14-3-3epsilon inhibits MK5-mediated cell migration by disrupting F-actin polymerization

Tak, Heejae; Jang, Eunsun; Kim, Seung Beom; Park, Jinhwi; Suk, Jinkyu; Yoon, Yoo Sik; Ahn, Jeong Keun; Lee, Jeung‐Hoon; Joe, Cheol O.

doi:10.1016/j.cellsig.2007.07.016

Cited by 68 publications

(78 citation statements)

References 38 publications

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Section: Discussionmentioning

confidence: 99%

“…The absence of PI3Kg was found to impair chemokine-induced vimentin serine phosphorylation as well as its subsequent association with phosphoserine-binding proteins of the 14-3-3 family. Interestingly, vimentin is known to sequester 14-3-3 [16] and reduced 14-3-3 binding to vimentin could per se cause cell migration defects: for example, overexpression of 14-3-3 proteins can interfere with actin polymerization and impair cell migration [39].PI3Kg-null BMDM stimulated with chemokines showed not only reduced vimentin serine phosphorylation but also a concomitant reduction in vimentin fiber disassembly. Association of vimentin phosphorylation and disassembly of its filament network has been detected in vitro and in different cell types including epithelial as well as mesenchymal cells [15,33].…”

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confidence: 99%

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Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

et al. 2009

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Phosphoinositide 3-kinase c (PI3Kc) plays a fundamental role in mediating leukocyte migration to inflammation sites. However, the downstream cytoplasmic events triggered by its signaling activity are still largely obscure. To address this issue, tyrosine and serine/threonine phosphorylated proteins of chemokine-stimulated WT or PI3Kc-null macrophages were investigated. Among the proteins analyzed, the intermediate filament vimentin was found as a downstream effector of the PI3Kc signaling pathway. Specific analysis of the phosphorylation state of vimentin in macrophages showed that this protein becomes rapidly phosphorylated in both tyrosine and serine residues upon chemokine stimulation. In the absence of PI3Kc or the kinase activity of PI3Kc (PI3Kc KD/KD ), phosphorylation of vimentin was reduced. PI3Kc-null macrophages displayed impaired chemokine-driven vimentin fiber disassembly as well as reduced ability to transmigrate across endothelial cells. While WT macrophages infected with a vimentin mutant resistant to N-terminal serine phosphorylation showed a reduction in transendothelial migration, infection of PI3Kc-null macrophages with a vimentin mutant mimicking serine phosphorylation of N-terminal residues rescued the transendothelial migration defect. These results define vimentin N-terminal phosphorylation and fiber reorganization as a target of chemokine-dependent PI3Kc signaling in leukocytes.Key words: Cell migration . Intermediate filaments . Phosphoinositide 3-kinases .Signal transduction IntroductionPhosphoinositide 3-kinases (PI3K) are a family of ubiquitously expressed lipid and protein kinases. They are activated downstream transmembrane receptors [1] and are involved in several cellular responses such as metabolic regulation, survival, proliferation, cell migration and adhesion. PI3K convert PtdIns(4,5)P 2 into PtdIns(3,4,5)P 3 , a second lipid messenger product forming a docking site for various proteins harboring lipid binding modules such as the pleckstrin homology domain [2].Ã These authors contributed equally to this work. 1136Class I PI3K are heterodimeric proteins composed of a p110 catalytic subunit (a, b, g and d) and a regulatory adaptor subunit. According to their mechanism of activation, these enzymes can be further classified into two subclasses: while class IA PI3K (PI3Ka, b and d) include an adaptor protein of the p85 family and are activated by tyrosine kinase receptors, the sole known element of class IB, PI3Kg, is specifically activated by G protein-coupled receptors (GPCR) [3]. This effect is regulated by the interaction of PI3Kg with Gbg subunits of active G proteins through the involvement of either the p101 adaptor or its homologue p84/p87 [4]. Among mammalian tissues, the highest level of PI3Kg expression is found in leukocytes where this enzyme directs the chemotactic response to GPCR agonists [3]. Indeed, PI3Kg-null granulocytes show a significant reduction in chemotaxis toward chemokines and severely impaired bacteria-elicited peritoneal recruitment [5,6]. This migrati...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

et al. 2009

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“…Evidence from different cell systems indicates that Hsp-27 controls cell locomotion by a common mechanism. In fibroblasts (Hirano et al, 2004), endothelium, neutrophils and epithelial cells, phosphorylation and polymerisation of Hsp-27 modulates transformation of G-F actin (Tak et al, 2007) to generate the mechanical force required for cell motility to occur through organisation of cytoskeletal components (Doshi et al, 2009). In endothelial cells, Hsp-27 co-localises with and regulates assembly of actin filaments following phosphorylation by p38 MAP kinase (Guay et al, 1997;Landry and Huot, 1999).…”

