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PubMed Central (PMC3 - NLM DTD) (2,805,745 recursos)
Archive of life sciences journal literature at the U.S. National Institutes of Health (NIH), developed and managed by NIH's National Center for Biotechnology Information (NCBI) in the National Library of Medicine (NLM).

Mostrando recursos 1 - 20 de 1,092

1. Non-muscle Mlck is required for β-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1β-mediated barrier dysfunction in brain endothelial cells - Beard, Richard S.; Haines, Ricci J.; Wu, Kevin Y.; Reynolds, Jason J.; Davis, Stephanie M.; Elliott, John E.; Malinin, Nikolay L.; Chatterjee, Victor; Cha, Byeong J.; Wu, Mack H.; Yuan, Sarah Y.
Aberrant elevation in the levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) contributes to neuroinflammatory diseases. Blood–brain barrier (BBB) dysfunction is a hallmark phenotype of neuroinflammation. It is known that IL-1β directly induces BBB hyperpermeability but the mechanisms remain unclear. Claudin-5 (Cldn5) is a tight junction protein found at endothelial cell–cell contacts that are crucial for maintaining brain microvascular endothelial cell (BMVEC) integrity. Transcriptional regulation of Cldn5 has been attributed to the transcription factors β-catenin and forkhead box protein O1 (FoxO1), and the signaling molecules regulating their nuclear translocation. Non-muscle myosin light chain kinase (nmMlck, encoded by the Mylk gene) is...

2. α-Catenin cytomechanics – role in cadherin-dependent adhesion and mechanotransduction - Barry, Adrienne K.; Tabdili, Hamid; Muhamed, Ismaeel; Wu, Jun; Shashikanth, Nitesh; Gomez, Guillermo A.; Yap, Alpha S.; Gottardi, Cara J.; de Rooij, Johan; Wang, Ning; Leckband, Deborah E.
The findings presented here demonstrate the role of α-catenin in cadherin-based adhesion and mechanotransduction in different mechanical contexts. Bead-twisting measurements in conjunction with imaging, and the use of different cell lines and α-catenin mutants reveal that the acute local mechanical manipulation of cadherin bonds triggers vinculin and actin recruitment to cadherin adhesions in an actin- and α-catenin-dependent manner. The modest effect of α-catenin on the two-dimensional binding affinities of cell surface cadherins further suggests that force-activated adhesion strengthening is due to enhanced cadherin–cytoskeletal interactions rather than to α-catenin-dependent affinity modulation. Complementary investigations of cadherin-based rigidity sensing also suggest that, although...

3. A cascade of ER exit site assembly that is regulated by p125A and lipid signals - Klinkenberg, David; Long, Kimberly R.; Shome, Kuntala; Watkins, Simon C.; Aridor, Meir
The inner and outer layers of COPII mediate cargo sorting and vesicle biogenesis. Sec16A and p125A (officially known as SEC23IP) proteins interact with both layers to control coat activity, yet the steps directing functional assembly at ER exit sites (ERES) remain undefined. By using temperature blocks, we find that Sec16A is spatially segregated from p125A-COPII-coated ERES prior to ER exit at a step that required p125A. p125A used lipid signals to control ERES assembly. Within p125A, we defined a C-terminal DDHD domain found in phospholipases and PI transfer proteins that recognized PA and phosphatidylinositol phosphates in vitro and was targeted...

4. Regulation of Src trafficking and activation by the endocytic regulatory proteins MICAL-L1 and EHD1 - Reinecke, James B.; Katafiasz, Dawn; Naslavsky, Naava; Caplan, Steve
Localization of the non-receptor tyrosine kinase Src to the cell periphery is required for its activation and to mediate focal adhesion turnover, cell spreading and migration. Inactive Src localizes to a perinuclear compartment and the movement of Src to the plasma membrane is mediated by endocytic transport. However, the precise pathways and regulatory proteins that are responsible for SRC transport are incompletely understood. Here, we demonstrate that Src partially colocalizes with the endocytic regulatory protein MICAL-L1 (molecule interacting with CasL-like protein 1) in mammalian cells. Furthermore, MICAL-L1 is required for growth-factor- and integrin-induced Src activation and transport to the cell...

5. Paxillin controls endothelial cell migration and tumor angiogenesis by altering neuropilin 2 expression - German, Alexandra E.; Mammoto, Tadanori; Jiang, Elisabeth; Ingber, Donald E.; Mammoto, Akiko
Although a number of growth factors and receptors are known to control tumor angiogenesis, relatively little is known about the mechanism by which these factors influence the directional endothelial cell migration required for cancer microvessel formation. Recently, it has been shown that the focal adhesion protein paxillin is required for directional migration of fibroblasts in vitro. Here, we show that paxillin knockdown enhances endothelial cell migration in vitro and stimulates angiogenesis during normal development and in response to tumor angiogenic factors in vivo. Paxillin produces these effects by decreasing expression of neuropilin 2 (NRP2). Moreover, soluble factors secreted by tumors...

