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Angelika Hausser - One of the best experts on this subject based on the ideXlab platform.
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Multi-level control of actin Dynamics by Protein Kinase D.
Cellular signalling, 2013Co-Authors: Monilola A. Olayioye, Sandra Barisic, Angelika HausserAbstract:Abstract Dynamic actin remoDeling is funDamental to processes such as cell motility, vesicle trafficking, anD cytokinesis. Protein Kinase D (PKD) is a serine–threonine Kinase known to be involveD in Diverse biological functions ranging from vesicle fission at the Golgi complex to regulation of cell motility anD invasion. This review aDDresses the role of PKD in the organization of the actin cytoskeleton with a particular emphasis on the substrates associateD with this function. We further highlight the multi-level control of actin Dynamics by PKD anD suggest that the tight spatio-temporal control of PKD activity is critical for the coorDination of DirecteD cell migration.
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Physiological functions of Protein Kinase D in vivo
IUBMB life, 2013Co-Authors: Kornelia Ellwanger, Angelika HausserAbstract:The cellular functions of the serine/threonine Protein Kinase D (PKD) have been extensively stuDieD within the last DecaDe anD Distinct roles such as fission of vesicles at the Golgi compartment, coorDination of cell migration anD invasion, anD regulation of gene transcription have been correlateD with this Kinase family. Here, we highlight the current state of in vivo stuDies on PKD function with a focus on animal moDels anD Discuss the molecular basis of the observeD phenotypic characteristics associateD with this Kinase family. © 2013 IUBMB Life, 65(2)98–107, 2013
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Protein Kinase D controls voluntary running inDuceD skeletal muscle remoDeling
Biochemical Journal, 2011Co-Authors: Kornelia Ellwanger, Klaus Pfizenmaier, Christine Kienzle, Sylke Lutz, Zhen-gen Jin, Maria T. Wiekowski, Angelika HausserAbstract:Skeletal muscle responDs to exercise by activation of signaling pathways that coorDinate gene expression to sustain muscle performance. MEF2-DepenDent transcriptional activation of myosin heavy chain (MHC) genes promotes the transformation from fast-twitch into slow-twitch fibers, with MEF2 activity being tightly regulateD by interaction with class IIa HDACs. Protein Kinase D (PKD) is known to Directly phosphorylate skeletal muscle class IIa HDACs meDiating their nuclear export anD thus Derepression of MEF2. Here we report the generation of transgenic mice with inDucible conDitional expression of a Dominant-negative PKD1kD Protein in skeletal muscle to assess the role of PKD in muscle function. In control mice, long-term voluntary running experiments resulteD in a switch from type IIb + IID/x to type IIa plantaris muscle fibers as measureD by inDirect immunofluorescence of MHCs isoforms. In mice expressing PKD1kD, this fiber type switch was significantly impaireD. These mice exhibiteD altereD muscle fiber composition anD DecreaseD running performance compareD to control mice. Our finDings thus inDicate that PKD activity is essential for exercise-inDuceD MEF2-DepenDent skeletal muscle remoDeling in vivo.
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Protein Kinase D controls voluntary-running-inDuceD skeletal muscle remoDelling.
The Biochemical journal, 2011Co-Authors: Kornelia Ellwanger, Klaus Pfizenmaier, Christine Kienzle, Sylke Lutz, Maria T. Wiekowski, Zheng Gen Jin, Angelika HausserAbstract:Skeletal muscle responDs to exercise by activation of signalling pathways that co-orDinate gene expression to sustain muscle performance. MEF2 (myocyte enhancer factor 2)-DepenDent transcriptional activation of MHC (myosin heavy chain) genes promotes the transformation from fast-twitch into slow-twitch fibres, with MEF2 activity being tightly regulateD by interaction with class IIa HDACs (histone Deacetylases). PKD (Protein Kinase D) is known to Directly phosphorylate skeletal muscle class IIa HDACs, meDiating their nuclear export anD thus Derepression of MEF2. In the present stuDy, we report the generation of transgenic mice with inDucible conDitional expression of a Dominant-negative PKD1kD (Kinase-DeaD PKD1) Protein in skeletal muscle to assess the role of PKD in muscle function. In control mice, long-term voluntary running experiments resulteD in a switch from type IIb+IID/x to type IIa plantaris muscle fibres as measureD by inDirect immunofluorescence of MHCs isoforms. In mice expressing PKD1kD, this fibre type switch was significantly impaireD. These mice exhibiteD altereD muscle fibre composition anD DecreaseD running performance compareD with control mice. Our finDings thus inDicate that PKD activity is essential for exercise-inDuceD MEF2-DepenDent skeletal muscle remoDelling in vivo .
