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Barbara Vodicska, Berati Cerikan, Elmar Schiebel, Ingrid Hoffmann
Precise mitotic spindle orientation is essential for both cell fate and tissue organization while defects in this process are associated with tumorigenesis and other diseases. In most animal cell types, the dynein motor complex is anchored at the cell cortex and exerts pulling forces on astral microtubules to position the spindle. The actin-binding protein MISP controls spindle orientation and mitotic progression in human cells. However, the exact underlying mechanism remains to be elucidated. Here we report that MISP interacts with the multidomain scaffolding protein IQGAP1...
April 20, 2018: Scientific Reports
Jia Yu, Chen Lai, Hoon Shim, Chengsong Xie, Lixin Sun, Cai-Xia Long, Jinhui Ding, Yan Li, Huaibin Cai
BACKGROUND: Dynactin p150Glued , the largest subunit of the dynactin macromolecular complex, binds to both microtubules and tubulin dimers through the N-terminal cytoskeleton-associated protein and glycine-rich (CAP-Gly) and basic domains, and serves as an anti-catastrophe factor in stabilizing microtubules in neurons. P150Glued also initiates dynein-mediated axonal retrograde transport. Multiple missense mutations at the CAP-Gly domain of p150Glued are associated with motor neuron diseases and other neurodegenerative disorders, further supporting the importance of microtubule domains (MTBDs) in p150Glued functions...
March 1, 2018: Molecular Neurodegeneration
Takayasu Mishima, Manami Deshimaru, Takuya Watanabe, Kaori Kubota, Mariko Kinoshita-Kawada, Junichi Yuasa-Kawada, Kotaro Takasaki, Yoshinari Uehara, Shozo Jinno, Katsunori Iwasaki, Yoshio Tsuboi
Perry syndrome is a rare neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and central hypoventilation. Our previously-conducted genome-wide association scan and subsequent studies identified nine mutations in DCTN1, the largest protein subunit of the dynactin complex, in patients with Perry syndrome. These included G71A in the microtubule-binding cytoskeleton-associated protein Gly-rich domain of p150Glued . The dynactin complex is essential for function of the microtubule-based cytoplasmic retrograde motor dynein...
February 14, 2018: Neuroscience Letters
Annie Andrieux, Laurence Aubry, Cécile Boscheron
In mammals, the C-terminal tyrosine residue of α-tubulin is subjected to removal/re-addition cycles resulting in tyrosinated microtubules and detyrosinated Glu-microtubules. CLIP170 and its yeast ortholog (Bik1) interact weakly with Glu-microtubules. Recently, we described a Microtubule- Rho1- and Bik1-dependent mechanism involved in Snc1 routing. Here, we further show a contribution of the yeast p150Glued ortholog (Nip100) in Snc1 trafficking. Both CLIP170 and p150Glued are CAP-Gly-containing proteins that belong to the microtubule +end-tracking protein family (known as +Tips)...
January 19, 2017: Small GTPases
Jie Ran, Youguang Luo, Yijun Zhang, Yang Yang, Miao Chen, Min Liu, Dengwen Li, Jun Zhou
Phosphorylation of end-binding protein 1 (EB1), a key member of microtubule plus end-tracking proteins (+TIPs), by apoptosis signal-regulating kinase 1 (ASK1) has been demonstrated to promote the stability of astral microtubules during mitosis by stimulating the binding of EB1 to microtubule plus ends. However, the roles of other members of the +TIPs family in ASK1/EB1-mediated regulation of astral microtubules are unknown. Herein, we show that ASK1-mediated phosphorylation of EB1 enhances the localization of cytoplasmic linker protein 170 (CLIP-170) and p150glued to the plus ends of astral microtubules...
February 7, 2017: Oncotarget
Sanne A M van Lith, Ilse Roodink, Joost J C Verhoeff, Petri I Mäkinen, Jari P Lappalainen, Seppo Ylä-Herttuala, Jos Raats, Erwin van Wijk, Ronald Roepman, Stef J Letteboer, Kiek Verrijp, William P J Leenders
Diffuse gliomas are primary brain cancers that are characterised by infiltrative growth. Whereas high-grade glioma characteristically presents with perinecrotic neovascularisation, large tumor areas thrive on pre-existent vasculature as well. Clinical studies have revealed that pharmacological inhibition of the angiogenic process does not improve survival of glioblastoma patients. Direct targeting of tumor vessels may however still be an interesting therapeutic approach as it allows pinching off the blood supply to tumor cells...
November 1, 2016: Oncotarget
Carla Lopes, Sophie Aubert, Fany Bourgois-Rocha, Monia Barnat, Ana Cristina Rego, Nicole Déglon, Anselme L Perrier, Sandrine Humbert
Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington's disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs...