6. Ube2g2–gp78-mediated HERP polyubiquitylation is involved in ER stress recovery - Yan, Long; Liu, Weixiao; Zhang, Huihui; Liu, Chao; Shang, Yongliang; Ye, Yihong; Zhang, Xiaodong; Li, Wei
A large number of studies have focused on how individual organisms respond to a stress condition, but little attention has been paid to the stress recovery process, such as the endoplasmic reticulum (ER) stress recovery. Homocysteine-induced ER protein (HERP) was originally identified as a chaperone-like protein that is strongly induced upon ER stress. Here we show that, after ER stress induction, HERP is rapidly degraded by Ube2g2–gp78-mediated ubiquitylation and proteasomal degradation. The polyubiquitylation of HERP in vitro depends on a physical interaction between the CUE domain of gp78 and the ubiquitin-like (UBL) domain of HERP, which is essential for HERP...

7. Modulation of hypoxia-signaling pathways by extracellular linc-RoR - Takahashi, Kenji; Yan, Irene K.; Haga, Hiroaki; Patel, Tushar
Resistance to adverse environmental conditions, such as hypoxia, contributes to the reduced efficacy of anticancer therapies and tumor progression. Although deregulated expression of many long noncoding RNA (lncRNA) occurs in human cancers, the contribution of such RNA to tumor responses to hypoxia are unknown. RNA expression profiling identified several hypoxia-responsive lncRNAs, including the long intergenic noncoding RNA, regulator of reprogramming (linc-RoR), which is also increased in expression in malignant liver cancer cells. Linc-RoR expression was increased in hypoxic regions within tumor cell xenografts in vivo. Tumor cell viability during hypoxia was reduced by small interfering RNA (siRNA) to linc-RoR. Compared...

8. An ancestral non-proteolytic role for presenilin proteins in multicellular development of the social amoeba Dictyostelium discoideum - Ludtmann, Marthe H. R.; Otto, Grant P.; Schilde, Christina; Chen, Zhi-Hui; Allan, Claire Y.; Brace, Selina; Beesley, Philip W.; Kimmel, Alan R.; Fisher, Paul; Killick, Richard; Williams, Robin S. B.
Mutations in either of two presenilin genes can cause familial Alzheimer's disease. Presenilins have both proteolysis-dependent functions, as components of the γ-secretase complex, and proteolysis-independent functions in signalling. In this study, we investigate a conserved function of human presenilins in the development of the simple model organism Dictyostelium discoideum. We show that the block in Dictyostelium development caused by the ablation of both Dictyostelium presenilins is rescued by the expression of human presenilin 1, restoring the terminal differentiation of multiple cell types. This developmental role is independent of proteolytic activity, because the mutation of both catalytic aspartates does not affect...

9. A central region of Gli2 regulates its localization to the primary cilium and transcriptional activity - Santos, Nicole; Reiter, Jeremy F.
Signaling through vertebrate Hedgehog (Hh) proteins depends on the primary cilium. In response to Hh signals, the transcriptional activator of the pathway, Gli2, accumulates at the ciliary tip, raising the possibility that ciliary localization is important for Gli2 activation. To test this hypothesis, we used the Floxin system to create knock-in Gli2 alleles in embryonic stem cells (ESCs) to allow methodical testing of which domains and residues are essential for the ciliary localization of Gli2. The Gli2 zinc fingers, transcriptional activation domain, repressor domain, phosphorylation cluster and a Sufu binding motif were each dispensable for ciliary localization. Mutating residues that...

10. sept7b is essential for pronephric function and development of left–right asymmetry in zebrafish embryogenesis - Dash, Surjya Narayan; Lehtonen, Eero; Wasik, Anita A.; Schepis, Antonino; Paavola, Jere; Panula, Pertti; Nelson, W. James; Lehtonen, Sanna
The conserved septin family of filamentous small GTPases plays important roles in mitosis, cell migration and cell morphogenesis by forming scaffolds and diffusion barriers. Recent studies in cultured cells in vitro indicate that a septin complex of septin 2, 7 and 9 is required for ciliogenesis and cilia function, but septin function in ciliogenesis in vertebrate organs in vivo is not understood. We show that sept7b is expressed in ciliated cells in different tissues during early zebrafish development. Knockdown of sept7b by using morpholino antisense oligonucleotides caused misorientation of basal bodies and cilia, reduction of apical actin and the shortening...