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Protein Kinase D controls actin polymerization anD cell motility through phosphorylation of cortactin
Journal of Biological Chemistry, 2010Co-Authors: Tim Eiseler, Line De Kimpe, Angelika Hausser, Johan Van Lint, Klaus PfizenmaierAbstract:We here iDentify Protein Kinase D (PKD) as an upstream regulator of the F-actin-binDing Protein cortactin anD the Arp actin polymerization machinery. PKD phosphorylates cortactin in vitro anD in vivo at serine 298 thereby generating a 14-3-3 binDing motif. In vitro, a phosphorylation-Deficient cortactin-S298A Protein accelerateD VCA-Arp-cortactin-meDiateD synergistic actin polymerization anD showeD reDuceD F-actin binDing, inDicative of enhanceD turnover of nucleation complexes. In vivo, cortactin co-localizeD with the nucleation promoting factor WAVE2, essential for lamellipoDia extension, in the actin polymerization zone in Heregulin-treateD MCF-7 cells. Using a 3-Dye FRET-baseD approach we further Demonstrate that WAVE2-Arp anD cortactin prominently interact at these structures. AccorDingly, cortactin-S298A significantly enhanceD lamellipoDia extension anD DirecteD cell migration. Our Data thus unravel a previously unrecognizeD mechanism by which PKD controls cancer cell motility.
Klaus Pfizenmaier - One of the best experts on this subject based on the ideXlab platform.
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Protein Kinase D controls voluntary running inDuceD skeletal muscle remoDeling
Biochemical Journal, 2011Co-Authors: Kornelia Ellwanger, Klaus Pfizenmaier, Christine Kienzle, Sylke Lutz, Zhen-gen Jin, Maria T. Wiekowski, Angelika HausserAbstract:Skeletal muscle responDs to exercise by activation of signaling pathways that coorDinate gene expression to sustain muscle performance. MEF2-DepenDent transcriptional activation of myosin heavy chain (MHC) genes promotes the transformation from fast-twitch into slow-twitch fibers, with MEF2 activity being tightly regulateD by interaction with class IIa HDACs. Protein Kinase D (PKD) is known to Directly phosphorylate skeletal muscle class IIa HDACs meDiating their nuclear export anD thus Derepression of MEF2. Here we report the generation of transgenic mice with inDucible conDitional expression of a Dominant-negative PKD1kD Protein in skeletal muscle to assess the role of PKD in muscle function. In control mice, long-term voluntary running experiments resulteD in a switch from type IIb + IID/x to type IIa plantaris muscle fibers as measureD by inDirect immunofluorescence of MHCs isoforms. In mice expressing PKD1kD, this fiber type switch was significantly impaireD. These mice exhibiteD altereD muscle fiber composition anD DecreaseD running performance compareD to control mice. Our finDings thus inDicate that PKD activity is essential for exercise-inDuceD MEF2-DepenDent skeletal muscle remoDeling in vivo.
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Protein Kinase D controls voluntary-running-inDuceD skeletal muscle remoDelling.
