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Journal of Cell Biology

Alexandria Colaço, Marja Jäättelä
The lysosomal Ragulator complex regulates cell metabolism and growth by coordinating the activities of metabolic signaling pathways with nutrient availability. In this issue, Filipek et al. (2017. J. Cell Biol. and Pu et al. (2017. J. Cell Biol. introduce a role for Ragulator in growth factor- and nutrient-regulated lysosomal trafficking.
November 14, 2017: Journal of Cell Biology
Alejandra I Romero-Morales, Natalya A Ortolano, Vivian Gama
Establishment of apico-basal polarity is critical for the lumenal epiblast-like morphogenesis of human pluripotent stem cells (hPSCs). In this issue, Taniguchi et al. (2017. J Cell Biol. describe a structure called the apicosome, generated in single hPSCs, that allows them to self-organize and form the lumenal epiblast-like stage.
November 14, 2017: Journal of Cell Biology
Xi Wu, Lanlan Li, Hui Jiang
Mitochondria are double-membraned organelles playing essential metabolic and signaling functions. The mitochondrial proteome is under surveillance by two proteolysis systems: the ubiquitin-proteasome system degrades mitochondrial outer-membrane (MOM) proteins, and the AAA proteases maintain the proteostasis of intramitochondrial compartments. We previously identified a Doa1-Cdc48(-Ufd1-Npl4) complex that retrogradely translocates ubiquitinated MOM proteins to the cytoplasm for degradation. In this study, we report the unexpected identification of MOM proteins whose degradation requires the Yme1(-Mgr1-Mgr3)i-AAA protease complex in mitochondrial inner membrane...
November 14, 2017: Journal of Cell Biology
Min Wu
The nature of signal transduction networks in the regulation of cell contractility is not entirely clear. In this study, Graessl et al. (2017. J. Cell Biol. visualized and characterized pulses and waves of Rho activation in adherent cells and proposed excitable Rho signaling networks underlying cell contractility.
November 14, 2017: Journal of Cell Biology
Alessandro Genna, Stefanie Lapetina, Nikola Lukic, Shams Twafra, Tomer Meirson, Ved P Sharma, John S Condeelis, Hava Gil-Henn
The nonreceptor tyrosine kinase Pyk2 is highly expressed in invasive breast cancer, but the mechanism by which it potentiates tumor cell invasiveness is unclear at present. Using high-throughput protein array screening and bioinformatic analysis, we identified cortactin as a novel substrate and interactor of proline-rich tyrosine kinase 2 (Pyk2). Pyk2 colocalizes with cortactin to invadopodia of invasive breast cancer cells, where it mediates epidermal growth factor-induced cortactin tyrosine phosphorylation both directly and indirectly via Src-mediated Abl-related gene (Arg) activation, leading to actin polymerization in invadopodia, extracellular matrix degradation, and tumor cell invasion...
November 13, 2017: Journal of Cell Biology
Alexander D Rhys, Pedro Monteiro, Christopher Smith, Malti Vaghela, Teresa Arnandis, Takuya Kato, Birgit Leitinger, Erik Sahai, Andrew McAinsh, Guillaume Charras, Susana A Godinho
Centrosome amplification is a common feature of human tumors. To survive, cancer cells cluster extra centrosomes during mitosis, avoiding the detrimental effects of multipolar divisions. However, it is unclear whether clustering requires adaptation or is inherent to all cells. Here, we show that cells have varied abilities to cluster extra centrosomes. Epithelial cells are innately inefficient at clustering even in the presence of HSET/KIFC1, which is essential but not sufficient to promote clustering. The presence of E-cadherin decreases cortical contractility during mitosis through a signaling cascade leading to multipolar divisions, and its knockout promotes clustering and survival of cells with multiple centrosomes...
November 13, 2017: Journal of Cell Biology
Junwan Fan, Yaqing Wang, Liang Liu, Hongsheng Zhang, Feng Zhang, Lei Shi, Mei Yu, Fei Gao, Zhiheng Xu
Proinsulin is synthesized in the endoplasmic reticulum (ER) in pancreatic β cells and transported to the Golgi apparatus for proper processing and secretion into plasma. Defects in insulin biogenesis may cause diabetes. However, the underlying mechanisms for proinsulin transport are still not fully understood. We show that β cell-specific deletion of cTAGE5, also known as Mea6, leads to increased ER stress, reduced insulin biogenesis in the pancreas, and severe glucose intolerance in mice. We reveal that cTAGE5/MEA6 interacts with vesicle membrane soluble N-ethyl-maleimide sensitive factor attachment protein receptor Sec22b...