11. Mutation of caspase-digestion sites in keratin 18 interferes with filament reorganization, and predisposes to hepatocyte necrosis and loss of membrane integrity - Weerasinghe, Sujith V. W.; Ku, Nam-On; Altshuler, Peter J.; Kwan, Raymond; Omary, M. Bishr
Keratin 18 (K18 or KRT18) undergoes caspase-mediated cleavage during apoptosis, the significance of which is poorly understood. Here, we mutated the two caspase-cleavage sites (D238E and D397E) in K18 (K18-DE), followed by transgenic overexpression of the resulting mutant. We found that K18-DE mice develop extensive Fas-mediated liver damage compared to wild-type mice overexpressing K18 (K18-WT). Fas-stimulation of K18-WT mice or isolated hepatocytes caused K18 degradation. By contrast, K18-DE livers or hepatocytes maintained intact keratins following Fas-stimulation, but showed hypo-phosphorylation at a major stress-kinase-related keratin 8 (K8) phosphorylation site. Although K18-WT and K18-DE hepatocytes showed similar Fas-mediated caspase activation, K18-DE hepatocytes...

12. HDAC1 activates FoxO and is both sufficient and required for skeletal muscle atrophy - Beharry, Adam W.; Sandesara, Pooja B.; Roberts, Brandon M.; Ferreira, Leonardo F.; Senf, Sarah M.; Judge, Andrew R.
The Forkhead box O (FoxO) transcription factors are activated, and necessary for the muscle atrophy, in several pathophysiological conditions, including muscle disuse and cancer cachexia. However, the mechanisms that lead to FoxO activation are not well defined. Recent data from our laboratory and others indicate that the activity of FoxO is repressed under basal conditions via reversible lysine acetylation, which becomes compromised during catabolic conditions. Therefore, we aimed to determine how histone deacetylase (HDAC) proteins contribute to activation of FoxO and induction of the muscle atrophy program. Through the use of various pharmacological inhibitors to block HDAC activity, we demonstrate...

13. The role of Hath6, a newly identified shear-stress-responsive transcription factor, in endothelial cell differentiation and function - Fang, Fang; Wasserman, Scott M.; Torres-Vazquez, Jesus; Weinstein, Brant; Cao, Feng; Li, Zongjin; Wilson, Kitchener D.; Yue, Wen; Wu, Joseph C.; Xie, Xiaoyan; Pei, Xuetao
The key regulators of endothelial differentiation that is induced by shear stress are mostly unclear. Human atonal homolog 6 (Hath6 or ATOH8) is an endothelial-selective and shear-stress-responsive transcription factor. In this study, we sought to elucidate the role of Hath6 in the endothelial specification of embryonic stem cells. In a stepwise human embryonic stem cell to endothelial cell (hESC-EC) induction system, Hath6 mRNA was upregulated synchronously with endothelial determination. Subsequently, gain-of-function and loss-of-function studies of Hath6 were performed using the hESC-EC induction model and endothelial cell lines. The overexpression of Hath6, which mimics shear stress treatment, resulted in an increased...

14. N-WASP-directed actin polymerization activates Cas phosphorylation and lamellipodium spreading - Zhang, Xian; Moore, Simon W.; Iskratsch, Thomas; Sheetz, Michael P.
Tyrosine phosphorylation of the substrate domain of Cas (CasSD) correlates with increased cell migration in healthy and diseased cells. Here, we address the mechanism leading to the phosphorylation of CasSD in the context of fibronectin-induced early spreading of fibroblasts. We have previously demonstrated that mechanical stretching of CasSD exposes phosphorylation sites for Src family kinases (SFKs). Surprisingly, phosphorylation of CasSD was independent of myosin contractile activity but dependent on actin polymerization. Furthermore, we found that CasSD phosphorylation in the early stages of cell spreading required: (1) integrin anchorage and integrin-mediated activation of SFKs, (2) association of Cas with focal adhesion...

15. Specific interaction of KIF11 with ZBP1 regulates the transport of β-actin mRNA and cell motility - Song, Tingting; Zheng, Yi; Wang, Yarong; Katz, Zachary; Liu, Xin; Chen, Shaoying; Singer, Robert H.; Gu, Wei
ZBP1-modulated localization of β-actin mRNA enables a cell to establish polarity and structural asymmetry. Although the mechanism of β-actin mRNA localization has been well established, the underlying mechanism of how a specific molecular motor contributes to the transport of the ZBP1 (also known as IGF2BP1) complex in non-neuronal cells remains elusive. In this study, we report the isolation and identification of KIF11, a microtubule motor, which physically interacts with ZBP1 and is a component of β-actin messenger ribonucleoprotein particles (mRNPs). We show that KIF11 colocalizes with the β-actin mRNA, and the ability of KIF11 to transport β-actin mRNA is dependent...

