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1.
Signalling roles of mammalian phospholipase D1 and D2 总被引:11,自引:0,他引:11
S. Cockcroft 《Cellular and molecular life sciences : CMLS》2001,58(11):1674-1687
Phospholipase D (PLD) catalyses the hydrolysis of phosphatidylcholine to generate the lipid second messenger, phosphatidate
(PA) and choline. PLD activity in mammalian cells is low and is transiently stimulated upon activation by G-protein-coupled
and receptor tyrosine kinase cell surface receptors. Two mammalian PLD enzymes (PLD1 and PLD2) have been cloned and their
intracellular regulators identified as ARF and Rho proteins, protein kinase Cα as well as the lipid, phosphatidylinositol
[4, 5] bisphosphate (PIP2). I discuss the regulation of these enzymes by cell surface receptors, their cellular localisation and the potential function
of PA as a second messenger. Evidence is presented for a role of PA in regulating the lipid kinase activity of PIP 5-kinase,
an enzyme that synthesises PIP2. A signalling role of phospholipase D via PA and indirectly via PIP2 in regulating membrane traffic and actin dynamics is indicated by the available data.
Received 25 April 2001; received after revision 15 June 2001; accepted 15 June 2001 相似文献
2.
The intracellular signaling pathways mediating the nuclear exclusion of the androgen receptor (AR) by melatonin were evaluated
in PC3 cells stably transfected with the AR. The melatonin-induced nuclear exclusion of the AR by melatonin (100 nM, 3 h)
was blocked by LY 83583 (an inhibitor of guanylyl cyclases). 8-Bromo-cGMP (a cell-permeable cGMP analog), mimicked the effect
of melatonin, as did ionomycin (a calcium ionophore) and PMA [an activator of protein kinase C (PKC)], and their effects were
blocked by GF-109203X (a selective PKC inhibitor). BAPTA (an intracellular calcium chelator) blocked the effects of melatonin
and 8-bromo-cGMP but not of PMA. Inhibition or activation of the protein kinase A pathway did not affect basal or melatonin-mediated
AR localization. We conclude that the melatonin-mediated rise in cGMP elicits AR nuclear exclusion via a pathway involving
increased intracellular calcium and PKC activation. These results define a novel signaling pathway that regulates AR localization
and androgen responses in target cells.
Received 31 July 2001; received after revision 18 September 2001; accepted 30 October 2001 相似文献
3.
Cell motility is defined as cell movement in the three-dimensional space leading to repositioning of the cell. Atypical protein kinase C (aPKC, including ζ and λ/ι) are a subfamily of PKC. Different from classic PKC and novel PKC, the activation of atypical PKC is not dependent on diacylglycerol or calcium. PKCζ can be activated by lipid components, such as phosphatidylinositols, phosphatidic acid, arachidonic acid, and ceramide. Both phosphatidylinositol (3,4,5)-trisphosphate and PDK1 are necessary for the complete and stable activation of PKCζ. Atypical PKC is involved in the regulation of cell polarization, directional sensing, formation of filopodia, and cell motility. It is essential for migration and invasion of multiple cancer cell types. Particularly, atypical PKC has been found in the regulation of the motility of hematopoietic cells. It also participates in the regulation of proteolytic activity of podosomes and invadopodia. It has been found that atypical PKC can work coordinately with other PKC subfamily members and other signaling pathways. Research on the roles of atypical PKC in cell motility may lead to new therapeutic strategies for cancer and other diseases. 相似文献
4.
On the basis of evidence collected from the literature, we propose a general model by which protein kinase (PK) A and the
different PKC isoforms can inversely affect cell growth. Molecular switches, which are able to direct the signal towards antiproliferative
or mitogenic pathways, are the different isoforms of Raf and PKC. Conflicting data are also reported and discussed in an attempt
to reconcile them.
Received 10 November 2005; received after revision 28 December 2005; accepted 3 January 2006 相似文献
5.
