scholarly journals Systematic dissection of dynein regulators in mitosis

2013 ◽  
Vol 201 (2) ◽  
pp. 201-215 ◽  
Author(s):  
Jonne A. Raaijmakers ◽  
Marvin E. Tanenbaum ◽  
René H. Medema
Keyword(s):  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Cytoplasmic Dynein ◽  
Comprehensive Overview ◽  
Motor Complex ◽  
Essential Components ◽  
Complex Thought ◽  
Specific Activities ◽  
Dynactin Complex

Cytoplasmic dynein is a large minus end–directed motor complex with multiple functions during cell division. The dynein complex interacts with various adaptor proteins, including the dynactin complex, thought to be critical for most dynein functions. Specific activities have been linked to several subunits and adaptors, but the function of the majority of components has remained elusive. Here, we systematically address the function of each dynein–dynactin subunit and adaptor protein in mitosis. We identify the essential components that are required for all mitotic functions of dynein. Moreover, we find specific dynein recruitment factors, and adaptors, like Nde1/L1, required for activation, but largely dispensable for dynein localization. Most surprisingly, our data show that dynactin is not required for dynein-dependent spindle organization, but acts as a dynein recruitment factor. These results provide a comprehensive overview of the role of dynein subunits and adaptors in mitosis and reveal that dynein forms distinct complexes requiring specific recruiters and activators to promote orderly progression through mitosis.

scholarly journals Dynein Light Chain 1 Regulates Dynamin-mediated F-Actin Assembly during Sperm Individualization in Drosophila

2005 ◽  
Vol 16 (7) ◽  
pp. 3107-3116 ◽  
Author(s):  
Anindya Ghosh-Roy ◽  
Bela S. Desai ◽  
Krishanu Ray
Keyword(s):  
Light Chain ◽  
Cytoplasmic Dynein ◽  
Actin Dynamics ◽  
Dynein Light Chain ◽  
Actin Assembly ◽  
Cellular Functions ◽  
Directed Movement ◽  
Cellular Processes ◽  
Dynactin Complex

Toward the end of spermiogenesis, spermatid nuclei are compacted and the clonally related spermatids individualize to become mature and active sperm. Studies in Drosophila showed that caudal end-directed movement of a microfilament-rich structure, called investment cone, expels the cytoplasmic contents of individual spermatids. F-actin dynamics plays an important role in this process. Here we report that the dynein light chain 1 (DLC1) of Drosophila is involved in two separate cellular processes during sperm individualization. It is enriched around spermatid nuclei during postelongation stages and plays an important role in the dynein-dynactin–dependent rostral retention of the nuclei during this period. In addition, DDLC1 colocalizes with dynamin along investment cones and regulates F-actin assembly at this organelle by retaining dynamin along the cones. Interestingly, we found that this process does not require the other subunits of cytoplasmic dynein-dynactin complex. Altogether, these observations suggest that DLC1 could independently regulate multiple cellular functions and established a novel role of this protein in F-actin assembly in Drosophila.

scholarly journals Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss

2019 ◽  
Vol 116 (4) ◽  
pp. 1347-1352 ◽  
Author(s):  
Chong Li ◽  
Guney Bademci ◽  
Asli Subasioglu ◽  
Oscar Diaz-Horta ◽  
Yi Zhu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Ras Signaling ◽  
Nonsyndromic Deafness ◽  
Auditory Hair Cells ◽  
Cytoskeleton Dynamics ◽  
Growth Factor Receptor Bound

We have identified a GRAP variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. GRAP encodes a member of the highly conserved growth factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein 2 (GRB2)-related adaptor protein (GRAP) in the auditory system is not known. Here, we show that, in mouse, Grap is expressed in the inner ear and the protein localizes to the neuronal fibers innervating cochlear and utricular auditory hair cells. Downstream of receptor kinase (drk), the Drosophila homolog of human GRAP, is expressed in Johnston’s organ (JO), the fly hearing organ, and the loss of drk in JO causes scolopidium abnormalities. drk mutant flies present deficits in negative geotaxis behavior, which can be suppressed by human wild-type but not mutant GRAP. Furthermore, drk specifically colocalizes with synapsin at synapses, suggesting a potential role of such adaptor proteins in regulating actin cytoskeleton dynamics in the nervous system. Our findings establish a causative link between GRAP mutation and nonsyndromic deafness and suggest a function of GRAP/drk in hearing.

