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1.
E. Cohen-Hillel R. Mintz T. Meshel B.-Z. Garty A. Ben-Baruch 《Cellular and molecular life sciences : CMLS》2009,66(5):884-899
The chemokine CXCL8 is a powerful inducer of directional cell motility, primarily during inflammation. In this study, we found
that CXCL8 stimulation led to paxillin phosphorylation in normal neutrophils, and that both CXCL8 receptors (CXCR1 and CXCR2)
mediated CXCL8-induced paxillin phosphorylation. In CXCR2-transfected cells, the process depended on Gαi and Gαs coupling to CXCR2. Dominant negative (DN) paxillin increased CXCL8-induced adhesion and migration, indicating that endogenous
paxillin keeps migration at submaximal levels. Furthermore, using activating antibodies to β1 integrins, analyses with focal
adhesion kinase (FAK) DN variant (FRNK) and co-immunoprecipitations of FAK and paxillin, we found that β1 integrin ligation
cooperates with CXCL8-induced stimulation, leading to FAK activation and thereafter to FAK-mediated paxillin phosphorylation.
Our findings indicate that paxillin keeps directional motility at a restrained magnitude, and suggest that perturbations in
its activation may lead to chemotactic imbalance and to pathological conditions associated with excessive or reduced leukocyte
migration.
R. Mintz, T. Meshel: These authors contributed equally to this work.
Received 31 July 2008; received after revision 14 December 2008; accepted 16 December 2008 相似文献
2.
Baumann P Thiele W Cremers N Muppala S Krachulec J Diefenbacher M Kassel O Mudduluru G Allgayer H Frame M Sleeman JP 《Cellular and molecular life sciences : CMLS》2012,69(3):435-448
Expression of the glycosylphosphatidylinositol-anchored membrane protein CD24 correlates with a poor prognosis for many human cancers, and in experimental tumors can promote metastasis. However, the mechanism by which CD24 contributes to tumor progression remains unclear. Here we report that in MTLy breast cancer cells CD24 interacts with and augments the kinase activity of c-src, a protein strongly implicated in promoting invasion and metastasis. This occurs within and is dependent upon intact lipid rafts. CD24-augmented c-src kinase activity increased formation of focal adhesion complexes, accelerated phosphorylation of FAK and paxillin and consequently enhanced integrin-mediated adhesion. Loss and gain of function approaches showed that c-src activity is necessary and sufficient to mediate the effects of CD24 on integrin-dependent adhesion and cell spreading, as well as on invasion. Together these results indicate that c-src is a CD24-activated mediator that promotes integrin-mediated adhesion and invasion, and suggest a mechanism by which CD24 might contribute to tumor progression through stimulating the activity of c-src or another member of the Src family. 相似文献
3.
Despite the absence of classical tyrosine kinases encrypted in the kinome of Plasmodium falciparum, biochemical analyses have detected significant tyrosine phosphorylation in its cell lysates. Supporting such phosphorylation
is critical for parasite development. These observations have thus raised queries regarding the plasmodial enzymes accountable
for tyrosine kinase activities in vivo. In the current investigation, immunoblot analysis intriguingly demonstrated that Pfnek3,
a plasmodial mitogen-activated protein kinase kinase (MAPKK), displayed both serine/threonine and tyrosine kinase activities
in autophosphorylation reactions as well as in phosphorylation of the exogenous myelin basic protein substrate. The results
obtained strongly support Pfnek3 as a novel dual-specificity kinase of the malarial parasite, even though it displays a HGDLKSTN
motif in the catalytic loop that resembles the consensus HRDLKxxN signature found in the serine/threonine kinases. Notably,
its serine/threonine and tyrosine kinase activities were found to be distinctly influenced by Mg2+ and Mn2+ cofactors. Further probing into the regulatory mechanism of Pfnek3 also revealed tyrosine phosphorylation to be a crucial
factor that stimulates its kinase activity. Through biocomputational analyses and functional assays, tyrosine residues Y117,
Y122, Y172, and Y238 were proposed as phosphorylation sites essential for mediating the catalytic activities of Pfnek3. The
discovery of Pfnek3’s dual role in phosphorylation marks its importance in closing the loop for cellular regulation in P. falciparum, which remains elusive to date. 相似文献
4.
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
5.
