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PubMed Central (PMC3 - NLM DTD) (2,795,904 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 1,078

1. 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...

2. 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....

3. 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,...

4. 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...

5. 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...

6. 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...

7. The NuRD nucleosome remodelling complex and NHK-1 kinase are required for chromosome condensation in oocytes - Nikalayevich, Elvira; Ohkura, Hiroyuki
Chromosome condensation during cell division is one of the most dramatic events in the cell cycle. Condensin and topoisomerase II are the most studied factors in chromosome condensation. However, their inactivation leads to only mild defects and little is known about the roles of other factors. Here, we took advantage of Drosophila oocytes to elucidate the roles of potential condensation factors by performing RNA interference (RNAi). Consistent with previous studies, depletion of condensin I subunits or topoisomerase II in oocytes only mildly affected chromosome condensation. In contrast, we found severe undercondensation of chromosomes after depletion of the Mi-2-containing NuRD nucleosome...

8. A non-mitotic role for Aurora kinase A as a direct activator of cell migration upon interaction with PLD, FAK and Src - Mahankali, Madhu; Henkels, Karen M.; Speranza, Francis; Gomez-Cambronero, Julian
Timely activation of Aurora kinase A (AURA, also known as AURKA) is vital for centrosome formation and the progression of mitosis. Nonetheless, it is still unclear if and when other cellular functions are activated by AURA. We report here that Src phosphorylates and activates AURA at T288, and AURA also activates focal adhesion kinase (FAK, also known as PTK2), leading to initiation of cell movement. An additional and new way by which AURA is regulated, is by phospholipase D2 (PLD2), which causes AURA activation. In addition, AURA phosphorylates PLD, so both proteins engage in a positive reinforcement loop. AURA and...

9. Probing the biomechanical contribution of the endothelium to lymphocyte migration: diapedesis by the path of least resistance - Martinelli, Roberta; Zeiger, Adam S.; Whitfield, Matthew; Sciuto, Tracey E.; Dvorak, Ann; Van Vliet, Krystyn J.; Greenwood, John; Carman, Christopher V.
Immune cell trafficking requires the frequent breaching of the endothelial barrier either directly through individual cells (‘transcellular’ route) or through the inter-endothelial junctions (‘paracellular’ route). What determines the loci or route of breaching events is an open question with important implications for overall barrier regulation. We hypothesized that basic biomechanical properties of the endothelium might serve as crucial determinants of this process. By altering junctional integrity, cytoskeletal morphology and, consequently, local endothelial cell stiffness of different vascular beds, we could modify the preferred route of diapedesis. In particular, high barrier function was associated with predominantly transcellular migration, whereas negative modulation...

10. Phosphorylation of nucleoporin Tpr governs its differential localization and is required for its mitotic function - Rajanala, Kalpana; Sarkar, Anshuk; Jhingan, Gagan Deep; Priyadarshini, Raina; Jalan, Manisha; Sengupta, Sagar; Nandicoori, Vinay Kumar
A major constituent of the nuclear basket region of the nuclear pore complex (NPC), nucleoporin Tpr, plays roles in regulating multiple important processes. We have previously established that Tpr is phosphorylated in both a MAP-kinase-dependent and MAP-kinase-independent manner, and that Tpr acts as both a substrate and as a scaffold for ERK2 (also known as MAPK1). Here, we report the identification of S2059 and S2094 as the major novel ERK-independent phosphorylation sites and T1677, S2020, S2023 and S2034 as additional ERK-independent phosphorylation sites found in the Tpr protein in vivo. Our results suggest that protein kinase A phosphorylates the S2094...

11. Rassf5 and Ndr kinases regulate neuronal polarity through Par3 phosphorylation in a novel pathway - Yang, Rui; Kong, Eryan; Jin, Jing; Hergovich, Alexander; Püschel, Andreas W.
The morphology and polarized growth of cells depend on pathways that control the asymmetric distribution of regulatory factors. The evolutionarily conserved Ndr kinases play important roles in cell polarity and morphogenesis in yeast and invertebrates but it is unclear whether they perform a similar function in mammalian cells. Here, we analyze the function of mammalian Ndr1 and Ndr2 (also known as STK38 or STK38L, respectively) in the establishment of polarity in neurons. We show that they act downstream of the tumor suppressor Rassf5 and upstream of the polarity protein Par3 (also known as PARD3). Rassf5 and Ndr1 or Ndr2 are...