November 13, 2017: Journal of Cell Biology
Courtney L Klaips, Gopal Gunanathan Jayaraj, F Ulrich Hartl
Ensuring cellular protein homeostasis, or proteostasis, requires precise control of protein synthesis, folding, conformational maintenance, and degradation. A complex and adaptive proteostasis network coordinates these processes with molecular chaperones of different classes and their regulators functioning as major players. This network serves to ensure that cells have the proteins they need while minimizing misfolding or aggregation events that are hallmarks of age-associated proteinopathies, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases...
November 10, 2017: Journal of Cell Biology
Jing Li, Timothy A Springer
Why do integrins differ in basal activity, and how does affinity for soluble ligand correlate with cellular adhesiveness? We show that basal conformational equilibrium set points for integrin α4β1 are cell type specific and differ from integrin α5β1 when the two integrins are coexpressed on the same cell. Although α4β1 is easier to activate, its high-affinity state binds vascular cell adhesion molecule and fibronectin 100- to 1,000-fold more weakly than α5β1 binds fibronectin. Furthermore, the difference in affinity between the high- and low-affinity states is more compressed in α4β1 (600- to 800-fold) than in α5β1 (4,000- to 6,000-fold)...
November 9, 2017: Journal of Cell Biology
Nadav Segev, Jeffrey E Gerst
Genome duplication in eukaryotes created paralog pairs of ribosomal proteins (RPs) that show high sequence similarity/identity. However, individual paralogs can confer vastly different effects upon cellular processes, e.g., specific yeast paralogs regulate actin organization, bud site selection, and mRNA localization, although how specificity is conferred is unknown. Changes in the RP composition of ribosomes might allow for specialized translation of different subsets of mRNAs, yet it is unclear whether specialized ribosomes exist and if paralog specificity controls translation...
November 8, 2017: Journal of Cell Biology
Ming-Xin An, Si Li, Han-Bing Yao, Chao Li, Jia-Mei Wang, Jia Sun, Xin-Yu Li, Xiao-Na Meng, Hua-Qin Wang
Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level...
November 7, 2017: Journal of Cell Biology
Brajendra K Tripathi, Tiera Grant, Xiaolan Qian, Ming Zhou, Philipp Mertins, Dunrui Wang, Alex G Papageorge, Sergey G Tarasov, Kent W Hunter, Steven A Carr, Douglas R Lowy
We report several receptor tyrosine kinase (RTK) ligands increase RhoA-guanosine triphosphate (GTP) in untransformed and transformed cell lines and determine this phenomenon depends on the RTKs activating the AKT serine/threonine kinase. The increased RhoA-GTP results from AKT phosphorylating three serines (S298, S329, and S567) in the DLC1 tumor suppressor, a Rho GTPase-activating protein (RhoGAP) associated with focal adhesions. Phosphorylation of the serines, located N-terminal to the DLC1 RhoGAP domain, induces strong binding of that N-terminal region to the RhoGAP domain, converting DLC1 from an open, active dimer to a closed, inactive monomer...
November 7, 2017: Journal of Cell Biology
Simon Pan, Jonah R Chan
Axon loss and neurodegeneration constitute clinically debilitating sequelae in demyelinating diseases such as multiple sclerosis, but the underlying mechanisms of secondary degeneration are not well understood. Myelinating glia play a fundamental role in promoting the maturation of the axon cytoskeleton, regulating axon trafficking parameters, and imposing architectural rearrangements such as the nodes of Ranvier and their associated molecular domains. In the setting of demyelination, these changes may be reversed or persist as maladaptive features, leading to axon degeneration...
November 7, 2017: Journal of Cell Biology
Domhnall McHugh, Jesús Gil
Aging is the major risk factor for cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. Although we are far from understanding the biological basis of aging, research suggests that targeting the aging process itself could ameliorate many age-related pathologies. Senescence is a cellular response characterized by a stable growth arrest and other phenotypic alterations that include a proinflammatory secretome. Senescence plays roles in normal development, maintains tissue homeostasis, and limits tumor progression...