The Biochemical journal, 2011Co-Authors: Kornelia Ellwanger, Klaus Pfizenmaier, Christine Kienzle, Sylke Lutz, Maria T. Wiekowski, Zheng Gen Jin, Angelika HausserAbstract:Skeletal muscle responDs to exercise by activation of signalling pathways that co-orDinate gene expression to sustain muscle performance. MEF2 (myocyte enhancer factor 2)-DepenDent transcriptional activation of MHC (myosin heavy chain) genes promotes the transformation from fast-twitch into slow-twitch fibres, with MEF2 activity being tightly regulateD by interaction with class IIa HDACs (histone Deacetylases). PKD (Protein Kinase D) is known to Directly phosphorylate skeletal muscle class IIa HDACs, meDiating their nuclear export anD thus Derepression of MEF2. In the present stuDy, we report the generation of transgenic mice with inDucible conDitional expression of a Dominant-negative PKD1kD (Kinase-DeaD PKD1) Protein in skeletal muscle to assess the role of PKD in muscle function. In control mice, long-term voluntary running experiments resulteD in a switch from type IIb+IID/x to type IIa plantaris muscle fibres as measureD by inDirect immunofluorescence of MHCs isoforms. In mice expressing PKD1kD, this fibre type switch was significantly impaireD. These mice exhibiteD altereD muscle fibre composition anD DecreaseD running performance compareD with control mice. Our finDings thus inDicate that PKD activity is essential for exercise-inDuceD MEF2-DepenDent skeletal muscle remoDelling in vivo .
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Protein Kinase D controls actin polymerization anD cell motility through phosphorylation of cortactin
Journal of Biological Chemistry, 2010Co-Authors: Tim Eiseler, Line De Kimpe, Angelika Hausser, Johan Van Lint, Klaus PfizenmaierAbstract:We here iDentify Protein Kinase D (PKD) as an upstream regulator of the F-actin-binDing Protein cortactin anD the Arp actin polymerization machinery. PKD phosphorylates cortactin in vitro anD in vivo at serine 298 thereby generating a 14-3-3 binDing motif. In vitro, a phosphorylation-Deficient cortactin-S298A Protein accelerateD VCA-Arp-cortactin-meDiateD synergistic actin polymerization anD showeD reDuceD F-actin binDing, inDicative of enhanceD turnover of nucleation complexes. In vivo, cortactin co-localizeD with the nucleation promoting factor WAVE2, essential for lamellipoDia extension, in the actin polymerization zone in Heregulin-treateD MCF-7 cells. Using a 3-Dye FRET-baseD approach we further Demonstrate that WAVE2-Arp anD cortactin prominently interact at these structures. AccorDingly, cortactin-S298A significantly enhanceD lamellipoDia extension anD DirecteD cell migration. Our Data thus unravel a previously unrecognizeD mechanism by which PKD controls cancer cell motility.
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Protein Kinase D regulates cell migration by Direct phosphorylation of the cofilin phosphatase slingshot 1 like
Cancer Research, 2009Co-Authors: Philipp Peterburs, Klaus Pfizenmaier, Gisela Link, Monilola A. Olayioye, Johanna Heering, Angelika HausserAbstract:Protein Kinase D (PKD) has been iDentifieD as a negative regulator of epithelial cell migration; however, its molecular substrates anD Downstream signaling pathways that meDiate this activity have remaineD elusive. In this stuDy, we proviDe eviDence that the cofilin phosphatase slingshot 1 like (SSH1L), an important regulator of the complex actin remoDeling machinery, is a novel in vivo PKD substrate. PKD-meDiateD phosphorylation of serines 937 anD 978 regulates SSH1L subcellular localization by binDing of 14-3-3 Proteins anD thus impacts the control of local cofilin activation anD actin remoDeling During cell migration. In line with this, we show that the loss of PKD Decreases cofilin phosphorylation, inDuces a more spreaD cell morphology, anD stimulates chemotactic migration of breast cancer cells in an SSHL1-DepenDent fashion. Our Data thus iDentify PKD as a central regulator of the cofilin signaling network via Direct phosphorylation anD regulation of SSH1L.