16. Unconventional PINK1 localization to the outer membrane of depolarized mitochondria drives Parkin recruitment - Okatsu, Kei; Kimura, Mayumi; Oka, Toshihiko; Tanaka, Keiji; Matsuda, Noriyuki
Dysfunction of PTEN-induced putative kinase 1 (PINK1), a Ser/Thr kinase with an N-terminal mitochondrial-targeting sequence (MTS), causes familial recessive parkinsonism. Reduction of the mitochondrial membrane potential limits MTS-mediated matrix import and promotes PINK1 accumulation on the outer mitochondrial membrane (OMM) of depolarized mitochondria. PINK1 then undergoes autophosphorylation and phosphorylates ubiquitin and Parkin, a cytosolic ubiquitin ligase, for clearance of damaged mitochondria. The molecular basis for PINK1 localization on the OMM of depolarized mitochondria rather than release to the cytosol is poorly understood. Here, we disentangle the PINK1 localization mechanism using deletion mutants and a newly established constitutively active PINK1 mutant....

17. A new cytoplasmic interaction between junctin and ryanodine receptor Ca2+ release channels - Li, Linwei; Mirza, Shamaruh; Richardson, Spencer J.; Gallant, Esther M.; Thekkedam, Chris; Pace, Suzy M.; Zorzato, Francesco; Liu, Dan; Beard, Nicole A.; Dulhunty, Angela F.
Junctin, a non-catalytic splice variant encoded by the aspartate-β-hydroxylase (Asph) gene, is inserted into the membrane of the sarcoplasmic reticulum (SR) Ca2+ store where it modifies Ca2+ signalling in the heart and skeletal muscle through its regulation of ryanodine receptor (RyR) Ca2+ release channels. Junctin is required for normal muscle function as its knockout leads to abnormal Ca2+ signalling, muscle dysfunction and cardiac arrhythmia. However, the nature of the molecular interaction between junctin and RyRs is largely unknown and was assumed to occur only in the SR lumen. We find that there is substantial binding of RyRs to full junctin,...

18. Integrin traffic – the update - De Franceschi, Nicola; Hamidi, Hellyeh; Alanko, Jonna; Sahgal, Pranshu; Ivaska, Johanna
Integrins are a family of transmembrane cell surface molecules that constitute the principal adhesion receptors for the extracellular matrix (ECM) and are indispensable for the existence of multicellular organisms. In vertebrates, 24 different integrin heterodimers exist with differing substrate specificity and tissue expression. Integrin–extracellular-ligand interaction provides a physical anchor for the cell and triggers a vast array of intracellular signalling events that determine cell fate. Dynamic remodelling of adhesions, through rapid endocytic and exocytic trafficking of integrin receptors, is an important mechanism employed by cells to regulate integrin–ECM interactions, and thus cellular signalling, during processes such as cell migration, invasion...

19. ESCRT-0 marks an APPL1-independent transit route for EGFR between the cell surface and the EEA1-positive early endosome - Flores-Rodriguez, Neftali; Kenwright, David A.; Chung, Pei-Hua; Harrison, Andrew W.; Stefani, Flavia; Waigh, Thomas A.; Allan, Victoria J.; Woodman, Philip G.
Endosomal sorting complexes required for transport (ESCRT)-0 sorts ubiquitylated EGFR within the early endosome so that the receptor can be incorporated into intralumenal vesicles. An important question is whether ESCRT-0 acts solely upon EGFR that has already entered the vacuolar early endosome (characterised by the presence of EEA1) or engages EGFR within earlier compartments. Here, we employ a suite of software to determine the localisation of ESCRT-0 at subpixel resolution and to perform particle-based colocalisation analysis with other endocytic markers. We demonstrate that although some of the ESCRT-0 subunit Hrs (also known as HGS) colocalises with the vacuolar early endosome...

20. The dynamic conformational landscape of γ-secretase - Elad, Nadav; De Strooper, Bart; Lismont, Sam; Hagen, Wim; Veugelen, Sarah; Arimon, Muriel; Horré, Katrien; Berezovska, Oksana; Sachse, Carsten; Chávez-Gutiérrez, Lucía
The structure and function of the γ-secretase proteases are of great interest because of their crucial roles in cellular and disease processes. We established a novel purification protocol for the γ-secretase complex that involves a conformation- and complex-specific nanobody, yielding highly pure and active enzyme. Using single particle electron microscopy, we analyzed the γ-secretase structure and its conformational variability. Under steady-state conditions, the complex adopts three major conformations, which differ in overall compactness and relative position of the nicastrin ectodomain. Occupancy of the active or substrate-binding sites by inhibitors differentially stabilizes subpopulations of particles with compact conformations, whereas a mutation...

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