Phosphorylation of moesin by c-Jun N-terminal kinase is important for podosome rosette formation in Src-transformed fibroblasts

Pan, Yi-Ru; Tseng, Wei Shan; Chang, Po Wei; Chen, Hong Chen

doi:10.1242/jcs.134361

Cited by 16 publications

(12 citation statements)

References 51 publications

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“…However, both studies showed ERM phosphorylation kinetics that peaked after one hour and contrast our finding of rapid (within 5 min) ERM phosphorylation, suggesting that immediate ERM phosphorylation by MAP4K4 is direct. Interestingly, a recent study revealed phosphorylation of the ERM protein moesin by JNK for podosome rosette formation in Src-transformed fibroblasts [60]. It is conceivable that an analogous JNK-mediated phosphorylation of ERM proteins may be active as well for parasite-dependent podosome formation in Theileria -transformed cells, which requires Src kinase activity too [4], possibly causing residual ERM phosphorylation in MAP4K4-depleted cells.…”

Section: Discussionmentioning

confidence: 99%

Intracellular Theileria annulata Promote Invasive Cell Motility through Kinase Regulation of the Host Actin Cytoskeleton

Baumgärtner

2014

PLoS Pathog

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The intracellular, protozoan Theileria species parasites are the only eukaryotes known to transform another eukaryotic cell. One consequence of this parasite-dependent transformation is the acquisition of motile and invasive properties of parasitized cells in vitro and their metastatic dissemination in the animal, which causes East Coast Fever (T. parva) or Tropical Theileriosis (T. annulata). These motile and invasive properties of infected host cells are enabled by parasite-dependent, poorly understood F-actin dynamics that control host cell membrane protrusions. Herein, we dissected functional and structural alterations that cause acquired motility and invasiveness of T. annulata-infected cells, to understand the molecular basis driving cell dissemination in Tropical Theileriosis. We found that chronic induction of TNFα by the parasite contributes to motility and invasiveness of parasitized host cells. We show that TNFα does so by specifically targeting expression and function of the host proto-oncogenic ser/thr kinase MAP4K4. Blocking either TNFα secretion or MAP4K4 expression dampens the formation of polar, F-actin-rich invasion structures and impairs cell motility in 3D. We identified the F-actin binding ERM family proteins as MAP4K4 downstream effectors in this process because TNFα-induced ERM activation and cell invasiveness are sensitive to MAP4K4 depletion. MAP4K4 expression in infected cells is induced by TNFα-JNK signalling and maintained by the inhibition of translational repression, whereby both effects are parasite dependent. Thus, parasite-induced TNFα promotes invasive motility of infected cells through the activation of MAP4K4, an evolutionary conserved kinase that controls cytoskeleton dynamics and cell motility. Hence, MAP4K4 couples inflammatory signaling to morphodynamic processes and cell motility, a process exploited by the intracellular Theileria parasite to increase its host cell's dissemination capabilities.

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Section: Discussionmentioning

confidence: 99%

Intracellular Theileria annulata Promote Invasive Cell Motility through Kinase Regulation of the Host Actin Cytoskeleton

Baumgärtner

2014

PLoS Pathog

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“…The plasmid pCMV-3Tag-3A-ADD1 for the FLAG epitope-tagged ADD1 (FLAG-ADD1) was constructed in our laboratory and described previously [28]. The plasmid pEGFP-C1-NLS SV40 was described previously [29]. For the GFP-C1-NLS SV40 -ADD1, ADD1 cDNA was cloned into the KpnI and BamHI sites of the pEGFP-C1-NLS SV40 plasmid.…”