Section: Discussionmentioning

confidence: 99%

Hsp-27 expression at diagnosis predicts poor clinical outcome in prostate cancer independent of ETS-gene rearrangement

et al. 2009

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Background: This study was performed to test the hypothesis that expression of small heat shock protein Hsp-27 is, at diagnosis, a reliable predictive biomarker of clinically aggressive prostate cancer. Methods: A panel of tissue microarrays constructed from a well-characterised cohort of 553 men with conservatively managed prostate cancer was stained immunohistochemically to detect Hsp-27 protein. Hsp-27 expression was compared with a series of pathological and clinical parameters, including outcome. Results: Hsp-27 staining was indicative of higher Gleason score ( P <0.001). In tissue cores having a Gleason score >7, the presence of Hsp-27 retained its power to independently predict poor clinical outcome ( P <0.002). Higher levels of Hsp-27 staining were almost entirely restricted to cancers lacking ERG rearrangements ( χ 2 trend=31.4, P <0.001), although this distribution did not have prognostic significance. Interpretation: This study has confirmed that, in prostate cancers managed conservatively over a period of more than 15 years, expression of Hsp-27 is an accurate and independent predictive biomarker of aggressive disease with poor clinical outcome ( P <0.001). These findings suggest that apoptotic and cell-migration pathways modulated by Hsp-27 may contain targets susceptible to the development of biologically appropriate chemotherapeutic agents that are likely to prove effective in treating aggressive prostate cancers.

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“…Recent studies have highlighted the importance of MK5 in ras-induced senescence, antiproliferation, tumor suppression, anxiety-related behavior, energy-depletioninduced suppression of mammalian target of rapamycin C1, rearrangements of the cytoskeleton, endothelial cell migration, and tumor angiogenesis [4][5][6][7][8][9] . Several bona fide substrates have been identified, including extracellular signal-regulated kinase (ERK)3, ERK4, 14-3-3ε, p53, Ras homolog enriched in brain (Rheb) and heat shock protein (Hsp)27 [6,8,[10][11][12][13][14][15] . The role of MK5 in actin architecture involves its link with 14-3-3ε and Hsp27 [14,15] , while MK5-mediated phosphorylation of p53 at Ser-37 results in increased transcription of p21 Cip1 , and inhibition of cell proliferation [6,16] .…”

Section: Introductionmentioning

confidence: 99%

“…Several bona fide substrates have been identified, including extracellular signal-regulated kinase (ERK)3, ERK4, 14-3-3ε, p53, Ras homolog enriched in brain (Rheb) and heat shock protein (Hsp)27 [6,8,[10][11][12][13][14][15] . The role of MK5 in actin architecture involves its link with 14-3-3ε and Hsp27 [14,15] , while MK5-mediated phosphorylation of p53 at Ser-37 results in increased transcription of p21 Cip1 , and inhibition of cell proliferation [6,16] . The biological relevance of MK5-ERK3 and MK5-ERK4 interactions remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Septin 8 is an interaction partner and in vitro substrate of MK5

Shiryaev

Kostenko²,

Dumitriu³

et al. 2012

WJBC

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AIM:To identify novel substrates for the mitogen-activated protein kinase-activated protein kinase 5 (MK5). METHODS:Yeast two-hybrid screening with MK5 as bait was used to identify novel possible interaction partners. The binding of putative partner was further examined by glutathione S-transferase (GST) pull-down, co-immunoprecipitation and fluorescence resonance energy transfer (FRET) analysis. In vitro kinase and peptide array assays were used to map MK5 phosphoacceptor sites on the new partner. Confocal microscopy was performed to study the subcellular localization of MK5 and its partners. RESULTS:Septin 8 was identified as a novel interaction partner for MK5 by yeast two-hybrid screening. This interaction was confirmed by GST pull-down, coimmunoprecipitation and FRET analysis. Septin 5, which can form a complex with septin 8, did not interact with MK5. Serine residues 242 and 271 on septin 8 were identified as in vitro MK5 phosphorylation sites. MK5and septin 8 co-localized in the perinuclear area and in cell protrusions. Moreover, both proteins co-localized with vesicle marker synaptophysin. CONCLUSION:Septin 8 is a bona fide interaction partner and in vitro substrate for MK5. This interaction may be implicated in vesicle trafficking.

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14-3-3epsilon inhibits MK5-mediated cell migration by disrupting F-actin polymerization

Cited by 68 publications

References 38 publications

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

Hsp-27 expression at diagnosis predicts poor clinical outcome in prostate cancer independent of ETS-gene rearrangement

Septin 8 is an interaction partner and in vitro substrate of MK5

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