These observations demonstrate that cooperating PKDs regulate a crucial nervous-system function. Dear Andy R Many thanks for your review.
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Your 67 Sixtyseven Sportsbar Team. We have eaten here a few times before hockey games. A varied menu with reasonable prices for Zug. Were lucky to be there on a Wednesday evening when they serve excellent ribs, as much as you want!!
Dear Andy R Many thanks for your review. It is a good place if you like Hamburger with friends. I tried the chicken burger which was very good and the fries were awesome! Dear Gep33 Many thanks for your review. We are looking forward to welcome you soon again. We come here for burgers - especially the 67 knock-out burger. Very well done as well as the fries that come with it According to friends, all other sandwiches and burgers are very good as well. The staff is friendly and fast.
Dear Anja H Many thanks for your review. Nice to hear that you like our 67 Knockout Burger, Triple Sandwich. We come here once in awhile for a burger. They are homemade burgers that can be cooked medium - a nice change from the frozen hamburger patties that can be found elsewhere in switzerland. The kids menu was standard. Kids enjoyed the colouring that was Dear simplefamilytravel Many thanks for your review.
Our 67 Knockout Burger is always homemade and has gramms of beef. It's not cheap, but worth the price. On par with korner or bite in zürich. Will definitely come back here to try their other food. Vielen herzlichen Dank für die super Burger Komplimente! All of your saved places can be found here in My Trips. Log in to get trip updates and message other travelers. Log in Join Recently viewed Bookings Inbox. Weststrasse 11 Arenaplatz , Zug , Switzerland.
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Future work should aim to express authentic substrates tagged with improved FRET reporters at physiological levels, allowing the determination of the distinctive dynamics of PKD-mediated signalling at the cytoplasmic surfaces of Golgi, mitochondrial and plasma membranes, as well as in the actin cytoskeleton and nuclei of intact cells. Such studies would expand our understanding of localized, organelle-specific PKD regulation and functions in normal and disease-derived cells.
Due to space limitations, studies on PKD-mediated phosphorylation of Hsp27, CREB and Par-1b were not included in this Review; readers are encouraged to consult the cited references for further information. PKD promotes cell survival after oxidative stress.
When hormones or phorbol dibutyrate activate PKDs at non-mitochondrial locations, Tyr 93 is not phosphorylated and MnSOD and other protective proteins are not induced. Isoforms of protein kinase D regulate crucial aspects of cell physiology. A Cell survival after oxidative stress. B Inhibition of cell migration. PKD phosphorylates SSH1L and cortactin in the F-actin cytoskeleton, leading to inhibition of actin-severing and polymerization activities that enable lamellipodium formation and, thus, inhibition of cell migration.
C Golgi-vesicle fission and transport. PKD1 activation leads to PI4P production, which enables the delivery of endoplasmic-reticulum-derived cholesterol and ceramide to Golgi membranes by the docking of transfer proteins with PI4P. There, ceramide and phosphocholine are converted to sphingomyelin and DAG.
Sphingomyelin and cholesterol are crucial for packaging and sorting of TGN vesicles and DAG increases the curvature of the TGN membrane, thereby facilitating fission and transport of vesicles to the plasma membrane inset. PKD1 prevents excessive, potentially toxic accumulation of cholesterol and ceramide through a negative-feedback loop.
De-repressed MEF2 recruits co-activators and drives cell-specific programmes of gene transcription. Specific pathways are detailed in the text. Our knowledge of PKD-mediated survival signalling is incomplete. Plasma-membrane-targeted PKD1 is activated after pre-T-cell receptor stimulation.
Cofilin severs actin filaments at the leading edge of motile cells, thereby generating barbed ends and a supply of actin monomers. This process is coupled to actin depolymerization at the rear of the cell, thus generating cellular movement. SSH1L— complexes translocate to the cytoplasm, where they are segregated from phospho-cofilin Fig 2B. The pSer 3—cofilin concentration increases, barbed-end formation is blocked and cell migration ceases. Stabilization disrupts repetition of the motile cycle underlying lamellipodium formation.
As a result, the affinity of CRK for F-actin remodelling proteins is diminished, leading-edge protrusions cannot be formed and cells become non-motile. PKD1 is essential for maintaining E-Cad gene transcription and repressing mesenchymal protein expression Du et al, Consequently, SNAIL target genes are de-repressed and E-Cad and other proteins that mediate adherens-junction formation and immobility are produced. Restoration of PKD1 expression in invasive breast-cancer cells decreased migration and invasion in transwell and matrigel assays.
