Macroautophagy (or autophagy) is a conserved degradative pathway that has been implicated in a number of biological processes, including organismal aging, innate immunity, and the progression of human cancers. This pathway was initially identified as a cellular response to nutrient deprivation and is essential for cell survival during these periods of starvation. Autophagy is highly regulated and is under the control of a number of signaling pathways, including the Tor pathway, that coordinate cell growth with nutrient availability. These pathways appear to target a complex of proteins that contains the Atg1 protein kinase. The data here show that autophagy in Saccharomyces cerevisiae is also controlled by the cAMP-dependent protein kinase (PKA) pathway. Elevated levels of PKA activity inhibited autophagy and inactivation of the PKA pathway was sufficient to induce a robust autophagy response. We show that in addition to Atg1, PKA directly phosphorylates Atg13, a conserved regulator of Atg1 kinase activity. This phosphorylation regulates Atg13 localization to the preautophagosomal structure, the nucleation site from which autophagy pathway transport intermediates are formed. Atg13 is also phosphorylated in a Tor-dependent manner, but these modifications appear to occur at positions distinct from the PKA phosphorylation sites identified here. In all, our data indicate that the PKA and Tor pathways function independently to control autophagy in S. cerevisiae, and that the Atg1/Atg13 kinase complex is a key site of signal integration within this degradative pathway.cAMP-dependent protein kinase ͉ macroautophagy ͉ stationary phase ͉ Tor protein kinase M acroautophagy (hereafter autophagy) is a highlyconserved membrane trafficking pathway that is responsible for the turnover of bulk cytoplasmic protein and organelles (1, 2). This pathway was initially identified as a cellular response to nutrient deprivation (3, 4). However, recent studies indicate that autophagy is involved in a wide variety of physiological processes, including tissue remodeling during development, the removal of protein aggregates, and innate immune responses (5, 6). During autophagy, an isolation membrane emanates from a nucleation site that is known as the preautophagosomal structure (PAS) in Saccharomyces cerevisiae and the phagophore assembly site in mammals (7,8). This double membrane encapsulates nearby cytoplasm and ultimately targets it to the vacuole/ lysosome for degradation. The breakdown products are then recycled to allow for the synthesis of the macromolecules needed for survival during the period of starvation (9). The cellular components mediating autophagy were initially described in S. cerevisiae, and orthologs of many of these Atg proteins have since been identified in other eukaryotes (10, 11).The flux through the autophagy pathway is tightly controlled by multiple signaling pathways, including the Tor pathway, that are responsible for coordinating cell growth with nutrient availability. One of the key targets of this control a...
S U M M A R Y3-D V P and V S models for the crust and upper mantle beneath the Taiwan area have been determined using selected high-resolution earthquake data from an island-wide seismic network and two local seismic arrays. Lateral structural variations in the upper crust, as also evident from surface geology, are responsible for the observed large traveltime residuals or station corrections. Prior shallow velocity information inferred from traveltime residuals and joint hypocentral determination (JHD) station corrections for the uppermost crust is essential to facilitate a reliable tomographic inversion. A finite-difference method, that is efficient and accurate for a highly heterogeneous velocity structure, is applied to calculate P-and S-wave traveltimes from the source to receiving stations. All earthquakes in the Taiwan Central Weather Bureau's catalogue are then relocated using the resultant 3-D V P and V S models. The depth of the Moho varies significantly, especially along the east-west direction. In the western Coastal Plain and Western Foothills the depth of the Moho is around 35 km, which deepens gradually eastward, reaches a maximum depth of ∼55 km beneath the eastern Central Mountain Range, shallows up rapidly beneath the Longitudinal Valley and Coastal Range, and merges with the thin Philippine Sea Plate offshore of eastern Taiwan. In central Taiwan, the Central Mountain Range is bounded to the east and west by two steeply westward dipping active faults from the upper crust to a depth of about 30 km. Therefore, the uplifted and thickened Central Mountain Range serves as a backstop for the converging Eurasian and Philippine Sea plates. The crust beneath the Central Mountain Range is characterized by a brittle, high-velocity and seismically active upper crust (<15 km) and a ductile, low-velocity and aseismic mid-to-lower crust (below 15 km), most probably due to the high geothermal activity from the excess heat supplied from the hot upper mantle beneath the thin oceanic crust to the east, from the surrounding hotter upper mantle beneath the thickened continental crust, and from shear heating during active collision. The collision zone in eastern Taiwan is characterized by an active and steeply eastward dipping seismic zone along a region of low V P and high V P /V S ratio near the Taitung region in southeastern Taiwan. It transforms into an active westward steeply dipping seismic zone along a transition zone between the high V P and V S oceanic crust and the low V P and V S continental crust near Hualien region in central eastern Taiwan. There is no apparent seismicity within many sedimentary basins imaged from the tomographic inversion. However, a few basins are either bounded on one side by an active fault or are characterized by blind faults beneath. The geometry of the subduction zone in northeastern Taiwan can be clearly imaged from the relocated earthquake locations. Behind the subduction, a region of low V P and high V P /V S ratio at depths of 5 to 10 km can be identified beneath the Tatun-Ch...