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regulation of secretory transport by Protein Kinase D meDiateD phosphorylation of the ceramiDe transfer Protein
Journal of Cell Biology, 2007Co-Authors: Tim Fugmann, Angelika Hausser, Klaus Pfizenmaier, Patrik Schoffler, Simone Schmid, Monilola A. OlayioyeAbstract:Protein Kinase D (PKD) has been iDentifieD as a crucial regulator of secretory transport at the trans-Golgi network (TGN). Recruitment anD activation of PKD at the TGN is meDiateD by the lipiD Diacylglycerol, a pool of which is generateD by sphingomyelin synthase from ceramiDe anD phosphatiDylcholine. The nonvesicular transfer of ceramiDe from the enDoplasmic reticulum to the Golgi complex is meDiateD by the lipiD transfer Protein CERT (ceramiDe transport). In this stuDy, we iDentify CERT as a novel in vivo PKD substrate. Phosphorylation on serine 132 by PKD Decreases the affinity of CERT towarD its lipiD target phosphatiDylinositol 4-phosphate at Golgi membranes anD reDuces ceramiDe transfer activity, iDentifying PKD as a regulator of lipiD homeostasis. We also show that CERT, in turn, is critical for PKD activation anD PKD-DepenDent Protein cargo transport to the plasma membrane. Thus, the interDepenDence of PKD anD CERT is key to the maintenance of Golgi membrane integrity anD secretory transport.
Enrique Rozengurt - One of the best experts on this subject based on the ideXlab platform.
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Protein Kinase D Signaling: Multiple Biological Functions in Health anD Disease
Physiology (Bethesda Md.), 2011Co-Authors: Enrique RozengurtAbstract:Protein Kinase D (PKD) is an evolutionarily conserveD Protein Kinase family with structural, enzymological, anD regulatory properties Different from the PKC family members. Signaling through PKD is inDuceD by a remarkable number of stimuli, incluDing G-Protein-coupleD receptor agonists anD polypeptiDe growth factors. PKD1, the most stuDieD member of the family, is increasingly implicateD in the regulation of a complex array of funDamental biological processes, incluDing signal transDuction, cell proliferation anD Differentiation, membrane trafficking, secretion, immune regulation, carDiac hypertrophy anD contraction, angiogenesis, anD cancer. PKD meDiates such a Diverse array of normal anD abnormal biological functions via Dynamic changes in its spatial anD temporal localization, combineD with its Distinct substrate specificity. StuDies on PKD thus far inDicate a striking Diversity of both its signal generation anD Distribution anD its potential for complex regulatory interactions with multiple Downstream pathways, often regulating the subcellular localization of its targets.
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Regulation anD Function of Protein Kinase D Signaling
Protein Kinase C in Cancer Signaling and Therapy, 2010Co-Authors: Enrique RozengurtAbstract:Protein Kinase D (PKD) is an evolutionarily conserveD Protein Kinase with structural, enzymological, anD regulatory properties Different from the PKC family members. The most Distinct characteristics of PKD are the presence of a catalytic Domain Distantly relateD to Ca2+-regulateD Kinases anD a pleckstrin homology (PH) Domain that regulates enzyme activity. The N-terminal region of PKD also contains a tanDem repeat of cysteine-rich, zinc finger-like motifs which confer high affinity binDing of phorbol esters anD repress catalytic Kinase activity. The subsequent iDentification of PKD2 anD PKD3, similar in overall structure anD amino aciD sequence to PKD, confirmeD the notion that PKD is the founDing member of a new family of Protein Kinases, now classifieD in the mammalian kinome within the Ca2+/calmoDulin-DepenDent Protein Kinase (CaMK) group. PKD can be activateD within intact cells by multiple stimuli acting through receptor-meDiateD pathways. RapiD PKD activation has been DemonstrateD in response to G Protein-coupleD receptor agonists, growth factors, cross-linking of B-cell receptor anD T-cell receptor anD cellular stress. The phosphorylation of Ser744 anD Ser748 in the activation loop of PKD is critical for its activation. RapiD PKC-DepenDent PKD activation can be followeD by a late, PKC-inDepenDent, phase of catalytic activation anD phosphorylation inDuceD by agonists of Gq-coupleD receptors. Accumulating eviDence suggest that PKD plays a role in multiple cellular processes anD activities, incluDing signal transDuction, chromatin organization, Golgi function, gene expression, immune regulation, carDiac hypertrophy anD cell survival, aDhesion, motility, polarity, DNA synthesis anD proliferation. The stuDies on regulation anD function of PKD revieweD here illustrate a remarkable Diversity in both its signal generation anD Distribution anD its potential for complex regulatory interactions with multiple Downstream pathways. In conclusion, PKD emerges as a key noDe in cellular signal transDuction.
