane counterpart, acts in the nucleus and modulates cell cycle progression and differentiation.We and others focused on PLCβ1, which is the most extensively investigated PLC isoform in the nuclear compartment. PLCβ1 is a key player in the regulation of nuclear inositol lipid signaling, and, as discussed above, its function could also be involved in nuclear structure because it hydrolyses PtdIns(4,5)P2, a well accepted regulator of chromatin remodelling. The evidence, in a number of patients with myelodysplastic syndromes, that the mono-allelic deletion of PLCβ1 is associated with an increased risk of developing acute myeloid leukemia paves the way for an entirely new field of investigation. Indeed the genetic defect evidenced, in addition to being a useful prognostic tool, also suggests that altered expression of this enzyme could have a role in the pathogenesis of this disease, by causing an imbalance between proliferation and apoptosis. The epigenetics of PLCβ1 expression in MDS has been reviewed as well.
Nuclear phospholipase C beta1 and cellular differentiation
Frontiers in Bioscience, 2008
Introduction 3. Nuclear phosphoinositides 3.1. The cycle of nuclear phosphoinositides 4. Roles and regulation of nuclear phosphoinositides and PI-PLC beta1 4.1. PIP 2 and chromatin remodeling 4.2. PI-PLC 4.3. PI-PLC beta1 is present in the nucleus, in nuclear speckles 4.4. Nuclear PI-PLC beta1 has a role in mitogenesis 4.5. Regulation of PI-PLC beta1 5. Role of PI-PLC beta1 in cellular differentiation 5.1. PI-PLC beta1 in mouse erythroleukemia 5.2. PI-PLC beta1 in muscle cells differentiation 6. Perspective 7. Acknowledgements 8. References
Phosphoinositide-specific phospholipase C (PI-PLC) β1 and nuclear lipid-dependent signaling
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2006
Over the last years, evidence has suggested that phosphoinositides, which are involved in the regulation of a large variety of cellular processes both in the cytoplasm and in the plasma membrane, are present also within the nucleus. A number of advances has resulted in the discovery that phosphoinositide-specific phospholipase C signalling in the nucleus is involved in cell growth and differentiation. Remarkably, the nuclear inositide metabolism is regulated independently from that present elsewhere in the cell. Even though nuclear inositol lipids hydrolysis generates second messengers such as diacylglycerol and inositol 1,4,5-trisphosphate, it is becoming increasingly clear that in the nucleus polyphosphoinositides may act by themselves to influence pre-mRNA splicing and chromatin structure. Among phosphoinositide-specific phospholipase C, the beta(1) isoform appears to be one of the key players of the nuclear lipid signaling. This review aims at highlighting the most significant and up-dated findings about phosphoinositide-specific phospholipase C beta(1) in the nucleus.
Molecular and Cellular Biology, 2001
It is well established that a phosphoinositide (PI) cycle which is operationally distinct from the classical plasma membrane PI cycle exists within the nucleus, where it is involved in both cell proliferation and differentiation. However, little is known about the regulation of the nuclear PI cycle. Here, we report that nucleus-localized phospholipase C (PLC) 1, the key enzyme for the initiation of this cycle, is a physiological target of extracellular signal-regulated kinase (ERK). Stimulation of Swiss 3T3 cells with insulin-like growth factor I (IGF-I) caused rapid nuclear translocation of activated ERK and concurrently induced phosphorylation of nuclear PLC 1, which was completely blocked by the MEK inhibitor PD 98059. Coimmunoprecipitation detected a specific association between the activated ERK and PLC 1 within the nucleus. In vitro studies revealed that recombinant PLC 1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by PKA. The ERK phosphorylation site was mapped to serine 982, which lies within a PSSP motif located in the characteristic carboxy-terminal tail of PLC 1. In cells overexpressing a PLC 1 mutant in which serine 982 is replaced by glycine (S982G), IGF-I failed to activate the nuclear PI cycle, and its mitogenic effect was also markedly attenuated. Expression of S982G was found to inhibit ERK-mediated phosphorylation of endogenous PLC 1. This result suggests that ERK-evoked phosphorylation of PLC 1 at serine 982 plays a critical role in the activation of the nuclear PI cycle and is also crucial to the mitogenic action of IGF-I.
Nuclear inositide specific phospholipase C signalling - interactions and activity
FEBS Journal, 2013
Evidence accumulated over the past 20 years has highlighted the presence of an autonomous nuclear inositol lipid metabolism, and suggests that lipid signalling molecules are important components of signalling pathways operating within the nucleus. Nuclear polyphosphoinositide (PI) signalling relies on the synthesis and metabolism of phosphatidylinositol 4,5-bisphosphate, which can modulate the activity of effector proteins and is a substrate of signalling enzymes. The regulation of the nuclear PI pool is totally independent from the plasma membrane counterpart, suggesting that the nucleus constitutes a functionally distinct compartment of inositol lipids metabolism. Among the nuclear enzymes involved in PI metabolism, inositide specific phospholipase C (PI-PLC) has been one of the most extensively studied. Several isoforms of PI-PLCs have been identified in the nucleus, namely PI-PLC-b1, c1, d1 and f; however, the b1 isozyme is the best characterized. In the present review, we focus on the signal transduction-related metabolism of nuclear PI-PLC and review the most convincing evidence for PI-PLC expression and activity being involved in differentiation and proliferation programmes in several cell systems. Moreover, nuclear PI-PLC is an intermediate effector and interactor for nuclear inositide signalling. The inositide cycle exists and shows a biological role inside the nucleus. It is an autonomous lipid-dependent signalling system, independently regulated with respect to the one at the plasma membrane counterpart, and is involved in cell cycle progression and differentiation.