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PubMed Central (PMC3 - NLM DTD) (2,911,653 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 1,185

1. The small GTPase Rab8 interacts with VAMP-3 to regulate the delivery of recycling T-cell receptors to the immune synapse - Finetti, Francesca; Patrussi, Laura; Galgano, Donatella; Cassioli, Chiara; Perinetti, Giuseppe; Pazour, Gregory J.; Baldari, Cosima T.
IFT20, a component of the intraflagellar transport (IFT) system that controls ciliogenesis, regulates immune synapse assembly in the non-ciliated T-cell by promoting T-cell receptor (TCR) recycling. Here, we have addressed the role of Rab8 (for which there are two isoforms Rab8a and Rab8b), a small GTPase implicated in ciliogenesis, in TCR traffic to the immune synapse. We show that Rab8, which colocalizes with IFT20 in Rab11+ endosomes, is required for TCR recycling. Interestingly, as opposed to in IFT20-deficient T-cells, TCR+ endosomes polarized normally beneath the immune synapse membrane in the presence of dominant-negative Rab8, but were unable to undergo the...

2. Nuclear FAM21 participates in NF-κB-dependent gene regulation in pancreatic cancer cells - Deng, Zhi-Hui; Gomez, Timothy S.; Osborne, Douglas G.; Phillips-Krawczak, Christine A.; Zhang, Jin-San; Billadeau, Daniel D.
The pentameric WASH complex is best known for its role in regulating receptor trafficking from retromer-rich endosomal subdomains. FAM21 functions to stabilize the WASH complex through its N-terminal head domain and localizes it to endosomes by directly binding the retromer through its extended C-terminal tail. Herein, we used affinity purification combined with mass spectrometry to identify additional FAM21-interacting proteins. Surprisingly, multiple components of the nuclear factor κB (NF-κB) pathway were identified, including the p50 and p65 (RelA) NF-κB subunits. We show that FAM21 interacts with these components and regulates NF-κB-dependent gene transcription at the level of p65 chromatin binding. We...

3. INPP5E interacts with AURKA, linking phosphoinositide signaling to primary cilium stability - Plotnikova, Olga V.; Seo, Seongjin; Cottle, Denny L.; Conduit, Sarah; Hakim, Sandra; Dyson, Jennifer M.; Mitchell, Christina A.; Smyth, Ian M.
Mutations in inositol polyphosphate 5-phosphatase E (INPP5E) cause the ciliopathies known as Joubert and MORM syndromes; however, the role of INPP5E in ciliary biology is not well understood. Here, we describe an interaction between INPP5E and AURKA, a centrosomal kinase that regulates mitosis and ciliary disassembly, and we show that this interaction is important for the stability of primary cilia. Furthermore, AURKA phosphorylates INPP5E and thereby increases its 5-phosphatase activity, which in turn promotes transcriptional downregulation of AURKA, partly through an AKT-dependent mechanism. These findings establish the first direct link between AURKA and phosphoinositide signaling and suggest that the function...

4. BRG1 promotes the repair of DNA double-strand breaks by facilitating the replacement of RPA with RAD51 - Qi, Wenjing; Wang, Ruoxi; Chen, Hongyu; Wang, Xiaolin; Xiao, Ting; Boldogh, Istvan; Ba, Xueqing; Han, Liping; Zeng, Xianlu
DNA double-strand breaks (DSBs) are a type of lethal DNA damage. The repair of DSBs requires tight coordination between the factors modulating chromatin structure and the DNA repair machinery. BRG1, the ATPase subunit of the chromatin remodelling complex Switch/Sucrose non-fermentable (SWI/SNF), is often linked to tumorigenesis and genome instability, and its role in DSB repair remains largely unclear. In the present study, we show that BRG1 is recruited to DSB sites and enhances DSB repair. Using DR-GFP and EJ5-GFP reporter systems, we demonstrate that BRG1 facilitates homologous recombination repair rather than nonhomologous end-joining (NHEJ) repair. Moreover, the BRG1–RAD52 complex mediates...

5. Selective synaptic targeting of the excitatory and inhibitory presynaptic organizers FGF22 and FGF7 - Terauchi, Akiko; Timmons, Kendall M.; Kikuma, Koto; Pechmann, Yvonne; Kneussel, Matthias; Umemori, Hisashi
Specific formation of excitatory and inhibitory synapses is crucial for proper functioning of the brain. Fibroblast growth factor 22 (FGF22) and FGF7 are postsynaptic-cell-derived presynaptic organizers necessary for excitatory and inhibitory presynaptic differentiation, respectively, in the hippocampus. For the establishment of specific synaptic networks, these FGFs must localize to appropriate synaptic locations – FGF22 to excitatory and FGF7 to inhibitory postsynaptic sites. Here, we show that distinct motor and adaptor proteins contribute to intracellular microtubule transport of FGF22 and FGF7. Excitatory synaptic targeting of FGF22 requires the motor proteins KIF3A and KIF17 and the adaptor protein SAP102 (also known as...