scholarly journals RUFY3 links Arl8b and JIP4-Dynein complex to regulate lysosome size and positioning

2021 ◽  
Author(s):  
Gaurav Kumar ◽  
Prateek Chawla ◽  
Sanya Chadha ◽  
Sheetal Sharma ◽  
Kanupriya Sethi ◽  
...  
Keyword(s):  
G Protein ◽  
Spatial Organization ◽  
Adaptor Protein ◽  
Retrograde Transport ◽  
Anterograde Transport ◽  
Motor Complex ◽  
Gtp Binding ◽  
Microtubule Motor ◽  
Mobile Fraction ◽  
Dynactin Complex

Abstract The whole-cell scale spatial organization of lysosomes is regulated by their bidirectional motility on microtubule tracks. Small GTP-binding (G) protein, Arl8b, stimulates the anterograde transport of lysosomes by recruiting adaptor protein SKIP (also known as PLEKHM2), which in turn couples the microtubule motor kinesin-1. Here, we have identified an Arl8b effector, RUN and FYVE domain-containing protein family member 3, RUFY3, which drives the retrograde transport of lysosomes. Artificial targeting of RUFY3 to the surface of mitochondria was sufficient to drive their perinuclear positioning. We find that RUFY3 interacts with the JIP4-Dynein-Dynactin complex and mediates Arl8b association with the retrograde motor complex. The mobile fraction of the total lysosomes per cell was significantly enhanced upon RUFY3 depletion, suggesting that RUFY3 maintains the lysosomes clustering within the perinuclear cloud. Expectedly, RUFY3 knockdown disrupted the perinuclear positioning of lysosomes upon nutrient starvation and/or serum depletion, although lysosome continued to undergo fusion with autophagosomes. Interestingly, lysosome fission events were more frequent in RUFY3-depleted cells and accordingly, there was a striking reduction in lysosome size, an effect that was also observed in dynein and JIP4 depleted cells. These findings indicate that the dynein-dependent “perinuclear cloud” arrangement of lysosomes also regulates the size of these proteolytic compartments and, likely, their cellular roles.

scholarly journals LIS1 at the microtubule plus end and its role in dynein-mediated nuclear migration

2003 ◽  
Vol 160 (3) ◽  
pp. 289-290 ◽  
Author(s):  
Xin Xiang
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Nuclear Migration ◽  
Cytoplasmic Dynein ◽  
Causal Gene ◽  
New Findings ◽  
Dynactin Complex

The cytoplasmic dynein complex and its accessory dynactin complex are involved in many cellular activities including nuclear migration in fungi (for review see Karki and Holzbaur, 1999). LIS1, the product of a causal gene for human lissencephaly (smooth brain), has also been implicated in dynein function based on studies in fungi and more recent studies in higher eukaryotic systems (for review see Gupta et al., 2002). Exactly how LIS1 may regulate the behavior of cytoplasmic dynein in various organisms is a fascinating question. In this issue, Lee et al. (2003) describe important new findings in Saccharomyces cerevisiae regarding the role of LIS1 (Pac1) in dynein-mediated nuclear migration.

scholarly journals A new calcium-activated dynein adaptor protein, CRACR2a, regulates clathrin-independent endocytic traffic in T cells

2018 ◽  
Author(s):  
Yuxiao Wang ◽  
Walter Huynh ◽  
Taylor D. Skokan ◽  
Ronald D. Vale
Keyword(s):  
T Cells ◽  
Coiled Coil ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Cytoplasmic Dynein ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Microtubule Organizing Center ◽  
Activated T Cells

AbstractCytoplasmic dynein is a microtubule minus-end-directed motor that transports numerous intracellular cargoes. Mammalian dynein transport is initiated by coiled-coil adaptor proteins that 1) join dynein and its co-factor dynactin into a complex capable of processive motility, and 2) interact with a cargo-bound receptor, which is frequently a Rab GTPase on an organelle. Here, we report two novel dynein adaptors, CRACR2a and Rab45, which have a coiled-coil adaptor domain, a pair of EF hands, and a Rab GTPase domain fused into a single polypeptide. We find that CRACR2a-mediated dynein-dynactin motility is activated by calcium in vitro and in cells. In activated T cells, CRACR2a localizes to clathrin-independent endosomes that require microtubule-based transport to detach from the actin cortex and travel towards the microtubule organizing center. Together these results represent the first known examples of Rab GTPases that directly act as dynein adaptors and implicate CRACR2a-dynein in regulation of endocytic trafficking in T cells.