Key Points• CLL exosomes exhibit a disease-relevant microRNA signature.• B-cell receptor signaling enhances exosome secretion in CLL that can be antagonized by ibrutinib.Multiple studies show that chronic lymphocytic leukemia (CLL) cells are heavily dependent on their microenvironment for survival. Communication between CLL cells and the microenvironment is mediated through direct cell contact, soluble factors, and extracellular vesicles. Exosomes are small particles enclosed with lipids, proteins, and small RNAs that can convey biological materials to surrounding cells. Our data herein demonstrate that CLL cells release significant amounts of exosomes in plasma that exhibit abundant CD37, CD9, and CD63 expression. Our work also pinpoints the regulation of B-cell receptor (BCR) signaling in the release of CLL exosomes: BCR activation by a-immunoglobulin (Ig)M induces exosome secretion, whereas BCR inactivation via ibrutinib impedes a-IgM-stimulated exosome release. Moreover, analysis of serial plasma samples collected from CLL patients on an ibrutinib clinical trial revealed that exosome plasma concentration was significantly decreased following ibrutinib therapy. Furthermore, microRNA (miR) profiling of plasma-derived exosomes identified a distinct exosome microRNA signature, including miR-29 family, miR-150, miR-155, and miR-223 that have been associated with CLL disease. Interestingly, expression of exosome miR-150 and miR-155 increases with BCR activation. In all, this study successfully characterized CLL exosomes, demonstrated the control of BCR signaling in the release of CLL exosomes, and uncovered a disease-relevant exosome microRNA profile. (Blood. 2015;125(21):3297-3305) IntroductionChronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the western world and remains incurable with current therapies. Understanding the different contributors to pathogenesis in CLL represents a path by which improved therapeutic options can be proposed. Although the pathogenesis of CLL for many years has been attributed to defective apoptosis of tumor cells, robust death is typically noted when these are removed from the body, suggesting a strong role of nurturing in the tumor microenvironment.1 In vivo, CLL cells reside in close contact with T lymphocytes, stromal cells, monocyte-derived nurse-like cells, follicular dendritic cells, and macrophages, collectively referred to as the "microenvironment." Interactions between these components result in CLL cell trafficking, survival, proliferation, and the increase of the apoptotic threshold, which may be partly dependent on direct physical cell-to-cell contact or mediated through soluble factors. This crosstalk between CLL and the microenvironment is bidirectional; thus, CLL cells are not only being supported by the microenvironment but also are capable of activating and signaling through the secretion of mediators that sustain and promote their survival advantage. In vitro models and gene expression profiles have identified important pathways for the...
SUMMARY Tetraspanins are commonly believed to act only as “molecular facilitators”, with no direct role in signal transduction. We herein demonstrate that upon ligation, CD37, a tetraspanin molecule expressed on mature normal and transformed B-cells, becomes tyrosine phosphorylated, associates with proximal signaling molecules, and initiates a cascade of events leading to apoptosis. Moreover, we have identified two tyrosine residues with opposing regulatory functions, one lies in the N-terminal domain of CD37 in a predicted “ITIM-like” motif and mediates SHP1-dependent death whereas the second lies in a predicted “ITAM motif” in the C-terminal domain of CD37 and counteracts death signals by mediating phosphatidylinositol 3-kinase-dependent survival.
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