Section: Methodsmentioning

confidence: 99%

Adducin family proteins possess different nuclear export potentials

et al. 2017

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BackgroundThe adducin (ADD) family proteins, namely ADD1, ADD2, and ADD3, are actin-binding proteins that play important roles in the stabilization of membrane cytoskeleton and cell-cell junctions. All the ADD proteins contain a highly conserved bipartite nuclear localization signal (NLS) at the carboxyl termini, but only ADD1 can localize to the nucleus. The reason for this discrepancy is not clear.MethodsTo avoid the potential effect of cell-cell junctions on the distribution of ADD proteins, HA epitope-tagged ADD proteins and mutants were transiently expressed in NIH3T3 fibroblasts and their distribution in the cytoplasm and nucleus was examined by immunofluorescence staining. Several nuclear proteins were identified to interact with ADD1 by mass spectrometry, which were further verified by co-immunoprecipitation.ResultsIn this study, we found that ADD1 was detectable both in the cytoplasm and nucleus, whereas ADD2 and ADD3 were detected only in the cytoplasm. However, ADD2 and ADD3 were partially (~40%) sequestered in the nucleus by leptomycin B, a CRM1/exportin1 inhibitor. Upon the removal of leptomycin B, ADD2 and ADD3 re-distributed to the cytoplasm. These results indicate that ADD2 and ADD3 possess functional NLS and are quickly transported to the cytoplasm upon entering the nucleus. Indeed, we found that ADD2 and ADD3 possess much higher potential to counteract the activity of the NLS derived from Simian virus 40 large T-antigen than ADD1. All the ADD proteins appear to contain multiple nuclear export signals mainly in their head and neck domains. However, except for the leucine-rich motif (377FEALMRMLDWLGYRT391) in the neck domain of ADD1, no other classic nuclear export signal was identified in the ADD proteins. In addition, the nuclear retention of ADD1 facilitates its interaction with RNA polymerase II and zinc-finger protein 331.ConclusionsOur results suggest that ADD2 and ADD3 possess functional NLS and shuttle between the cytoplasm and nucleus. The discrepancy in the subcellular localization of the ADD isoforms arises due to their different nuclear export capabilities. In addition, the interaction of ADD1 with RNA polymerase II and zinc-finger protein 331 implicates a potential role for ADD1 in the regulation of transcription.

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“…The two-step model explaining Moesin activation [13], [19] suggests that membrane recruitment of ERM proteins renders a regulatory threonine residue in C-ERMAD accessible for phosphorylation by specific kinases. Serine/threonine kinases including NCK interacting kinase (NIK) [36], Lymphocyte Oriented Kinase (LOK) [37], leucine-rich repeat protein kinase 2 (LRRK2) [38], CDK5, Protein Kinase Cα, Protein Kinase Cθ [39], Macrophage stimulating4 (Mst4), Rho-associated kinase [40], JNK [41] and Slik [42]–[45] can phosphorylate the threonine residue in C-ERMAD of ERM proteins. In addition, tyrosine residues in Ezrin that are conserved between mammalian ERMs are phosphorylated by the receptor tyrosine kinase -EGFR [46]–[48].…”

Section: Introductionmentioning

confidence: 99%

Slik and the Receptor Tyrosine Kinase Breathless Mediate Localized Activation of Moesin in Terminal Tracheal Cells

et al. 2014

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A key element in the regulation of subcellular branching and tube morphogenesis of the Drosophila tracheal system is the organization of the actin cytoskeleton by the ERM protein Moesin. Activation of Moesin within specific subdomains of cells, critical for its interaction with actin, is a tightly controlled process and involves regulatory inputs from membrane proteins, kinases and phosphatases. The kinases that activate Moesin in tracheal cells are not known. Here we show that the Sterile-20 like kinase Slik, enriched at the luminal membrane, is necessary for the activation of Moesin at the luminal membrane and regulates branching and subcellular tube morphogenesis of terminal cells. Our results reveal the FGF-receptor Breathless as an additional necessary cue for the activation of Moesin in terminal cells. Breathless-mediated activation of Moesin is independent of the canonical MAP kinase pathway.

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Phosphorylation of moesin by c-Jun N-terminal kinase is important for podosome rosette formation in Src-transformed fibroblasts

Cited by 16 publications

References 51 publications

Intracellular Theileria annulata Promote Invasive Cell Motility through Kinase Regulation of the Host Actin Cytoskeleton

Intracellular Theileria annulata Promote Invasive Cell Motility through Kinase Regulation of the Host Actin Cytoskeleton

Adducin family proteins possess different nuclear export potentials

Slik and the Receptor Tyrosine Kinase Breathless Mediate Localized Activation of Moesin in Terminal Tracheal Cells

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