Silberman DM Zorrilla-Zubilete M Cremaschi GA Genaro AM 《Cellular and molecular life sciences : CMLS》2005,62(15):1744-1754
Chronic stress has been associated with impaired immune function. In this work we studied the effect of chronic mild stress (CMS) exposure on the early intracellular pathways involved in T cells after stimulation with mitogen. We found that mitogen stimulation of T lymphocytes from CMS-exposed mice resulted in a reduction of the intracellular [Ca2+] rise, an impairment of growth-promoting protein kinase C (PKC) activation, a lower NF-κB activation and an increase in the inhibitory cAMP-protein kinase A (PKA) pathway activity with respect to those found in control lymphocytes. However, T cell activation with the direct PKC activator phorbol 12-myristate 13-acetate plus calcium ionophore led to a similar proliferative response in both CMS and control lymphocytes, indicating that signals downstream of PKC would not be affected by stress. In summary, our results show that chronic stress induced an alteration in T cell early transduction signals that result in an impairment of the proliferative response.Received 11 February 2005; received after revision 20 May 2005; accepted 6 June 2005 相似文献
6.
P. J. M. Van Haastert 《Cellular and molecular life sciences : CMLS》1995,51(12):1144-1154
AggregatingDictyostelium cells secrete cAMP during cell aggregation. cAMP induces two fast responses, the production of more cAMP (relay) and directed cell locomotion (chemotaxis). Extracellular cAMP binds to G-protein-coupled receptors leading to the activation of second messenger pathways, including the activation of adenylyl cyclase, guanylyl cyclase, phospholipase C and the opening of plasma membrane Ca2+ channels. Many genes encoding these sensory transduction proteins have been cloned and null mutants of nearly all components have been characterized in detail. Undoubtedly, activation of adenylyl cyclase is the most complex, involving G-proteins, a soluble protein called CRAC and components of the MAP kinase pathway. Null mutants in this pathway do not aggregate, but can exhibit chemotaxis and develop normally when supplied with exogenous cAMP. The pathways leading to the activation of phospholipase C were identified, but unexpectedly, deletion of the phospholipase C gene has no effect on chemotaxis and development, nor on intracellular Ins(1,4,5)P3 levels; the metabolism of this second messenger will be discussed in some detail. Activation of guanylyl cyclase is G-protein-dependent and essential for chemotaxis. Analysis of a collection of chemotactic mutants reveals that most mutants are defective in either the production or intracellular detection of cGMP, thereby placing this second messenger at the center of chemotactic signal transduction. Analysis of the cAMP-mediated opening of plasma membrane calcium channels in signal transduction mutants suggests that it has two components, one that depends on G-proteins and intracellular cGMP and one that is G-protein-independent. 相似文献
7.
Martelli AM Bortul R Tabellini G Bareggi R Manzoli L Narducci P Cocco L 《Cellular and molecular life sciences : CMLS》2002,59(7):1129-1137
Several independent groups have shown that lipid-dependent signal transduction systems operate in the nucleus and that they
are regulated independently from their membrane and cytosolic counterparts. A sizable body of evidence suggests that nuclear
lipid signaling controls critical biological functions such as cell proliferation and differentiation. Diacylglycerol is a
fundamental lipid second messenger which is produced in the nucleus. The levels of nuclear diacylglycerol fluctuate during
the cell cycle progression, suggesting that such a molecule has important regulatory roles. Most likely, nuclear diacylglycerol
serves as a chemoattractant for some isoforms of protein kinase C that migrate to the nucleus in response to a variety of
agonists. The nucleus also contains diacylglycerol kinases, i.e. the enzymes that, by converting diacylglycerol into phosphatidic
acid, terminate diacylglycerol-dependent events. A number of diacylglycerol kinases encoded by separate genes are present
in the mammalian genome. This review aims at highlighting the different isotypes of diacylglycerol kinases identified at the
nuclear level as well as at discussing their potential function and regulation.
Received 4 December 2001; received after revision 28 January 2002; accepted 31 January 2002 相似文献
8.
Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance 总被引:3,自引:0,他引:3
Balaraman Y Limaye AR Levey AI Srinivasan S 《Cellular and molecular life sciences : CMLS》2006,63(11):1226-1235
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading
cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the
serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an important role in
the formation of neurofibrillary tangles and senile plaques, the two classical pathological hallmarks of AD. In this review,
we discuss the interaction between GSK-3β and several key molecules involved in AD, including the presenilins, amyloid precursor
protein, tau, and β-amyloid. We identify the signal transduction pathways involved in the pathogenesis of AD, including Wnt,
Notch, and the PI3 kinase/Akt pathway. These may be potential therapeutic targets in AD.