6. Leiomodin 3 and tropomodulin 4 have overlapping functions during skeletal myofibrillogenesis - Nworu, Chinedu U.; Kraft, Robert; Schnurr, Daniel C.; Gregorio, Carol C.; Krieg, Paul A.
Precise regulation of thin filament length is essential for optimal force generation during muscle contraction. The thin filament capping protein tropomodulin (Tmod) contributes to thin filament length uniformity by regulating elongation and depolymerization at thin filament ends. The leiomodins (Lmod1–3) are structurally related to Tmod1–4 and also localize to actin filament pointed ends, but in vitro biochemical studies indicate that Lmods act instead as robust nucleators. Here, we examined the roles of Tmod4 and Lmod3 during Xenopus skeletal myofibrillogenesis. Loss of Tmod4 or Lmod3 resulted in severe disruption of sarcomere assembly and impaired embryonic movement. Remarkably, when Tmod4-deficient embryos were...

7. Skeletal muscle intermediate filaments form a stress-transmitting and stress-signaling network - Palmisano, Michelle G.; Bremner, Shannon N.; Hornberger, Troy A.; Meyer, Gretchen A.; Domenighetti, Andrea A.; Shah, Sameer B.; Kiss, Balázs; Kellermayer, Miklos; Ryan, Allen F.; Lieber, Richard L.
A fundamental requirement of cells is their ability to transduce and interpret their mechanical environment. This ability contributes to regulation of growth, differentiation and adaptation in many cell types. The intermediate filament (IF) system not only provides passive structural support to the cell, but recent evidence points to IF involvement in active biological processes such as signaling, mechanotransduction and gene regulation. However, the mechanisms that underlie these processes are not well known. Skeletal muscle cells provide a convenient system to understand IF function because the major muscle-specific IF, desmin, is expressed in high abundance and is highly organized. Here, we...

8. Cadherin controls nectin recruitment into adherens junctions by remodeling the actin cytoskeleton - Troyanovsky, Regina B.; Indra, Indrajyoti; Chen, Chi-Shuo; Hong, Soonjin; Troyanovsky, Sergey M.
The mechanism that coordinates activities of different adhesion receptors is poorly understood. We investigated this mechanism by focusing on the nectin-2 and E-cadherin adherens junction receptors. We found that, cadherin was not required for the basic process of nectin junction formation because nectin-2 formed junctions in cadherin-deficient A431D cells. Formation of nectin-2 junctions in these cells, however, became regulated by cadherin as soon as E-cadherin was re-expressed. E-cadherin recruited nectin-2 into adherens junctions, where both proteins formed distinct but tightly associated clusters. Live-cell imaging showed that the appearance of E-cadherin clusters often preceded that of nectin-2 clusters at sites of...

9. EFR3s are palmitoylated plasma membrane proteins that control responsiveness to G-protein-coupled receptors - Bojjireddy, Naveen; Guzman-Hernandez, Maria Luisa; Reinhard, Nathalie Renée; Jovic, Marko; Balla, Tamas
The yeast Efr3p protein is a main regulator of the Stt4p phosphatidylinositol 4-kinase at contact sites between the endoplasmic reticulum and the plasma membrane. A mutation in its fly homologue Rbo, leads to diminished light responses in the eye attributed to progressively impaired PLC signaling. Here, we find that Efr3s plays a role in maintaining responsiveness to the type-I angiotensin II (AngII) receptors. siRNA-mediated depletion of EFR3A and EFR3B impaired the sustained phase of cytosolic Ca2+ response to high concentration of AngII in HEK293 cells that express wild type but not truncated AGTR1 (AT1a receptor), missing the phosphorylation sites. Efr3...

10. A complex of p190RhoGAP-A and anillin modulates RhoA-GTP and the cytokinetic furrow in human cells - Manukyan, Arkadi; Ludwig, Kirsten; Sanchez-Manchinelly, Sergio; Parsons, Sarah J.; Stukenberg, P. Todd
The cytokinetic furrow is organized by the RhoA GTPase, which recruits actin and myosin II to the furrow and drives contractility. Here, we show that the RhoA GTPase-activting protein (GAP) p190RhoGAP-A (also known as ARHGAP35) has a role in cytokinesis and is involved in regulating levels of RhoA-GTP and contractility. Cells depleted of p190RhoGAP-A accumulate high levels of RhoA-GTP and markers of high RhoA activity in the furrow, resulting in failure of the cytokinetic furrow to progress to abscission. The loss of p190RhoGAP-A can be rescued by a low dose of the myosin II inhibitor blebbistatin, suggesting that cells fail...