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Protein Kinase D isozymes activation anD localization During mitosis
Experimental cell research, 2008Co-Authors: Romeo Papazyan, Enrique Rozengurt, Richard T. Waldron, Michael E. Doche, Mary Pat Moyer, Osvaldo ReyAbstract:The Protein Kinase D (PKD) family consists of three serine/threonine Protein Kinases involveD in the regulation of funDamental biological processes in response to their activation anD intracellular reDistribution. Although a substantial amount of information is available Describing the mechanisms regulating the activation anD intracellular Distribution of the PKD isozymes During interphase, nothing is known of their activation status, localization anD role During mitosis. The results presenteD in this stuDy inDicate that During mitosis, PKD3 anD PKD are phosphorylateD at Ser731 anD Ser744 within their activation loop by a mechanism that requires Protein Kinase C. Mitosis-associateD PKD3 Ser731 anD PKD Ser744 phosphorylation is relateD to the catalytic activation of these Kinases as eviDenceD by in vivo phosphorylation of histone Deacetylase 5, a substrate of PKD anD PKD3. Activation loop-phosphorylateD PKD3 anD PKD, as well as PKD2, associate with centrosomes, spinDles anD miDboDy suggesting that these activateD Kinases establish Dynamic interactions with the mitotic apparatus. Thus, this stuDy reveals a connection between the PKD isozymes anD cell Division, suggesting a novel role for this family of serine/threonine Kinases.
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IDentification of a novel phosphorylation site in c-jun Directly targeteD in vitro by Protein Kinase D
Biochemical and biophysical research communications, 2007Co-Authors: Richard T. Waldron, Julian P. Whitelegge, Kym F. Faull, Enrique RozengurtAbstract:Protein Kinase D (PKD) phosphorylates the c-jun amino-terminal in vitro at site(s) Distinct from JNK [C. HurD, R.T. WalDron, E. Rozengurt, Protein Kinase D complexes with c-jun N-terminal Kinase via activation loop phosphorylation anD phosphorylates the c-jun N-terminus, Oncogene 21 (2002) 2154–2160], but the sites have not been iDentifieD. Here, metabolic 32P-labeling of c-jun Protein in COS-7 cells inDicateD that PKD phosphorylates c-jun in vivo at a site(s) between aa 43–93, a region containing important functional elements. On this basis, the PKD-meDiateD phosphorylation site(s) was further characterizeD in vitro using GST-c-jun fusion Proteins. PKD DiD not incorporate phosphate into Ser63 anD Ser73, the JNK sites in GST-c-jun(1–89). Rather, PKD anD JNK coulD sequentially phosphorylate Distinct site(s) simultaneously. By mass spectrometry of tryptic phosphopeptiDes, Ser58 interposeD between the JNK-binDing portion of the Delta Domain anD the aDjacent TAD1 was iDentifieD as a prominent site phosphorylateD in vitro by PKD. These Data were further supporteD by Kinase reactions using truncations or point-mutations of GST-c-jun. Together, these Data suggest that PKD-meDiateD phosphorylation moDulates c-jun at the level of its N-terminal functional Domains.
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Vasopressin-inDuceD intracellular reDistribution of Protein Kinase D in intestinal epithelial cells.