Received 19 December 2005; received after revision 24 January 2006; accepted 6 February 2006 相似文献
9.
S. P. Yun M. Y. Lee J. M. Ryu H. J. Han 《Cellular and molecular life sciences : CMLS》2009,66(9):1603-1616
Identifying the small molecules that permit precise regulation of embryonic stem (ES) cell proliferation should further support
our understanding of the underlying molecular mechanisms of self renewal. In the present study, we showed that PGE2 increased [3H]-thymidine incorporation in a time and dose dependent manner. In addition, PGE2 increased the expression of cell cycle regulatory proteins, the percentage of cells in S phase and the total number of cells.
PGE2 obviously increased E-type prostaglandin (EP) receptor 1 mRNA expression level compare to 2, 3, 4 subtypes. EP1 antagonist
also blocked PGE2-induced cell cycle regulatory protein expression and thymidine incorporation. PGE2 caused phosphorylation of protine kinase C, Src, epidermal growth factor (EGF) receptor, phosphatidylinositol 3-kinase (PI3K)/Akt
phosphorylation, and p44/42 mitogen-activated protein kinase (MAPK), which were blocked by each inhibitors. In conclusion,
PGE2-stimulated proliferation is mediated by MAPK via EP1 receptor-dependent PKC and EGF receptor-dependent PI3K/Akt signaling
pathways in mouse ES cells.
Received 30 January 2009; received after revision 03 March 2009; accepted 10 March 2009 相似文献
10.
Signaling pathways between the plasma membrane and endoplasmic reticulum calcium stores 总被引:6,自引:0,他引:6
This review discusses multiple ways in which the endoplasmic reticulum participates in and is influenced by signal transduction pathways. The endoplasmic reticulum provides a Ca2+ store that can be mobilized either by calcium-induced calcium release or by the diffusible messenger inositol 1,4,5-trisphosphate. Depletion of endoplasmic reticulum Ca2+ stores provides a signal that activates surface membrane Ca2+ channels, a process known as capacitative calcium entry. Depletion of endoplasmic reticulum stores can also signal long-term cellular responses such as gene expression and programmed cell death or apoptosis. In addition to serving as a source of cellular signals, the endoplasmic reticulum is also functionally and structurally modified by the Ca2+ and protein kinase C pathways. Elevated cytoplasmic Ca2+ causes a rearrangement and fragmentation of endoplasmic reticulum membranes. Protein kinase C activation reduces the storage capacity of the endoplasmic reticulum Ca2+ pool. In some cell types, protein kinase C inhibits capacitative calcium entry. Protein kinase C activation also protects the endoplasmic reticulum from the structural effects of high cytoplasmic Ca2+. The emerging view is one of a complex network of pathways through which the endoplasmic reticulum and the Ca2+ and protein kinase C signaling pathways interact at various levels regulating cellular structure and function. 相似文献
11.
Protein kinase C (PKC) is an important signaling molecule in the heart, but its targets remain unclear. Using a PKC substrate
antibody, we detected a 40-kDa phosphorylated cardiac protein that was subsequently identified by tandem mass spectroscopy
as muscle creatine kinase (M-CK) with phosphorylation at serine 128. The forward reaction using ATP to generate phosphocreatine
was reduced, while the reverse reaction using phosphocreatine to generate ATP was increased following dephosphorylation of
immunoprecipitated M-CK with protein phosphatase 2A (PP2A) or PP2C. Despite higher PKC levels in diabetic hearts, decreased
phosphorylation of M-CK was more prominent than the reduction in its expression. Changes in CK activity in diabetic hearts
were similar to those found following dephosphorylation of M-CK from control hearts. The decrease in phosphorylation may act
as a compensatory mechanism to maintain CK activity at an appropriate level for cytosolic ATP regeneration in the diabetic
heart.
Received 15 September 2008; received after revision 30 September 2008; accepted 13 October 2008 相似文献
12.