12. PKA-regulated VASP phosphorylation promotes extrusion of transformed cells from the epithelium - Anton, Katarzyna A.; Sinclair, John; Ohoka, Atsuko; Kajita, Mihoko; Ishikawa, Susumu; Benz, Peter M.; Renne, Thomas; Balda, Maria; Jorgensen, Claus; Matter, Karl; Fujita, Yasuyuki
At the early stages of carcinogenesis, transformation occurs in single cells within tissues. In an epithelial monolayer, such mutated cells are recognized by their normal neighbors and are often apically extruded. The apical extrusion requires cytoskeletal reorganization and changes in cell shape, but the molecular switches involved in the regulation of these processes are poorly understood. Here, using stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative mass spectrometry, we have identified proteins that are modulated in transformed cells upon their interaction with normal cells. Phosphorylation of VASP at serine 239 is specifically upregulated in RasV12-transformed cells when...

13. Basal localization of MT1-MMP is essential for epithelial cell morphogenesis in 3D collagen matrix - Weaver, Sarah A.; Wolters, Brit; Ito, Noriko; Woskowicz, Anna M.; Kaneko, Kazuyo; Shitomi, Yasuyuki; Seiki, Motoharu; Itoh, Yoshifumi
The membrane-anchored collagenase membrane type 1 matrix metalloprotease (MT1-MMP) has been shown to play an essential role during epithelial tubulogenesis in 3D collagen matrices; however, its regulation during tubulogenesis is not understood. Here, we report that degradation of collagen in polarized epithelial cells is post-translationally regulated by changing the localization of MT1-MMP from the apical to the basal surface. MT1-MMP predominantly localizes at the apical surface in inert polarized epithelial cells, whereas treatment with HGF induced basal localization of MT1-MMP followed by collagen degradation. The basal localization of MT1-MMP requires the ectodomains of the enzyme because deletion of the MT-loop...

14. A Pil1–Sle1–Syj1–Tax4 functional pathway links eisosomes with PI(4,5)P2 regulation - Kabeche, Ruth; Roguev, Assen; Krogan, Nevan J.; Moseley, James B.
Stable compartments of the plasma membrane promote a wide range of cellular functions. In yeast cells, cytosolic structures called eisosomes generate prominent cortical invaginations of unknown function. Through a series of genetic screens in fission yeast, we found that the eisosome proteins Pil1 and Sle1 function with the synaptojanin-like lipid phosphatase Syj1 and its ligand Tax4. This genetic pathway connects eisosome function with the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] in cells. Defects in PI(4,5)P2 regulation led to eisosome defects, and we found that the core eisosome protein Pil1 can bind to and tubulate liposomes containing PI(4,5)P2. Mutations in components of...

15. PIPKIγ targets to the centrosome and restrains centriole duplication - Xu, Qingwen; Zhang, Yuxia; Xiong, Xunhao; Huang, Yan; Salisbury, Jeffery L.; Hu, Jinghua; Ling, Kun
Centriole biogenesis depends on the polo-like kinase (PLK4) and a small group of structural proteins. The spatiotemporal regulation of these proteins at pre-existing centrioles is essential to ensure that centriole duplication occurs once per cell cycle. Here, we report that phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C, hereafter referred to as PIPKIγ) plays an important role in centriole fidelity. PIPKIγ localized in a ring-like pattern in the intermediate pericentriolar materials around the proximal end of the centriole in G1, S and G2 phases, but not in M phase. This localization was dependent upon an association with centrosomal protein of 152 KDa...