2016: PloS One
Dick Jaarsma, Casper C Hoogenraad
The Golgi apparatus is a dynamic organelle involved in processing and sorting of lipids and proteins. In neurons, the Golgi apparatus is important for the development of axons and dendrites and maintenance of their highly complex polarized morphology. The motor protein complex cytoplasmic dynein has an important role in Golgi apparatus positioning and function. Together, with dynactin and other regulatory factors it drives microtubule minus-end directed motility of Golgi membranes. Inhibition of dynein results in fragmentation and dispersion of the Golgi ribbon in the neuronal cell body, resembling the Golgi abnormalities observed in some neurodegenerative disorders, in particular motor neuron diseases...
2015: Frontiers in Neuroscience
Fatima Verissimo, Aliaksandr Halavatyi, Rainer Pepperkok, Matthias Weiss
Newly synthesized proteins are sorted into COPII-coated transport carriers at the endoplasmic reticulum (ER). Assembly of the COPII coat complex, which occurs at ER exit sites (ERES), is initiated by membrane association and GTP loading of SAR1, followed by the recruitment of the SEC23-SEC24 and SEC13-SEC31 subcomplexes. Both of these two subcomplexes stimulate GTP hydrolysis and coat disassembly. This inherent disassembly capacity of COPII complexes needs to be regulated to allow sufficient time for cargo sorting and transport carrier formation...
November 15, 2015: Journal of Cell Science
Mohammed Abdullahel Amin, Kinue Kobayashi, Kozo Tanaka
The cytoplasmic linker protein (CLIP)-170 localizes to kinetochores and is suggested to function in stable attachment of kinetochores to microtubule ends. Here we show that defects in kinetochore-microtubule attachment and chromosome alignment in CLIP-170-depleted cells were rescued by co-depletion of p150glued, a dynactin subunit required for kinetochore localization of CLIP-170. CLIP-170 recruited p150glued to microtubule ends. Kinetochore localization at microtubule ends was perturbed by CLIP-170 depletion, which was rescued by co-depleting p150glued...
September 14, 2015: FEBS Letters
Raquel Muñoz-Moreno, Lucía Barrado-Gil, Inmaculada Galindo, Covadonga Alonso
African swine fever virus (ASFV) is a double-stranded DNA virus causing a hemorrhagic fever disease with high mortality rates and severe economic losses in pigs worldwide. ASFV replicates in perinuclear sites called viral factories (VFs) that are morphologically similar to cellular aggresomes. This fact raises the possibility that both VFs and aggresomes may be the same structure. However, little is known about the process involved in the formation of these viral replication platforms. In order to expand our knowledge on the assembly of ASFV replication sites, we have analyzed the involvement of both canonical aggresome pathways in the formation of ASFV VFs: HDAC6 and BAG3...
April 2015: Viruses
Terry D Heiman-Patterson, Elizabeth P Blankenhorn, Roger B Sher, Juliann Jiang, Priscilla Welsh, Meredith C Dixon, Jeremy I Jeffrey, Philip Wong, Gregory A Cox, Guillermo M Alexander
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily affecting motor neurons in the central nervous system. Although most cases of ALS are sporadic, about 5-10% of cases are familial (FALS) with approximately 20% of FALS caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene. We have reported that hSOD1-G93A transgenic mice modeling this disease show a more severe phenotype when the transgene is bred on a pure SJL background and a milder phenotype when bred on a pure B6 background and that these phenotype differences link to a region on mouse Chromosome 17...
2015: PloS One
Shin Kedashiro, Strahil I Pastuhov, Tomoki Nishioka, Takashi Watanabe, Kozo Kaibuchi, Kunihiro Matsumoto, Hiroshi Hanafusa
No abstract text is available yet for this article.
February 15, 2015: Journal of Cell Science
Shin Kedashiro, Strahil Iv Pastuhov, Tomoki Nishioka, Takashi Watanabe, Kozo Kaibuchi, Kunihiro Matsumoto, Hiroshi Hanafusa
The binding of ligand to epidermal growth factor receptor (EGFR) causes the receptor to become activated and stimulates the endocytosis of EGFR. Early endosomes containing activated EGFR migrate along microtubules as they mature into late endosomes. We have recently shown that LRRK1, which is related to the familial Parkinsonism gene product Park8 (also known as LRRK2), regulates this EGFR transport in a manner dependent on LRRK1 kinase activity. However, the downstream targets of LRRK1 that might modulate this transport function have not been identified...