Controlling iron/oxygen chemistry in biology depends on multiple genes, regulatory messenger RNA (mRNA) structures, signaling
pathways and protein catalysts. Ferritin, a protein nanocage around an iron/oxy mineral, centralizes the control. Complementary
DNA (antioxidant responsive element/Maf recognition element) and mRNA (iron responsive element) responses regulate ferritin
synthesis rates. Multiple iron-protein interactions control iron and oxygen substrate movement through the protein cage, from
dynamic gated pores to catalytic sites related to di-iron oxygenase cofactor sites. Maxi-ferritins concentrate iron for the
bio-synthesis of iron/heme proteins, trapping oxygen; bacterial mini-ferritins, DNA protection during starvation proteins,
reverse the substrate roles, destroying oxidants, trapping iron and protecting DNA. Ferritin is nature’s unique and conserved
approach to controlled, safe use of iron and oxygen, with protein synthesis in animals adjusted by dual, genetic DNA and mRNA
sequences that selectively respond to iron or oxidant signals and link ferritin to proteins of iron, oxygen and antioxidant
metabolism.
Received 25 June 2005; received after revision 17 October 2005; accepted 25 November 2005 相似文献
13.
Elena Rapizzi Maria Letizia Taddei Tania Fiaschi Chiara Donati Paola Bruni Paola Chiarugi 《Cellular and molecular life sciences : CMLS》2009,66(19):3207-3218
Sphingosine 1-phosphate (S1P) is a bioactive lipid that acts through a family of G-protein-coupled receptors. Herein, we report
evidence of a novel redox-based cross-talk between S1P and insulin signaling pathways. In skeletal muscle cells S1P, through
engagement of its S1P2 receptor, is found to produce a transient burst of reactive oxygen species through a calcium-dependent activation of the
small GTPase Rac1. S1P-induced redox-signaling is sensed by protein tyrosine phosphatase-1B, the main negative regulator of
insulin receptor phosphorylation, which undergoes oxidation and enzymatic inhibition. This redox-based inhibition of the phosphatase
provokes a ligand-independent trans-phosphorylation of insulin receptor and a strong increase in glucose uptake. Our results propose a new role of S1P, recognizing
the lipid as an insulin-mimetic cue and pointing at reactive oxygen species as critical regulators of the cross-talk between
S1P and insulin pathways. Any possible implication of S1P-directed insulin signaling in diabetes and insulin resistance remains
to be established. 相似文献
14.
T-cell signal transduction and the role of protein kinase C 总被引:3,自引:0,他引:3
The T lymphocyte has a vital part to play in maintaining the host response to bacterial and viral infection and also appears
to play a key pathological role in autoimmune diseases such as rheumatoid arthritis. In this review, we summarize the signalling
pathways which trigger antigen-driven T-cell proliferation and examine the evidence which suggests that protein kinase C (PKC)
is fundamental to this process. Finally, we discuss the therapeutic potential that PKC inhibitors may have in the treatment
of autoimmune disease.
Received 31 March 1998; received after revision 19 May 1998; accepted 19 May 1998 相似文献
15.
Wnt-frizzled signaling to G-protein-coupled effectors 总被引:2,自引:0,他引:2
16.
ERKs are the point of divergence of PKA and PKC activation by PTHrP in human skin fibroblasts 总被引:3,自引:0,他引:3
Fortino V Torricelli C Gardi C Valacchi G Rossi Paccani S Maioli E 《Cellular and molecular life sciences : CMLS》2002,59(12):2165-2171
Parathyroid hormone-related peptide (PTHrP) receptors, coupled to trimeric G proteins, operate in most target cells through
at least three different transduction routes: Gαs-mediated stimulation of adenylylcyclase (AC), Gαq-mediated activation of
phospholipase Cβ (PLC) and mitogen-activated protein kinase (MAPK) activation. In this study we investigated the relative
role of different pathways in human skin fibroblast prolifera-tion. Using chemical inhibitors and activators of signal transduction,
we demonstrated that: (i) AC/cAMP and PLC/1,4,5 inositol triphosphate/diacylglycerol second-messenger systems are simultaneously
activated following PTHrP binding to its receptors; (ii) the mitogenic response to PTHrP derives from a balance between two
counteracting pathways – an activating route mediated by protein kinase C (PKC) and an inhibitory route mediated by protein
kinase A (PKA); (iii) PTHrP mitogenic effects are largely dependent on MAPKs, whose activity can be modulate
d by both PKA and PKC. Our results indicate that MAPKs are common targets of both transduction routes and, at the same time,
their point of divergence in mediating PTHrP dual and opposite mitogenic effects.