16. Integrin α3β1 controls mRNA splicing that determines Cox-2 mRNA stability in breast cancer cells - Subbaram, Sita; Lyons, Scott P.; Svenson, Kimberly B.; Hammond, Sean L.; McCabe, Lorena G.; Chittur, Sridar V.; DiPersio, C. Michael
It is unknown how cues from the tumor microenvironment can regulate post-transcriptional mechanisms, such as alternative splicing, that control genes that drive malignant growth. The induction of cyclooxygenase 2 (Cox-2) by integrin α3β1 in breast cancer cells can promote tumor progression. We have used RNAi to suppress α3β1 in human MDA-MB-231 breast cancer cells and then investigated changes in global gene expression. Numerous mRNAs, including Cox-2, show altered expression and/or alternative exon usage (AEU) in α3β1-deficient cells. AEU included patterns predicted to render an mRNA susceptible to degradation, such as 3′-UTR variations or retention of elements that target an mRNA...

17. Autoregulation of glypican-1 by intronic microRNA-149 fine tunes the angiogenic response to FGF2 in human endothelial cells - Chamorro-Jorganes, Aránzazu; Araldi, Elisa; Rotllan, Noemi; Cirera-Salinas, Daniel; Suárez, Yajaira
MicroRNA-149 (miR-149) is located within the first intron of the glypican-1 (GPC1) gene. GPC1 is a low affinity receptor for fibroblast growth factor (FGF2) that enhances FGF2 binding to its receptor (FGFR1), subsequently promoting FGF2–FGFR1 activation and signaling. Using bioinformatic approaches, both GPC1 and FGFR1 were identified and subsequently validated as targets for miR-149 (both the mature strand, miR-149, and the passenger strand, miR-149*) in endothelial cells (ECs). As a consequence of their targeting activity towards GPC1 and FGFR1, both miR-149 and miR-149* regulated FGF2 signaling and FGF2-induced responses in ECs, namely proliferation, migration and cord formation. Moreover, lentiviral overexpression...

18. Genetically encoded molecular probes to visualize and perturb signaling dynamics in living biological systems - Sample, Vedangi; Mehta, Sohum; Zhang, Jin
In this Commentary, we discuss two sets of genetically encoded molecular tools that have significantly enhanced our ability to observe and manipulate complex biochemical processes in their native context and that have been essential in deepening our molecular understanding of how intracellular signaling networks function. In particular, genetically encoded biosensors are widely used to directly visualize signaling events in living cells, and we highlight several examples of basic biosensor designs that have enabled researchers to capture the spatial and temporal dynamics of numerous signaling molecules, including second messengers and signaling enzymes, with remarkable detail. Similarly, we discuss a number of...

19. Cdk1-dependent phosphorylation of Iqg1 governs actomyosin ring assembly prior to cytokinesis - Naylor, Stephen G.; Morgan, David O.
Contraction of the actomyosin ring (AMR) provides the centripetal force that drives cytokinesis. In budding yeast (Saccharomyces cerevisiae), assembly and contraction of the AMR is coordinated with membrane deposition and septum formation at the bud neck. A central player in this process is Iqg1, which promotes recruitment of actin to the myosin ring and links AMR assembly with that of septum-forming components. We observed early actin recruitment in response to inhibition of cyclin-dependent kinase 1 (Cdk1) activity, and we find that the Cdk1-dependent phosphorylation state of Iqg1 is a determining factor in the timing of bud neck localization of both...

20. Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin-43-containing gap junctions in cardiac myocytes - Zemljic-Harpf, Alice E.; Godoy, Joseph C.; Platoshyn, Oleksandr; Asfaw, Elizabeth K.; Busija, Anna R.; Domenighetti, Andrea A.; Ross, Robert S.
Vinculin (Vcl) links actin filaments to integrin- and cadherin-based cellular junctions. Zonula occludens-1 (ZO-1, also known as TJP1) binds connexin-43 (Cx43, also known as GJA1), cadherin and actin. Vcl and ZO-1 anchor the actin cytoskeleton to the sarcolemma. Given that loss of Vcl from cardiomyocytes causes maldistribution of Cx43 and predisposes cardiomyocyte-specific Vcl-knockout mice with preserved heart function to arrhythmia and sudden death, we hypothesized that Vcl and ZO-1 interact and that loss of this interaction destabilizes gap junctions. We found that Vcl, Cx43 and ZO-1 colocalized at the intercalated disc. Loss of cardiomyocyte Vcl caused parallel loss of ZO-1...

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