January 15, 2015: Journal of Cell Science
Ke Li, Lin Yang, Cheng Zhang, Yang Niu, Wei Li, Jia-Jia Liu
Hermansky-Pudlak syndrome 6 protein (HPS6) has originally been identified as a subunit of the BLOC-2 protein complex that is involved in the biogenesis of lysosome-related organelles. Here, we demonstrate that HPS6 directly interacts with the dynactin p150(Glued) subunit of the dynein-dynactin motor complex and acts as cargo adaptor for the retrograde motor to mediate the transport of lysosomes from the cell periphery to the perinuclear region. Small interfering RNA (siRNA)-mediated knockdown of HPS6 in HeLa cells not only partially blocks centripetal movement of lysosomes but also causes delay in lysosome-mediated protein degradation...
November 1, 2014: Journal of Cell Science
Christian Duellberg, Martina Trokter, Rupam Jha, Indrani Sen, Michel O Steinmetz, Thomas Surrey
Growing microtubule end regions recruit a variety of proteins collectively termed +TIPs, which confer local functions to the microtubule cytoskeleton. +TIPs form dynamic interaction networks whose behaviour depends on a number of potentially competitive and hierarchical interaction modes. The rules that determine which of the various +TIPs are recruited to the limited number of available binding sites at microtubule ends remain poorly understood. Here we examined how the human dynein complex, the main minus-end-directed motor and an important +TIP (refs , , ), is targeted to growing microtubule ends in the presence of different +TIP competitors...
August 2014: Nature Cell Biology
Kei-Ichi Ishikawa, Shinji Saiki, Norihiko Furuya, Daisuke Yamada, Yoko Imamichi, Yuanzhe Li, Sumihiro Kawajiri, Hironori Sasaki, Masato Koike, Yoshio Tsuboi, Nobutaka Hattori
Mutations in p150glued cause hereditary motor neuropathy with vocal cord paralysis (HMN7B) and Perry syndrome (PS). Here we show that both overexpression of p150glued mutants and knockdown of endogenous p150glued induce apoptosis. Overexpression of a p150glued plasmid containing either a HMN7B or PS mutation resulted in cytoplasmic p150glued-positive aggregates and was associated with cell death. Cells containing mutant p150glued aggregates underwent apoptosis that was characterized by an increase in cleaved caspase-3- or Annexin V-positive cells and was attenuated by both zVAD-fmk (a pan-caspase inhibitor) application and caspase-3 siRNA knockdown...
2014: PloS One
Tomáš Mazel, Anja Biesemann, Magda Krejczy, Janos Nowald, Olga Müller, Leif Dehmelt
Microtubules are under the influence of forces mediated by cytoplasmic dynein motors associated with the cell cortex. If such microtubules are free to move, they are rapidly transported inside cells. Here we directly observe fluorescent protein-labeled cortical dynein speckles and motile microtubules. We find that several dynein complex subunits, including the heavy chain, the intermediate chain, and the associated dynactin subunit Dctn1 (also known as p150glued) form spatially resolved, dynamic speckles at the cell cortex, which are preferentially associated with microtubules...
January 2014: Molecular Biology of the Cell
David Reboutier, Marie-Bérengère Troadec, Jean-Yves Cremet, Lucie Chauvin, Vincent Guen, Patrick Salaun, Claude Prigent
Knowledge of Aurora A kinase functions is limited to premetaphase events, particularly centrosome maturation, G2/M transition, and mitotic spindle assembly. The involvement of Aurora A in events after metaphase has only been suggested because appropriate experiments are technically difficult. We report here the design of the first human Aurora A kinase (as-AurA) engineered by chemical genetics techniques. This kinase is fully functional biochemically and in cells, and is rapidly and specifically inhibited by the ATP analogue 1-Naphthyl-PP1 (1-Na-PP1)...
April 1, 2013: Journal of Cell Biology
Dae Joong Kim, Luis A Martinez-Lemus, George E Davis
Vascular tube morphogenesis requires the establishment of endothelial cell (EC) apical-basal polarity in three-dimensional (3D) extracellular matrices. To date, there is little understanding of how EC polarity is controlled during these highly dynamic and rapid morphogenic events. We show that the microtubule tip complex proteins, end binding 1 (EB1), p150(Glued), and Clasp1, control human EC tube formation by (1) inducing microtubule assembly and asymmetric cytoskeletal polarization, whereby acetylated and detyrosinated tubulins distribute in a subapical membrane location and filamentous actin distributes basally; (2) increasing tubulin posttranslational modifications, including required acetylation events; and (3) regulating an EC lumen signaling cascade that involves membrane type 1 matrix metallopatrinase (MT1-MMP)-dependent proteolysis as well as Pak, Raf, and Erk kinases...
April 25, 2013: Blood
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