The mechanism through which this occurs is unknown. Thus, targeted PKD1 gene therapy, re-expression of PKD1 by drugs that counter DNA or chromatin modification, or compounds that optimally activate pre-existing PKD1, might diminish migration and metastasis of breast and prostate tumour cells.
The attractive idea that PKD1 opposes EMT in developing cancers—by acting as a tumour or metastasis suppressor Du et al, —needs further evaluation because the available data are inconclusive.
Microarray analysis of human prostate tumour samples revealed correlations between decreased PKD1 and E-Cad mRNA levels and metastasis in one study, but no statistically significant associations were found in a second, larger collection of tumours. Determination of the relative importance of these effectors in various normal and transformed cell types and physiological contexts is a central theme for further investigation Sidebar A.
The quantification of the contributions of individual effectors to the integrated effects of PKD on cell motility will enhance our understanding of stable tissue organization, EMT and acquisition of metastatic potential by cancer cells.
In principle, PKD signalling to the actin cytoskeleton can be diversified and amplified by interactions among D-kinase effectors. Golgi vesicle fission and transport. The non-redundant PKDs might be spatially segregated in TGN sub-compartments, regulate distinct functions or operate as heterodimers. However, only small amounts of total PKD2 and PKD3 proteins are engaged in complexes, and it is not known whether heterodimers accumulate on Golgi membranes.
Thus, these mechanisms link ceramide, sphingomyelin and cholesterol levels to PKD-stimulated export of TGN cargo to the plasma membrane. This negative feedback loop Fig 2C could fine-tune Golgi sphingomyelin and DAG synthesis, and prevent build-up of toxic levels of cholesterol and sphingomyelin. The PKDs direct sorting and packaging of integral membrane proteins in TGN-derived vesicles, which fuse selectively with the plasma membrane that envelops dendrites Bisbal et al, ; Czondor et al, This generates and maintains neuronal polarity and specialized post-synaptic functions.
Increases or decreases in PKD activity cause parallel changes in dendritic branching. PKD depletion increases the endocytosis of dendritic-membrane proteins, but has no effect on vesicle fission Bisbal et al, Thus, neuronal, Golgi-bound PKDs sustain cell polarity and dendritic specialization by ensuring differential protein sorting, packaging and targeting in the TGN and suppressing endocytosis of dendritic membrane proteins.
The PKD effectors that are relevant to these processes are unknown. PKD1 phosphorylates KI Table 1 , a transmembrane scaffold protein that accumulates at the dendritic plasma membrane Sanchez-Ruiloba et al, and modulates phosphorylation of MAP1 and stathmin by other protein kinases.
KI regulates neuronal development, morphogenesis and polarity Higuero et al, Autophosphorylation of PKD1 Ser is a crucial step in routing KI from the TGN to the plasma membrane, but the underlying mechanism for this is not completely understood Sanchez-Ruiloba et al, PKD1 is a key downstream effector that links binding of ACh by the receptor to enhanced, glucose-dependent insulin secretion Kong et al, Thus, PKD1 mediates neural regulation of insulin release and contributes to homeostatic regulation of glucose metabolism.
These proteins degrade the performance of the adult heart, leading to compensatory hypertrophy, and eventually heart failure Fielitz et al, These observations and studies in mice lacking or overexpressing heart PKD1 Fielitz et al, indicate that PKD1 is a central mediator of persistent, stress-induced cardiac hypertrophy. PKD1 also mediates dynamic, non-transcriptional regulation of myocardial excitation—contraction coupling.
Depletion of PKD1 in skeletal muscle diminishes endurance, but unexpectedly does not alter contractile protein expression.
Thus, further work is needed to establish a molecular explanation for the anti-fatigue effects of PKD1.
As a consequence, MEF2-dependent and -independent angiogenic gene expression is switched on Ha et al, ; Wang et al, HDAC7-regulated gene repression and de-repression are indispensable for endothelial-cell migration, tube formation and genesis of capillaries; other HDACs are nonessential. Bone morphogenetic proteins promote bone formation and maintain the skeleton by activating signalling pathways that converge on RUNX, a regulator of osteoblast gene transcription.
Animals homozygous for a dkf-2 -null allele develop and reproduce normally Feng et al, and can be reconstituted with wild-type or mutant transgenes and challenged with different stimuli to analyse DKF-2 regulation and function in vivo.