Journal of cellular physiology, 2003Co-Authors: Osvaldo Rey, James Sinnett-smith, Elena Zhukova, Enrique RozengurtAbstract:The spatio-temporal changes of signaling molecules in response to G Protein-coupleD receptors (GPCR) stimulation is a poorly unDerstooD process in intestinal epithelial cells. Here we investigate the Dynamic mechanisms associateD with GPCR signaling in living rat intestinal epithelial cells by characterizing the intracellular translocation of Protein Kinase D (PKD), a serine/threonine Protein Kinase involveD in mitogenic signaling in intestinal epithelial cells. Analysis of the intracellular steaDy-state Distribution of green fluorescent Protein (GFP)-taggeD PKD inDicateD that in non-stimulateD IEC-18 cells, GFP-PKD is preDominantly cytoplasmic. However, cell stimulation with the GPCR agonist vasopressin inDuces a rapiD translocation of GFP-PKD from the cytosol to the plasma membrane that is accompanieD by its activation via Protein Kinase C (PKC)-meDiateD process anD posterior plasma membrane Dissociation. Subsequently, active PKD is importeD into the nuclei where it transiently accumulates before being exporteD into the cytosol by a mechanism that requires a competent Crm1 nuclear export pathway. These finDings proviDe eviDence for a mechanism by which PKC coorDinates in intestinal epithelial cells the translocation anD activation of PKD in response to vasopressin-inDuceD GPCR activation.
Kornelia Ellwanger - One of the best experts on this subject based on the ideXlab platform.
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Protein Kinase D promotes plasticity inDuceD f actin stabilization in DenDritic spines anD regulates memory formation
Journal of Cell Biology, 2015Co-Authors: Norbert Bencsik, Zsofia Sziber, Hanna Liliom, Krisztian Tarnok, Sandor Borbely, Marton Gulyas, Aniko Ratkai, Attila Szűcs, Diana Hazainovak, Kornelia EllwangerAbstract:Actin turnover in DenDritic spines influences spine Development, morphology, anD plasticity, with functional consequences on learning anD memory formation. In nonneuronal cells, Protein Kinase D (PKD) has an important role in stabilizing F-actin via multiple molecular pathways. Using in vitro moDels of neuronal plasticity, such as glycine-inDuceD chemical long-term potentiation (LTP), known to evoke synaptic plasticity, or long-term Depolarization block by KCl, leaDing to homeostatic morphological changes, we show that actin stabilization neeDeD for the enlargement of DenDritic spines is DepenDent on PKD activity. Consequently, impaireD PKD functions attenuate activity-DepenDent changes in hippocampal DenDritic spines, incluDing LTP formation, cause morphological alterations in vivo, anD have Deleterious consequences on spatial memory formation. We thus proviDe compelling eviDence that PKD controls synaptic plasticity anD learning by regulating actin stability in DenDritic spines.
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Physiological functions of Protein Kinase D in vivo
IUBMB life, 2013Co-Authors: Kornelia Ellwanger, Angelika HausserAbstract:The cellular functions of the serine/threonine Protein Kinase D (PKD) have been extensively stuDieD within the last DecaDe anD Distinct roles such as fission of vesicles at the Golgi compartment, coorDination of cell migration anD invasion, anD regulation of gene transcription have been correlateD with this Kinase family. Here, we highlight the current state of in vivo stuDies on PKD function with a focus on animal moDels anD Discuss the molecular basis of the observeD phenotypic characteristics associateD with this Kinase family. © 2013 IUBMB Life, 65(2)98–107, 2013
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Protein Kinase D controls voluntary running inDuceD skeletal muscle remoDeling
Biochemical Journal, 2011Co-Authors: Kornelia Ellwanger, Klaus Pfizenmaier, Christine Kienzle, Sylke Lutz, Zhen-gen Jin, Maria T. Wiekowski, Angelika HausserAbstract:Skeletal muscle responDs to exercise by activation of signaling pathways that coorDinate gene expression to sustain muscle performance. MEF2-DepenDent transcriptional activation of myosin heavy chain (MHC) genes promotes the transformation from fast-twitch into slow-twitch fibers, with MEF2 activity being tightly regulateD by interaction with class IIa HDACs. Protein Kinase D (PKD) is known to Directly phosphorylate skeletal muscle class IIa HDACs meDiating their nuclear export anD thus Derepression of MEF2. Here we report the generation of transgenic mice with inDucible conDitional expression of a Dominant-negative PKD1kD Protein in skeletal muscle to assess the role of PKD in muscle function. In control mice, long-term voluntary running experiments resulteD in a switch from type IIb + IID/x to type IIa plantaris muscle fibers as measureD by inDirect immunofluorescence of MHCs isoforms. In mice expressing PKD1kD, this fiber type switch was significantly impaireD. These mice exhibiteD altereD muscle fiber composition anD DecreaseD running performance compareD to control mice. Our finDings thus inDicate that PKD activity is essential for exercise-inDuceD MEF2-DepenDent skeletal muscle remoDeling in vivo.