Received 2 August 2002; received after revision 10 September 2002; accepted 18 October 2002
RID="*"
ID="*"Corresponding author. 相似文献
17.
Alvi F Idkowiak-Baldys J Baldys A Raymond JR Hannun YA 《Cellular and molecular life sciences : CMLS》2007,64(3):263-270
The protein kinase C (PKC) family of isoenzymes has been shown to regulate a variety of cellular processes, including receptor
desensitization and internalization, and this has sparked interest in further delineation of the roles of specific isoforms
of PKC in membrane trafficking and endocytosis. Recent studies have identified a novel translocation of PKC to a juxtanuclear
compartment, the pericentrion, which is distinct from the Golgi complex but epicentered on the centrosome. Sustained activation
of PKC (longer than 30 min) also results in sequestration of plasma membrane lipids and proteins to the same compartment,
demonstrating a global effect on endocytic trafficking. This review summarizes these studies, particularly focusing on the
characterization of the pericentrion as a distinct PKC-dependent subset of recycling endosomes. We also discuss emerging insights
into a role for PKC as a central hub in regulating vesicular transport pathways throughout the cell, with implications for
a wide range of pathobiologic processes, e.g. diabetes and abnormal neurotransmission or receptor desensitization.
Received 11 August 2006; received after revision 20 September 2006; accepted 7 November 2006 相似文献
18.
Camille Faure Mariana Ramos Jean-Antoine Girault 《Cellular and molecular life sciences : CMLS》2013,70(1):137-152
Cytonuclear signaling is essential for long-term alterations of cellular properties. Several pathways involving regulated nuclear accumulation of Ser/Thr kinases have been described but little is known about cytonuclear trafficking of tyrosine kinases. Proline-rich tyrosine kinase 2 (Pyk2) is a cytoplasmic non-receptor tyrosine kinase enriched in neurons and involved in functions ranging from synaptic plasticity to bone resorption, as well as in cancer. We previously showed the Ca2+-induced, calcineurin-dependent, nuclear localization of Pyk2. Here, we characterize the molecular mechanisms of Pyk2 cytonuclear localization in transfected PC12 cells. The 700–841 linker region of Pyk2 recapitulates its depolarization-induced nuclear accumulation. This region includes a nuclear export motif regulated by phosphorylation at residue S778, a substrate of cAMP-dependent protein kinase and calcineurin. Nuclear import is controlled by a previously identified sequence in the N-terminal domain and by a novel nuclear targeting signal in the linker region. Regulation of cytonuclear trafficking is independent of Pyk2 activity. The region regulating nuclear localization is absent from the non-neuronal shorter splice isoform of Pyk2. Our results elucidate the mechanisms of Ca2+-induced nuclear accumulation of Pyk2. They also suggest that Pyk2 nuclear accumulation is a novel type of signaling response that may contribute to specific long-term adaptations in neurons. 相似文献
19.
Adducin: structure, function and regulation 总被引:7,自引:0,他引:7
Adducin is a ubiquitously expressed membrane-skeletal protein localized at spectrin-actin junctions that binds calmodulin and is an in vivo substrate for protein kinase C (PKC) and Rho-associated kinase. Adducin is a tetramer comprised of either alpha/beta or alpha/gamma heterodimers. Adducin subunits are related in sequence and all contain an N-terminal globular head domain, a neck domain and a C-terminal protease-sensitive tail domain. The tail domains of all adducin subunits end with a highly conserved 22-residue myristoylated alanine-rich C kinase substrate (MARCKS)-related domain that has homology to MARCKS protein. Adducin caps the fast-growing ends of actin filaments and also preferentially recruits spectrin to the ends of filaments. Both the neck and the MARCKS-related domains are required for these activities. The neck domain self-associates to form oligomers. The MARCKS-related domain binds calmodulin and contains the major phosphorylation site for PKC. Calmodulin, gelsolin and phosphorylation by the kinase inhibit in vitro activities of adducin involving actin and spectrin. Recent observations suggest a role for adducin in cell motility, and as a target for regulation by Rho-dependent and Ca2+-dependent pathways. Prominent physiological sites of regulation of adducin include dendritic spines of hippocampal neurons, platelets and growth cones of axons. 相似文献