Activated DKF-2A induces high-level accumulation of 85 mRNAs encoding antimicrobial peptides and proteins that sustain intestinal epithelium. Thus, the integration of signals produced by DAG—PKD controlled pathways in both neurons and intestinal cells is required to generate a learned behaviour: These observations demonstrate that cooperating PKDs regulate a crucial nervous-system function.
Whether DKF-2A contributes to behavioural plasticity by transducing a starvation signal in the intestine remains to be determined.
DKF-2A activation might trigger secretion of a diffusible gut hormone that binds to neuronal receptors, thereby coupling an intestinal signal to regulation of neuronal physiology. The regulation and function of PKD isoforms can be markedly different Fig 3.
Animals lacking PKD2, which is abundantly expressed in T and B lymphocytes, develop and reproduce normally. PKD2 deficiency does not alter T- and B-cell development, but T-cell-receptor-stimulated cytokine production and T-cell-dependent immunoglobulin G and immunoglobulin M production are inhibited Matthews et al, , thereby revealing unique functions of PKD2.
Intracellular distribution of protein kinase D effectors. PKDs provide integrated physiological responses to extracellular stimuli by disseminating signals carried by DAG to distinct groups of effectors located in several cell compartments. Details are provided in the text.
PKD2 shuttles between the cytoplasm and nucleus of gastric cancer cells. Pkd3 gene disruption causes only a minor skeletal defect in mice, indicating that it has a minimal role in development Matthews et al, This is associated with upregulation of pro-survival signalling pathways and progression of invasive prostate cancer Chen et al, Hence, PKD3 might be a marker and a drug target in prostate cancer. This suggests that PKD isoforms colocalize with one or a subset of receptor—PLC signalling modules at discrete plasma membrane micro-domains.
If differentially regulated PKDs phosphorylate a shared substrate, then the concentration and net activity of phospho-effectors would reflect integrated input signals from several pathways. However, pathway-specific effectors cannot be excluded. The observations that PKDs promote cardiac hypertrophy, angiogenesis and migration of some cancer cells prompted development of PKD inhibitors as therapeutic agents. Go, an indolocarbazole, effectively inhibits PKDs Table 2. In combination with other tools, Go facilitated characterization of PKD functions in cell lines.
However, Go also inhibits other protein kinases at the concentrations required for PKD inhibition Bain et al, , making it difficult to interpret results. Data on cross-inhibition of other protein kinases by CRT compounds were not available when this Review was completed.
NB, a benzoxoloazepinolone, is a less-promiscuous PKD inhibitor that partly suppresses prostate-cancer-cell migration, invasion and proliferation in culture Lavalle et al, Nevertheless, some effects of NB might reflect inhibition of a few off-target kinases Table 2.
Anticipated improvements in specificity and cytotoxicity, along with testing in animals, might yield benzoxoloazepinolone PKD inhibitors suitable for clinical trials on prostate cancer Lavalle et al, Unexpectedly, BPKDi did not diminish hypertrophy, which might be due to insufficient drug availability or compensatory cardiac gene expression. Systematic pharmacological manipulations and the development of sensitive assays for PKD1 activation in heart muscle will be needed to assess further the efficacy of amidobipyridyl inhibitors.
Oral administration of CRT reduces tumour growth in subcutaneous and orthotopic pancreatic cancer xenografts in mice Harikumar et al, Angiogenesis is also inhibited in CRTtreated tumour explants Ochi et al, These results suggest that PKDs could be targets for therapy in a high-mortality cancer that has limited treatment options.
PKDs are expressed in many mammalian tissues, but knowledge of their in vivo functions is limited to glucose- and ACh-regulated insulin release, a subset of TCR-regulated functions, and epinephrine- or ET1-stimulated cardiac hypertrophy. Thus, generation of mouse models—such as conditional knockouts of PKD isoforms and tissue-specific knock-in of mutated Pkd genes—are high priorities.
The characterization of pertinent mutants will expand our understanding of the physiological consequences of PKD activation. The discovery of key roles for gut and neuronal PKDs in C. Ultimately, comprehensive, mechanistic understanding of PKD function will require detailed characterization of D-kinase trans - and autophosphorylation and substrate phosphorylation dynamics at all relevant intracellular locations.
Thus, it will be essential to identify the locations and quantify the contributions of various DAG generators to understand the intracellular and molecular basis for PKD activation. A recent study indicates that persistent phosphorylation of HDAC7 by constitutively active PKDs is crucial for maintaining differentiation and functions of cytotoxic T-lymphocytes Navarro et al,