1,025 research outputs found
Synapses are regulated by the cytoplasmic tyrosine kinase Fer in a pathway mediated by p120catenin, Fer, SHP-2, and β-catenin
Localization of presynaptic components to synaptic sites is critical for hippocampal synapse formation. Cell adhesion–regulated signaling is important for synaptic development and function, but little is known about differentiation of the presynaptic compartment. In this study, we describe a pathway that promotes presynaptic development involving p120catenin (p120ctn), the cytoplasmic tyrosine kinase Fer, the protein phosphatase SHP-2, and β-catenin. Presynaptic Fer depletion prevents localization of active zone constituents and synaptic vesicles and inhibits excitatory synapse formation and synaptic transmission. Depletion of p120ctn or SHP-2 similarly disrupts synaptic vesicle localization with active SHP-2, restoring synapse formation in the absence of Fer. Fer or SHP-2 depletion results in elevated tyrosine phosphorylation of β-catenin. β-Catenin overexpression restores normal synaptic vesicle localization in the absence of Fer or SHP-2. Our results indicate that a presynaptic signaling pathway through p120ctn, Fer, SHP-2, and β-catenin promotes excitatory synapse development and function
Cancer cells exploit an orphan RNA to drive metastatic progression.
Here we performed a systematic search to identify breast-cancer-specific small noncoding RNAs, which we have collectively termed orphan noncoding RNAs (oncRNAs). We subsequently discovered that one of these oncRNAs, which originates from the 3' end of TERC, acts as a regulator of gene expression and is a robust promoter of breast cancer metastasis. This oncRNA, which we have named T3p, exerts its prometastatic effects by acting as an inhibitor of RISC complex activity and increasing the expression of the prometastatic genes NUPR1 and PANX2. Furthermore, we have shown that oncRNAs are present in cancer-cell-derived extracellular vesicles, raising the possibility that these circulating oncRNAs may also have a role in non-cell autonomous disease pathogenesis. Additionally, these circulating oncRNAs present a novel avenue for cancer fingerprinting using liquid biopsies
An AMPKa2-specific phospho-switch controls lysosomal targeting for activation
AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) are metabolic kinases that co-ordinate nutrient supply with cell growth. AMPK negatively regulates mTORC1, and mTORC1 reciprocally phosphorylates S345/7 in both AMPK α-isoforms. We report that genetic or torin1-induced loss of α2-S345 phosphorylation relieves suppression of AMPK signaling; however, the regulatory effect does not translate to α1-S347 in HEK293T or MEF cells. Dephosphorylation of α2-S345, but not α1-S347, transiently targets AMPK to lysosomes, a cellular site for activation by LKB1. By mass spectrometry, we find that α2-S345 is basally phosphorylated at 2.5-fold higher stoichiometry than α1-S347 in HEK293T cells and, unlike α1, phosphorylation is partially retained after prolonged mTORC1 inhibition. Loss of α2-S345 phosphorylation in endogenous AMPK fails to sustain growth of MEFs under amino acid starvation conditions. These findings uncover an α2-specific mechanism by which AMPK can be activated at lysosomes in the absence of changes in cellular energy
Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis
AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis and a therapeutic target for metabolic diseases. Co/post-translational N-myristoylation of glycine-2 (Gly2) of the AMPK β subunit has been suggested to regulate the distribution of the kinase between the cytosol and membranes through a “myristoyl switch” mechanism. However, the relevance of AMPK myristoylation for metabolic signaling in cells and in vivo is unclear. Here, we generated knockin mice with a Gly2-to-alanine point mutation of AMPKβ1 (β1-G2A). We demonstrate that non-myristoylated AMPKβ1 has reduced stability but is associated with increased kinase activity and phosphorylation of the Thr172 activation site in the AMPK α subunit. Using proximity ligation assays, we show that loss of β1 myristoylation impedes colocalization of the phosphatase PPM1A/B with AMPK in cells. Mice carrying the β1-G2A mutation have improved metabolic health with reduced adiposity, hepatic lipid accumulation, and insulin resistance under conditions of high-fat diet-induced obesity
Isolation of Flow and Nonflow Correlations by Two- and Four-Particle Cumulant Measurements of Azimuthal Harmonics in 200 GeV Au+Au Collisions
A data-driven method was applied to measurements of Au+Au collisions at
200 GeV made with the STAR detector at RHIC to isolate
pseudorapidity distance -dependent and -independent
correlations by using two- and four-particle azimuthal cumulant measurements.