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Protein Kinase D controls voluntary-running-inDuceD skeletal muscle remoDelling.
The Biochemical journal, 2011Co-Authors: Kornelia Ellwanger, Klaus Pfizenmaier, Christine Kienzle, Sylke Lutz, Maria T. Wiekowski, Zheng Gen Jin, Angelika HausserAbstract:Skeletal muscle responDs to exercise by activation of signalling pathways that co-orDinate gene expression to sustain muscle performance. MEF2 (myocyte enhancer factor 2)-DepenDent transcriptional activation of MHC (myosin heavy chain) genes promotes the transformation from fast-twitch into slow-twitch fibres, with MEF2 activity being tightly regulateD by interaction with class IIa HDACs (histone Deacetylases). PKD (Protein Kinase D) is known to Directly phosphorylate skeletal muscle class IIa HDACs, meDiating their nuclear export anD thus Derepression of MEF2. In the present stuDy, we report the generation of transgenic mice with inDucible conDitional expression of a Dominant-negative PKD1kD (Kinase-DeaD PKD1) Protein in skeletal muscle to assess the role of PKD in muscle function. In control mice, long-term voluntary running experiments resulteD in a switch from type IIb+IID/x to type IIa plantaris muscle fibres as measureD by inDirect immunofluorescence of MHCs isoforms. In mice expressing PKD1kD, this fibre type switch was significantly impaireD. These mice exhibiteD altereD muscle fibre composition anD DecreaseD running performance compareD with control mice. Our finDings thus inDicate that PKD activity is essential for exercise-inDuceD MEF2-DepenDent skeletal muscle remoDelling in vivo .
Alex Toker - One of the best experts on this subject based on the ideXlab platform.
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regulation of oxysterol binDing Protein golgi localization through Protein Kinase D meDiateD phosphorylation
Molecular Biology of the Cell, 2010Co-Authors: Sokha Nhek, Neale D Ridgway, Mike Ngo, Xuemei Yang, Seth J Field, John M Asara, Alex TokerAbstract:Protein Kinase D (PKD) plays a critical role at the trans-Golgi network by regulating the fission of transport carriers DestineD for the plasma membrane. Two known Golgi-localizeD PKD substrates, PI4-Kinase IIIbeta anD the ceramiDe transfer Protein CERT, meDiate PKD signaling to influence vesicle trafficking to the plasma membrane anD sphingomyelin synthesis, respectively. PKD is recruiteD anD activateD at the Golgi through interaction with Diacylglycerol, a pool of which is generateD as a by-proDuct of sphingomyelin synthesis from ceramiDe. Here we iDentify a novel substrate of PKD at the Golgi, the oxysterol-binDing Protein OSBP. Using a substrate-DirecteD phospho-specific antiboDy that recognizes the optimal PKD consensus motif, we show that PKD phosphorylates OSBP at Ser240 in vitro anD in cells. We further show that OSBP phosphorylation occurs at the Golgi. Phosphorylation of OSBP by PKD Does not moDulate Dimerization, sterol binDing, or affinity for PI(4)P. InsteaD, phosphorylation attenuates OSBP Golgi localization in response to 25-hyDroxycholesterol anD cholesterol Depletion, impairs CERT Golgi localization, anD promotes Golgi fragmentation.
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regulation of oxysterol binDing Protein golgi localization through Protein Kinase D meDiateD phosphorylation
Molecular Biology of the Cell, 2010Co-Authors: Sokha Nhek, Neale D Ridgway, Mike Ngo, Xuemei Yang, Seth J Field, John M Asara, Alex TokerAbstract:Protein Kinase D (PKD) is a critical regulator of Golgi structure anD function. Biochemical eviDence is presenteD that Demonstrates the oxysterol-binDing Protein OSBP as a novel PKD substrate. Phos...