Tang J Wu YM Zhao P Yang XM Jiang JL Chen ZN 《Cellular and molecular life sciences : CMLS》2008,65(18):2933-2942
Mechanism of HAb18G/CD147 underlying the metastasis process of human hepatoma cells has not been determined. In the present
study, we found that integrin α3β1 colocalizes with HAb18G/CD147 in human 7721 hepatoma cells. The enhancing effect of HAb18G/CD147
on adhesion, invasion capacities and matrix metalloproteinases (MMPs) secretion was decreased by integrin α3β1 antibodies
(p<0.01). The expressions of integrin downstream molecules including focal adhesion kinase (FAK), phospho-FAK (p-FAK), paxillin,
and phospho-paxillin (p-paxillin) were increased in human hepatoma cells overexpressing HAb18G/CD147. Deletion of HAb18G/CD147
reduces the quantity of focal adhesions and rearranges cytoskeleton. Wortmannin and LY294002, specific phosphatidylinositol
kinase (PI3K) inhibitors, reversed the effect of HAb18G/CD147 on the regulation of intracellular Ca2+ mobilization, significantly reducing cell adhesion, invasion and MMPs secretion potential (p<0.01). Together, these results suggest that HAb18G/CD147 enhances the invasion and metastatic potentials of human hepatoma
cells via integrin α3β1-mediated FAK-paxillin and FAKPI3K-Ca2+ signal pathways.
Received 5 June 2008; received after revision 16 July 2008; accepted 23 July 2008 相似文献
6.
Arachiche A Badirou I Dachary-Prigent J Garcin I Geldwerth-Feniger D Kerbiriou-Nabias D 《Cellular and molecular life sciences : CMLS》2008,65(23):3861-3871
Rapid Ca2+-dependent phospholipid (PL) reorganization (scrambling) at the plasma membrane is a mechanism common to hematopoietic cells
exposing procoagulant phosphatidylserine (PS). The aim of this research was to determine whether activation of the extracellular
signal-regulated kinase (ERK) pathway was required for PL scrambling, based on a single report analyzing both responses induced
by Ca2+ ionophores in megakaryoblastic HEL cells. Ca2+ ionophore-stimulated ERK phosphorylation was induced in platelets without external Ca2+, whereas exogenous Ca2+ entry was crucial for ERK activation in Jurkat T cells. In both cells, membrane scrambling only occurred following Ca2+ entry and was not blocked by inhibiting ERK phosphorylation. Furthermore, ERK proteins are strongly phosphorylated in transformed
B lymphoblastic cell lines, which do not expose PS in their resting state. Overall, the data demonstrated that ERK activation
and membrane scrambling are independent mechanisms.
A. Arachiche, I. Badirou: These authors contributed equally to this work.
Received 18 June 2008; received after revision 24 September 2008; accepted 1 October 2008 相似文献
7.
The parvins 总被引:5,自引:0,他引:5
The parvins are a family of proteins involved in linking integrins and associated proteins with intracellular pathways that
regulate actin cytoskeletal dynamics and cell survival. Both α-parvin (PARVA) and β-parvin (PARVB) localize to focal adhesions
and function in cell adhesion, spreading, motility and survival through interactions with partners, such as integrin-linked
kinase (ILK), paxillin, α-actinin and testicular kinase 1. A complex of PARVA with ILK and the LIM protein PINCH-1 is critical
for cell survival in a variety of cells, including certain cancer cells, kidney podocytes and cardiac myocytes. While PARVA
inhibits the activities of Rac1 and testicular kinase 1 and cell spreading, PARVB binds αPIX and α-actinin, and can promote
cell spreading. In contrast to PARVA, PARVB inhibits ILK activity and reverses some of its oncogenic effects in cancer cells.
This review focuses on the structure and function of the parvins and some possible roles in human diseases.
Received 5 August 2005; received after revision 5 September 2005; accepted 22 September 2005 相似文献
8.
A. Hamadi T. B. Deramaudt K. Takeda P. Rondé 《Cellular and molecular life sciences : CMLS》2009,66(2):324-338
Cell migration requires the coordinated turnover of focal adhesions, a process that involves FAK phosphorylation. Since Src
is the major kinase implicated in FAK phosphorylation, we focus here on the role of Src activation on adhesion remodelling.
In astrocytoma cells, constitutively activated Src induces both FAK phosphorylation and adhesion rearrangement. To evaluate
how Src controls these processes, we used a recently described Src reporter to monitor the dynamics of Src phosphorylation.
Upon Src activation, focal adhesions started to disassemble while Src appeared highly expressed at newly formed membrane ruffles.