We identified a component of the correlation that is -independent,
which is likely dominated by anisotropic flow and flow fluctuations. It was
also found to be independent of within the measured range of
pseudorapidity . The relative flow fluctuation was found to be for particles of transverse momentum
less than GeV/. The -dependent part may be attributed to
nonflow correlations, and is found to be relative to the
flow of the measured second harmonic cumulant at
Centrality and transverse momentum dependence of elliptic flow of multi-strange hadrons and meson in Au+Au collisions at = 200 GeV
We present high precision measurements of elliptic flow near midrapidity
() for multi-strange hadrons and meson as a function of
centrality and transverse momentum in Au+Au collisions at center of mass energy
200 GeV. We observe that the transverse momentum dependence of
and is similar to that of and , respectively,
which may indicate that the heavier strange quark flows as strongly as the
lighter up and down quarks. This observation constitutes a clear piece of
evidence for the development of partonic collectivity in heavy-ion collisions
at the top RHIC energy. Number of constituent quark scaling is found to hold
within statistical uncertainty for both 0-30 and 30-80 collision
centrality. There is an indication of the breakdown of previously observed mass
ordering between and proton at low transverse momentum in the
0-30 centrality range, possibly indicating late hadronic interactions
affecting the proton .Comment: 7 pages and 4 figures, Accepted for publication in Physical Review
Letter
Charged-to-neutral correlation at forward rapidity in Au+Au collisions at =200 GeV
Event-by-event fluctuations of the ratio of inclusive charged to photon
multiplicities at forward rapidity in Au+Au collision at =200
GeV have been studied. Dominant contribution to such fluctuations is expected
to come from correlated production of charged and neutral pions. We search for
evidences of dynamical fluctuations of different physical origins. Observables
constructed out of moments of multiplicities are used as measures of
fluctuations. Mixed events and model calculations are used as baselines.
Results are compared to the dynamical net-charge fluctuations measured in the
same acceptance. A non-zero statistically significant signal of dynamical
fluctuations is observed in excess to the model prediction when charged
particles and photons are measured in the same acceptance. We find that, unlike
dynamical net-charge fluctuation, charge-neutral fluctuation is not dominated
by correlation due to particle decay. Results are compared to the expectations
based on the generic production mechanism of pions due to isospin symmetry, for
which no significant (<1%) deviation is observed.Comment: 14 pages, 6 figure
Beam energy dependent two-pion interferometry and the freeze-out eccentricity of pions in heavy ion collisions at STAR
We present results of analyses of two-pion interferometry in Au+Au collisions
at = 7.7, 11.5, 19.6, 27, 39, 62.4 and 200 GeV measured in the
STAR detector as part of the RHIC Beam Energy Scan program. The extracted
correlation lengths (HBT radii) are studied as a function of beam energy,
azimuthal angle relative to the reaction plane, centrality, and transverse mass
() of the particles. The azimuthal analysis allows extraction of the
eccentricity of the entire fireball at kinetic freeze-out. The energy
dependence of this observable is expected to be sensitive to changes in the
equation of state. A new global fit method is studied as an alternate method to
directly measure the parameters in the azimuthal analysis. The eccentricity
shows a monotonic decrease with beam energy that is qualitatively consistent
with the trend from all model predictions and quantitatively consistent with a
hadronic transport model.Comment: 27 pages; 27 figure
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