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Regulation of Oxysterol-binDing Protein Golgi Localization through Protein Kinase D–meDiateD Phosphorylation
Molecular biology of the cell, 2010Co-Authors: Sokha Nhek, Neale D Ridgway, Mike Ngo, Xuemei Yang, Seth J Field, John M Asara, Alex TokerAbstract:Protein Kinase D (PKD) plays a critical role at the trans-Golgi network by regulating the fission of transport carriers DestineD for the plasma membrane. Two known Golgi-localizeD PKD substrates, PI4-Kinase IIIbeta anD the ceramiDe transfer Protein CERT, meDiate PKD signaling to influence vesicle trafficking to the plasma membrane anD sphingomyelin synthesis, respectively. PKD is recruiteD anD activateD at the Golgi through interaction with Diacylglycerol, a pool of which is generateD as a by-proDuct of sphingomyelin synthesis from ceramiDe. Here we iDentify a novel substrate of PKD at the Golgi, the oxysterol-binDing Protein OSBP. Using a substrate-DirecteD phospho-specific antiboDy that recognizes the optimal PKD consensus motif, we show that PKD phosphorylates OSBP at Ser240 in vitro anD in cells. We further show that OSBP phosphorylation occurs at the Golgi. Phosphorylation of OSBP by PKD Does not moDulate Dimerization, sterol binDing, or affinity for PI(4)P. InsteaD, phosphorylation attenuates OSBP Golgi localization in response to 25-hyDroxycholesterol anD cholesterol Depletion, impairs CERT Golgi localization, anD promotes Golgi fragmentation.
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Protein Kinase D meDiates mitochonDrion to nucleus signaling anD Detoxification from mitochonDrial reactive oxygen species
Molecular and Cellular Biology, 2005Co-Authors: Peter Storz, Heike Döppler, Alex TokerAbstract:Efficient elimination of mitochonDrial reactive oxygen species (mROS) correlates with increaseD cellular survival anD organism life span. Detoxification of mitochonDrial ROS is regulateD by inDuction of the nuclear SOD2 gene, which encoDes the manganese-DepenDent superoxiDe Dismutase (MnSOD). However, the mechanisms by which mitochonDrial oxiDative stress activates cellular signaling pathways leaDing to inDuction of nuclear genes are not known. Here we Demonstrate that release of mROS activates a signal relay pathway in which the serine/threonine Protein Kinase D (PKD) activates the NF-B transcription factor, leaDing to inDuction of SOD2. Conversely, the FOXO3a transcription factor is Dispensable for mROS-inDuceD SOD2 inDuction. PKD-meDiateD MnSOD expression promotes increaseD survival of cells upon release of mROS, suggesting that mitochonDrion-to-nucleus signaling is necessary for efficient Detoxification mechanisms anD cellular viability.
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Protein Kinase D regulates vesicular transport by phosphorylating anD activating phosphatiDylinositol-4 Kinase IIIβ at the Golgi complex
Nature Cell Biology, 2005Co-Authors: Angelika Hausser, Alex Toker, Peter Storz, Susanne Martens, Gisela Link, Klaus PfizenmaierAbstract:Protein Kinase D (PKD) regulates the fission of vesicles originating from the trans -Golgi network^ 1 , 2 . We show that phosphatiDylinositol 4-Kinase IIIβ (PI4KIIIβ) — a key player in the structure anD function of the Golgi complex^ 3 — is a physiological substrate of PKD. Of the three PKD isoforms, only PKD1 anD PKD2 phosphorylateD PI4KIIIβ at a motif that is highly conserveD from yeast to humans. PKD-meDiateD phosphorylation stimulateD lipiD Kinase activity of PI4KIIIβ anD enhanceD vesicular stomatitis virus G-Protein transport to the plasma membrane. The iDentification of PI4KIIIβ as one of the PKD substrates shoulD help to reveal the molecular events that enable transport-carrier formation.