Kinetic analysis of time-lapse movies showed that loss of phospho-Src at focal adhesions was time-correlated with the appearance
of membrane ruffles containing phospho-Src. Moreover, FLIP analysis revealed a dynamic equilibrium of Src between focal adhesions
and membrane ruffles. We conclude that upon phosphorylation, Src is directly translocated from focal adhesions to membrane
ruffles, thereby promoting formation of new adhesion complexes.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 21 July 2008; received after revision 10 October 2008; accepted 03 November 2008 相似文献
9.
Myelin basic protein: a multifunctional protein 总被引:1,自引:1,他引:0
Boggs JM 《Cellular and molecular life sciences : CMLS》2006,63(17):1945-1961
Myelin basic protein (MBP), the second most abundant protein in central nervous system myelin, is responsible for adhesion
of the cytosolic surfaces of multilayered compact myelin. A member of the ‘intrinsically disordered’ or conformationally adaptable
protein family, it also appears to have several other functions. It can interact with a number of polyanionic proteins including
actin, tubulin, Ca2+-calmodulin, and clathrin, and negatively charged lipids, and acquires structure on binding to them. It may act as a membrane
actin-binding protein, which might allow it to participate in transmission of extracellular signals to the cytoskeleton in
oligodendrocytes and tight junctions in myelin. Some size isoforms of MBP are transported into the nucleus and thus they may
also bind polynucleotides. Extracellular signals received by myelin or cultured oligodendrocytes cause changes in phosphorylation
of MBP, suggesting that MBP is also involved in signaling. Further study of this very abundant protein will reveal how it
is utilized by the oligodendrocyte and myelin for different purposes.
Received 2 March 2006; received after revision 12 April 2006; accepted 16 May 2006 相似文献
10.
Interaction of galectin-1 with caveolae induces mouse embryonic stem cell proliferation through the Src, ERas, Akt and mTOR signaling pathways 总被引:1,自引:0,他引:1
M. Y. Lee S. H. Lee J. H. Park H. J. Han 《Cellular and molecular life sciences : CMLS》2009,66(8):1467-1478
Galectins have the potential to provide a promising alternative for unveiling the complexity of embryonic stem (ES) cell self-renewal,
although the mechanism by which galectins maintain ES cell self-renewal has yet to be identified. Galectin-1 increased [3H]-thymidine incorporation as well as cyclin expression and decreased p27kip1 expression. Src and caveolin-1 phosphorylation was increased by galectin-1, and phospho-caveolin-1 was inhibited by PP2.
In addition, inhibition of caveolin-1 by small interfering RNA and methyl-β-cyclodextrin (Mβ-CD) decreased galectin-1-induced
cyclin expression and [3H]-thymidine incorporation. Galectin-1 caused Akt and mTOR phosphorylation, which is involved in cyclin expression. Galectin-1-induced
phospho-Akt and -mTOR was inhibited by PP2, ERas siRNA, caveolin-1 siRNA and Mβ-CD. Furthermore, mTOR phosphorylation was
decreased by LY294002 and Akt inhibitor. Galectin-1-induced increase in cyclin expression and decrease in p27kip1 was blocked by Akt inhibitor and rapamycin. In conclusion, galectin-1 increased DNA synthesis in mouse ES cells via Src,
caveolin-1 Akt, and mTOR signaling pathways.
Received 30 October 2008; received after revision 18 February 2009; accepted 24 February 2009 相似文献
11.
Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/Rac1 pathway 总被引:6,自引:0,他引:6
Enhanced cell migration is one of the underlying mechanisms in cancer invasion and metastasis. Therefore, inhibition of cell migration is considered to be an effective strategy for prevention of cancer metastasis. We found that emodin (3-methyl-1,6,8-trihydroxyanthraquinone), an active component from the rhizome of Rheum palmatum, significantly inhibited epidermal growth factor (EGF)- induced migration in various human cancer cell lines. In the search for the underlying molecular mechanisms, we demonstrated that phosphatidylinositol 3-kinase (PI3K) serves as the molecular target for emodin. In addition, emodin markedly suppressed EGF-induced activation of Cdc42 and Rac1 and the corresponding cytoskeleton changes. Moreover, emodin, but not LY294002, was able to block cell migration in cells transfected with constitutively active (CA)-Cdc42 and CA-Rac1 by interference with the formation of Cdc42/Rac1 and the p21-activated kinase complex. Taken together, data from this study suggest that emodin inhibits human cancer cell migration by suppressing the PI3K-Cdc42/Rac1 signaling pathway.Received 7 February 2005; received after revision 11 March 2005; accepted 18 March 2005 相似文献
12.
13.