November 7, 2017: Journal of Cell Biology
Laura L Thomas, Aaron M N Joiner, J Christopher Fromme
Rab GTPases serve as molecular switches to regulate eukaryotic membrane trafficking pathways. The transport protein particle (TRAPP) complexes activate Rab GTPases by catalyzing GDP/GTP nucleotide exchange. In mammalian cells, there are two distinct TRAPP complexes, yet in budding yeast, four distinct TRAPP complexes have been reported. The apparent differences between the compositions of yeast and mammalian TRAPP complexes have prevented a clear understanding of the specific functions of TRAPP complexes in all cell types...
November 6, 2017: Journal of Cell Biology
Elias Cornejo, Philipp Schlaermann, Shaeri Mukherjee
Intracellular bacterial pathogens have developed versatile strategies to generate niches inside the eukaryotic cells that allow them to survive and proliferate. Making a home inside the host offers many advantages; however, intracellular bacteria must also overcome many challenges, such as disarming innate immune signaling and accessing host nutrient supplies. Gaining entry into the cell and avoiding degradation is only the beginning of a successful intracellular lifestyle. To establish these replicative niches, intracellular pathogens secrete various virulence proteins, called effectors, to manipulate host cell signaling pathways and subvert host defense mechanisms...
November 2, 2017: Journal of Cell Biology
Jinchao Liu, Meijiao Li, Lin Li, She Chen, Xiaochen Wang
Apoptotic cells generated by programmed cell death are engulfed by phagocytes and enclosed within membrane-bound phagosomes. Maturation of apoptotic cell-containing phagosomes leads to formation of phagolysosomes where cell corpses are degraded. The class III phosphatidylinositol 3-kinase (PI3-kinase) VPS-34 coordinates with PIKI-1, a class II PI3-kinase, to produce PtdIns3P on phagosomes, thus promoting phagosome closure and maturation. Here, we identified UBC-13, an E2 ubiquitin-conjugating enzyme that functions in the same pathway with VPS-34 but in parallel to PIKI-1 to regulate PtdIns3P generation on phagosomes...
November 1, 2017: Journal of Cell Biology
Amriya Naufer, Victoria E B Hipolito, Suriakarthiga Ganesan, Akriti Prashar, Vanina Zaremberg, Roberto J Botelho, Mauricio R Terebiznik
Phagocytosis of filamentous bacteria occurs through tubular phagocytic cups (tPCs) and takes many minutes to engulf these filaments into phagosomes. Contravening the canonical phagocytic pathway, tPCs mature by fusing with endosomes. Using this model, we observed the sequential recruitment of early and late endolysosomal markers to the elongating tPCs. Surprisingly, the regulatory early endosomal lipid phosphatidylinositol-3-phosphate (PtdIns(3)P) persists on tPCs as long as their luminal pH remains neutral...
October 31, 2017: Journal of Cell Biology
Shinichi Nakamuta, Yu-Ting Yang, Chia-Lin Wang, Nicholas B Gallo, Jia-Ray Yu, Yilin Tai, Linda Van Aelst
Throughout life, stem cells in the ventricular-subventricular zone generate neuroblasts that migrate via the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into local interneurons. Although progress has been made toward identifying extracellular factors that guide the migration of these cells, little is known about the intracellular mechanisms that govern the dynamic reshaping of the neuroblasts' morphology required for their migration along the RMS. In this study, we identify DOCK7, a member of the DOCK180-family, as a molecule essential for tangential neuroblast migration in the postnatal mouse forebrain...
October 31, 2017: Journal of Cell Biology
Hang Liu, Shimin Wang, Weijian Hang, Jinghu Gao, Wenjuan Zhang, Zihang Cheng, Chao Yang, Jun He, Jie Zhou, Juan Chen, Anbing Shi
RAB-10/Rab10 is a master regulator of endocytic recycling in epithelial cells. To better understand the regulation of RAB-10 activity, we sought to identify RAB-10(GDP)-interacting proteins. One novel RAB-10(GDP)-binding partner that we identified, LET-413, is the Caenorhabditis elegans homologue of Scrib/Erbin. Here, we focus on the mechanistic role of LET-413 in the regulation of RAB-10 within the C. elegans intestine. We show that LET-413 is a RAB-5 effector and colocalizes with RAB-10 on endosomes, and the overlap of LET-413 with RAB-10 is RAB-5 dependent...
October 27, 2017: Journal of Cell Biology
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