11. The exocyst is required for trypanosome invasion and the repair of mechanical plasma membrane wounds - Fernandes, Maria Cecilia; Corrotte, Matthias; Miguel, Danilo C.; Tam, Christina; Andrews, Norma W.
The process of host cell invasion by Trypanosoma cruzi shares mechanistic elements with plasma membrane injury and repair. Both processes require Ca2+-triggered exocytosis of lysosomes, exocytosis of acid sphingomyelinase and formation of ceramide-enriched endocytic compartments. T. cruzi invades at peripheral sites, suggesting a need for spatial regulation of membrane traffic. Here, we show that Exo70 and Sec8 (also known as EXOC7 and EXOC4, respectively), components of the exocyst complex, accumulate in nascent T. cruzi vacuoles and at sites of mechanical wounding. Exo70 or Sec8 depletion inhibits T. cruzi invasion and Ca2+-dependent resealing of mechanical wounds, but does not affect the...

12. Subcellular optogenetics – controlling signaling and single-cell behavior - Karunarathne, W. K. Ajith; O'Neill, Patrick R.; Gautam, Narasimhan
Variation in signaling activity across a cell plays a crucial role in processes such as cell migration. Signaling activity specific to organelles within a cell also likely plays a key role in regulating cellular functions. To understand how such spatially confined signaling within a cell regulates cell behavior, tools that exert experimental control over subcellular signaling activity are required. Here, we discuss the advantages of using optogenetic approaches to achieve this control. We focus on a set of optical triggers that allow subcellular control over signaling through the activation of G-protein-coupled receptors (GPCRs), receptor tyrosine kinases and downstream signaling proteins,...

13. Ciliopathy proteins establish a bipartite signaling compartment in a C. elegans thermosensory neuron - Nguyen, Phuong Anh T.; Liou, Willisa; Hall, David H.; Leroux, Michel R.
How signaling domains form is an important, yet largely unexplored question. Here, we show that ciliary proteins help establish two contiguous, yet distinct cyclic GMP (cGMP) signaling compartments in Caenorhabditis elegans thermosensory AFD neurons. One compartment, a bona fide cilium, is delineated by proteins associated with Bardet–Biedl syndrome (BBS), Meckel syndrome and nephronophthisis at its base, and requires NPHP-2 (known as inversin in mammals) to anchor a cGMP-gated ion channel within the proximal ciliary region. The other, a subcompartment with profuse microvilli and a different lipid environment, is separated from the dendrite by a cellular junction and requires BBS-8 and...

14. Epiprofin orchestrates epidermal keratinocyte proliferation and differentiation - Nakamura, Takashi; Yoshitomi, Yasuo; Sakai, Kiyoshi; Patel, Vyomesh; Fukumoto, Satoshi; Yamada, Yoshihiko
The basal layer of the epidermis contains stem cells and transit amplifying cells that rapidly proliferate and differentiate further into the upper layers of the epidermis. A number of molecules have been identified as regulators of this process, including p63 (also known as tumor protein 63) and Notch1. However, little is known about the mechanisms that regulate the transitions from stem cell to proliferating or differentiating transit amplifying cell. Here, we demonstrate that epiprofin (Epfn, also known as Sp6) plays crucial distinct roles in these transition stages as a cell cycle regulator and a transcription factor. Epfn knockout mice have...

15. Delivery of CSF-1R to the lumen of macropinosomes promotes its destruction in macrophages - Lou, Jieqiong; Low-Nam, Shalini T.; Kerkvliet, Jason G.; Hoppe, Adam D.
Activation of the macrophage colony stimulating factor-1 receptor (CSF-1R) by CSF-1 stimulates pronounced macropinocytosis and drives proliferation of macrophages. Although the role of macropinocytosis in CSF-1R signaling remains unknown, we show here that, despite internalizing large quantities of plasma membrane, macropinosomes contribute little to the internalization of the CSF-1–CSF-1R complex. Rather, internalization of the CSF-1R in small endocytic vesicles that are sensitive to clathrin disruption, outcompetes macropinosomes for CSF-1R endocytosis. Following internalization, small vesicles carrying the CSF-1R underwent homotypic fusion and then trafficked to newly formed macropinosomes bearing Rab5. As these macropinosomes matured, acquiring Rab7, the CSF-1R was transported into...