G. M. C. Janssen P. Schwertman T. A. T. Wanga R. S. Jahangir Tafrechi P. J. A. van den Broek A. K. Raap 《Cellular and molecular life sciences : CMLS》2009,66(4):721-730
Cytoplasmic translation is under sophisticated control but how cells adapt its rate to constitutive loss of mitochondrial
oxidative phosphorylation is unknown. Here we show that translation is repressed in cells with the pathogenic A3243G mtDNA
mutation or in mtDNA-less ρ0 cells by at least two distinct pathways, one transiently targeting elongation factor eEF-2 and the other initiation factor
eIF-2α constitutively. Under conditions of exponential cell growth and mammalian target of rapamycin (mTOR) activation, eEF-2
becomes transiently phosphorylated by an AMP-activated protein kinase (AMPK)-dependent pathway, especially high in mutant
cells. Independent of AMPK and mTOR, eIF-2α is constitutively phosphorylated in mutant cells, likely a signature of endoplasmic
reticulum (ER)-stress response induced by the loss of oxidative phosphorylation. While the AMPK/eEF-2K/eEF-2 pathway appears
to function in adaptation to physiological fluctuations in ATP levels in the mutant cells, the ER stress signified by constitutive
protein synthesis inhibition through eIF-2α-mediated repression of translation initiation may have pathobiochemical consequences.
Received 29 October 2008; received after revision 11 December 2008; accepted 16 December 2008 相似文献
14.
15.
Porcelli AM Ghelli A Iommarini L Mariani E Hoque M Zanna C Gasparre G Rugolo M 《Cellular and molecular life sciences : CMLS》2008,65(18):2943-2951
Human thyroid carcinoma XTC.UC1 cells harbor a homoplasmic frameshift mutation in the MT-ND1 subunit of respiratory complex
I. When forced to use exclusively oxidative phosphorylation for energy production by inhibiting glycolysis, these cells triggered
a caspase-independent cell death pathway, which was associated to a significant imbalance in glutathione homeostasis and a
cleavage of the actin cytoskeleton. Overexpression of the anti-apoptotic Bcl-2 protein significantly increased the level of
endogenous reduced glutathione, thus preventing its oxidation after the metabolic stress. Furthermore, Bcl-2 completely inhibited
actin cleavage and increased cell adhesion, but was unable to improve cellular viability. Similar effects were obtained when
XTC.UC1 cells were incubated with exogenous glutathione. We hence propose that Bcl-2 can safeguard cytoskeletal stability
through an antioxidant function.
Received 28 May 2008; received after revision 8 July 2008; accepted 29 July 2008 相似文献
16.
Mitochondrial dysfunction and protein kinase C (PKC) activation are consistently found in diabetic cardiomyopathy but their
relationship remains unclear. This study identified mitochondrial aconitase as a downstream target of PKC activation using
immunoblotting and mass spectrometry, and then characterized phosphorylation-induced changes in its activity in hearts from
type 1 diabetic rats. PKCβ2 co-immunoprecipitated with phosphorylated aconitase from mitochondria isolated from diabetic hearts. Augmented phosphorylation
of mitochondrial aconitase in diabetic hearts was found to be associated with an increase in its reverse activity (isocitrate
to aconitate), while the rate of the forward activity was unchanged. Similar results were obtained on phosphorylation of mitochondrial
aconitase by PKCβ2 in vitro. These results demonstrate the regulation of mitochondrial aconitase activity by PKC-dependent phosphorylation. This may
influence the activity of the tricarboxylic acid cycle, and contribute to impaired mitochondrial function and energy metabolism
in diabetic hearts.
Received 31 October 2008; received after revision 17 December 2008; accepted 2 January 2009 相似文献
17.
A. Venerando L. Cesaro O. Marin A. Donella-Deana L. A. Pinna 《Cellular and molecular life sciences : CMLS》2014,71(12):2193-2196
The motif “SYDE”, incorporating the protein kinase CK2 consensus sequence (S-x-x-E) has been found to be phosphorylated at both its serine and tyrosine residues in several proteins. Of special interest is the case of cystic fibrosis Transmembrane-conductance Regulator (CFTR), where this motif is close to the residue (F508), whose deletion is the by far commonest cause of cystic fibrosis. Intriguingly, however, CFTR S511 cannot be phosphorylated by CK2 to any appreciable extent. Using a number of peptide substrates encompassing the CFTR “SYDE” site we have recently shown that: (1) failure of CK2 to phosphorylate the S511YDE motif is due to the presence of Y512; (2) CK2 readily phosphorylates S511 if Y512 is replaced by a phospho-tyrosine; (3) the Src family protein tyrosine kinase Lyn phosphorylates Y512 in a manner that is enhanced by the deletion of F508. These data, in conjunction with the recent observation that by inhibiting CK2 the degradation of F508delCFTR is reduced, lead us to hypothesize that the hierarchical phosphorylation of the motif SYDE by the concerted action of protein tyrosine kinases and CK2 is one of the mechanisms that cooperate to the premature degradation of F508delCFTR. 相似文献
18.