16. Podosome-regulating kinesin KIF1C translocates to the cell periphery in a CLASP-dependent manner - Efimova, Nadia; Grimaldi, Ashley; Bachmann, Alice; Frye, Keyada; Zhu, Xiaodong; Feoktistov, Alexander; Straube, Anne; Kaverina, Irina
The kinesin KIF1C is known to regulate podosomes, actin-rich adhesion structures that remodel the extracellular matrix during physiological processes. Here, we show that KIF1C is a player in the podosome-inducing signaling cascade. Upon induction of podosome formation by protein kinase C (PKC), KIF1C translocation to the cell periphery intensifies and KIF1C accumulates both in the proximity of peripheral microtubules that show enrichment for the plus-tip-associated proteins CLASPs and around podosomes. Importantly, without CLASPs, both KIF1C trafficking and podosome formation are suppressed. Moreover, chimeric mitochondrially targeted CLASP2 recruits KIF1C, suggesting a transient CLASP–KIF1C association. We propose that CLASPs create preferred microtubule...

17. Nanoclustering as a dominant feature of plasma membrane organization - Garcia-Parajo, Maria F.; Cambi, Alessandra; Torreno-Pina, Juan A.; Thompson, Nancy; Jacobson, Ken
Early studies have revealed that some mammalian plasma membrane proteins exist in small nanoclusters. The advent of super-resolution microscopy has corroborated and extended this picture, and led to the suggestion that many, if not most, membrane proteins are clustered at the plasma membrane at nanoscale lengths. In this Commentary, we present selected examples of glycosylphosphatidyl-anchored proteins, Ras family members and several immune receptors that provide evidence for nanoclustering. We advocate the view that nanoclustering is an important part of the hierarchical organization of proteins in the plasma membrane. According to this emerging picture, nanoclusters can be organized on the mesoscale...

18. Phosphorylation of threonine 3 on histone H3 by haspin kinase is required for meiosis I in mouse oocytes - Nguyen, Alexandra L.; Gentilello, Amanda S.; Balboula, Ahmed Z.; Shrivastava, Vibha; Ohring, Jacob; Schindler, Karen
Meiosis I (MI), the division that generates haploids, is prone to errors that lead to aneuploidy in females. Haspin is a kinase that phosphorylates histone H3 on threonine 3, thereby recruiting Aurora kinase B (AURKB) and the chromosomal passenger complex (CPC) to kinetochores to regulate mitosis. Haspin and AURKC, an AURKB homolog, are enriched in germ cells, yet their significance in regulating MI is not fully understood. Using inhibitors and overexpression approaches, we show a role for haspin during MI in mouse oocytes. Haspin-perturbed oocytes display abnormalities in chromosome morphology and alignment, improper kinetochore–microtubule attachments at metaphase I and aneuploidy...

19. Phosphorylation of the cytoskeletal protein CAP1 controls its association with cofilin and actin - Zhou, Guo-Lei; Zhang, Haitao; Wu, Huhehasi; Ghai, Pooja; Field, Jeffrey
Cell signaling can control the dynamic balance between filamentous and monomeric actin by modulating actin regulatory proteins. One family of actin regulating proteins that controls actin dynamics comprises cyclase-associated proteins 1 and 2 (CAP1 and 2, respectively). However, cell signals that regulate CAPs remained unknown. We mapped phosphorylation sites on mouse CAP1 and found S307 and S309 to be regulatory sites. We further identified glycogen synthase kinase 3 as a kinase phosphorylating S309. The phosphomimetic mutant S307D/S309D lost binding to its partner cofilin and, when expressed in cells, caused accumulation of actin stress fibers similar to that in cells with...

20. KIF13B regulates angiogenesis through Golgi to plasma membrane trafficking of VEGFR2 - Yamada, Kaori H.; Nakajima, Yuki; Geyer, Melissa; Wary, Kishore K.; Ushio-Fukai, Masuko; Komarova, Yulia; Malik, Asrar B.
Although the trafficking of newly synthesized VEGFR2 to the plasma membrane is a key determinant of angiogenesis, the molecular mechanisms of Golgi to plasma membrane trafficking are unknown. Here, we have identified a key role of the kinesin family plus-end molecular motor KIF13B in delivering VEGFR2 cargo from the Golgi to the endothelial cell surface. KIF13B is shown to interact directly with VEGFR2 on microtubules. We also observed that overexpression of truncated versions of KIF13B containing the binding domains that interact with VEGFR2 inhibited VEGF-induced capillary tube formation. KIF13B depletion prevented VEGF-mediated endothelial migration, capillary tube formation and neo-vascularization in...

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