Therian mammals (marsupials and placentals) have an XX female: XY male sex chromosome system, which is homologous to autosomes
in other vertebrates. The testis-determining gene, SRY, is conserved on the Y throughout therians, but is absent in other vertebrates, suggesting that the mammal system evolved
about 310 million years ago (MYA). However, recent work on the basal monotreme mammals has completely changed our conception
of how and when this change occurred. Platypus and echidna lack SRY, and the therian X and Y are represented by autosomes, implying that SRY evolved in therians after their divergence from monotremes only 166 MYA. Clues to the ancestral mechanism usurped by SRY in therians are provided by the monotremes, whose sex chromosomes are homologous to the ZW of birds. This suggests that the
therian X and Y, and the SRY gene, evolved from an ancient bird-like sex chromosome system which predates the divergence of mammals and reptiles 310 MYA.
Received 4 March 2008; received after revision 22 April 2008; accepted 3 June 2008 相似文献
19.
Steven H. Back Naga Suresh Adapala Mary F. Barbe Nick C. Carpino Alexander Y. Tsygankov Archana Sanjay 《Cellular and molecular life sciences : CMLS》2013,70(7):1269-1284
Bone is a dynamic tissue that depends on the intricate relationship between protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP) for maintaining homeostasis. PTKs and PTPs act like molecular on and off switches and help modulate differentiation and the attachment of osteoclasts to bone matrix regulating bone resorption. The protein T cell ubiquitin ligand-2 (TULA-2), which is abundantly expressed in osteoclasts, is a novel histidine phosphatase. Our results show that of the two family members, only TULA-2 is expressed in osteoclasts and that its expression is sustained throughout the course of osteoclast differentiation, suggesting that TULA-2 may play a role during early as well late stages of osteoclast differentiation. Skeletal analysis of mice that do not express TULA or TULA-2 proteins (DKO mice) revealed that there was a decrease in bone volume due to increased osteoclast numbers and function. Furthermore, in vitro experiments indicated that bone marrow precursor cells from DKO mice have an increased potential to form osteoclasts. At the molecular level, the absence of TULA-2 in osteoclasts results in increased Syk phosphorylation at the Y352 and Y525/526 residues and activation of phospholipase C gamma 2 (PLCγ2) upon engagement of immune-receptor-tyrosine-based-activation-motif (ITAM)—mediated signaling. Furthermore, expression of a phosphatase-dead TULA-2 leads to increased osteoclast function. Taken together, these results suggest that TULA-2 negatively regulates osteoclast differentiation and function. 相似文献
20.
Sarah De Clercq Olivier Zwaenepoel Evelien Martens Joël Vandekerckhove Aude Guillabert Jan Gettemans 《Cellular and molecular life sciences : CMLS》2013,70(5):909-922
The T cell integrin receptor LFA-1 orchestrates adhesion between T cells and antigen-presenting cells (APCs), resulting in formation of a contact zone known as the immune synapse (IS) which is supported by the cytoskeleton. L-plastin is a leukocyte-specific actin bundling protein that rapidly redistributes to the immune synapse following T cell–APC engagement. We used single domain antibodies (nanobodies, derived from camelid heavy-chain only antibodies) directed against functional and structural modules of L-plastin to investigate its contribution to formation of an immune synapse between Raji cells and human peripheral blood mononuclear cells or Jurkat T cells. Nanobodies that interact either with the EF hands or the actin binding domains of L-plastin both trapped L-plastin in an inactive conformation, causing perturbation of IS formation, MTOC docking towards the plasma membrane, T cell proliferation and IL-2 secretion. Both nanobodies delayed Ser5 phosphorylation of L-plastin which is required for enhanced bundling activity. Moreover, one nanobody delayed LFA-1 phosphorylation, reduced the association between LFA-1 and L-plastin and prevented LFA-1 enrichment at the IS. Our findings reveal subtle mechanistic details that are difficult to attain by conventional means and show that L-plastin contributes to immune synapse formation at distinct echelons. 相似文献