scholarly journals Combinatorial regulation of the balance between dynein microtubule end accumulation and initiation of directed motility

2017 ◽  
Author(s):  
Rupam Jha ◽  
Johanna Roostalu ◽  
Martina Trokter ◽  
Thomas Surrey
Keyword(s):  
Adaptor Protein ◽  
Cytoplasmic Dynein ◽  
Dependent Manner ◽  
Cellular Functions ◽  
Combinatorial Regulation ◽  
Directed Motility ◽  
The Individual ◽  
Dynactin Complex ◽  
Insight Into ◽  
Dynamic Microtubule

ABSTRACTCytoplasmic dynein is involved in a multitude of essential cellular functions. Dynein’s activity is controlled by the combinatorial action of several regulators. The molecular mechanism of this regulation is poorly understood. Using purified proteins, we reconstitute the regulation of the human dynein complex by three prominent regulators on dynamic microtubules in the presence of end binding proteins (EBs). We find that dynein can be in biochemically and functionally distinct pools: either passively tracking dynamic microtubule plus-ends in an EB-dependent manner or moving processively towards minus ends in an adaptor protein-dependent manner. Whereas both dynein pools share the dynactin complex, they have opposite preferences for binding other regulators, either the adaptor protein Bicaudal D2 (BicD2) or the multifunctional regulator Lisencephaly-1 (Lis1). Remarkably, dynactin, but not EBs, strongly biases motility initiation locally from microtubule plus ends by autonomous plus end recognition. BicD2 and Lis1 together control the overall efficiency of motility initiation. Our study provides insight into the mechanism of dynein activity regulation by dissecting the distinct functional contributions of the individual members of a dynein regulatory network.

scholarly journals Assembly and activation of dynein–dynactin by the cargo adaptor protein Hook3

2016 ◽  
Vol 214 (3) ◽  
pp. 309-318 ◽  
Author(s):  
Courtney M. Schroeder ◽  
Ronald D. Vale
Keyword(s):  
Crystal Structure ◽  
Crucial Role ◽  
Ternary Complex ◽  
Adaptor Protein ◽  
Cytoplasmic Dynein ◽  
Allosteric Activation ◽  
Structural Details ◽  
Dynactin Complex ◽  
Insight Into ◽  
Intermediate Chain

Metazoan cytoplasmic dynein moves processively along microtubules with the aid of dynactin and an adaptor protein that joins dynein and dynactin into a stable ternary complex. Here, we examined how Hook3, a cargo adaptor involved in Golgi and endosome transport, forms a motile dynein–dynactin complex. We show that the conserved Hook domain interacts directly with the dynein light intermediate chain 1 (LIC1). By solving the crystal structure of the Hook domain and using structure-based mutagenesis, we identify two conserved surface residues that are each critical for LIC1 binding. Hook proteins with mutations in these residues fail to form a stable dynein–dynactin complex, revealing a crucial role for LIC1 in this interaction. We also identify a region of Hook3 specifically required for an allosteric activation of processive motility. Our work reveals the structural details of Hook3’s interaction with dynein and offers insight into how cargo adaptors form processive dynein–dynactin motor complexes.

scholarly journals c-Src Recruitment is Involved in c-MET-Mediated Malignant Behaviour of NT2D1 Non-Seminoma Cells

2019 ◽  
Vol 20 (2) ◽  
pp. 320 ◽  
Author(s):  
Erica Leonetti ◽  
Luisa Gesualdi ◽  
Katia Corano Scheri ◽  
Simona Dinicola ◽  
Luigi Fattore ◽  
...  
Keyword(s):  
Chemotherapy Resistance ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Migration And Invasion ◽  
Testicular Germ Cell ◽  
Testicular Germ Cell Tumours ◽  
Src Inhibitor ◽  
Src Activation ◽  
The Relationship

: c-MET pathway over-activation is the signature of malignancy acquisition or chemotherapy resistance of many cancers. We recently demonstrated that type II Testicular Germ Cell Tumours (TGCTs) express c-MET receptor. In particular, we elucidated that the non-seminoma lesions express c-MET protein at higher level, compared with the seminoma ones. In line with this observation, NTERA-2 clone D1 (NT2D1) non-seminoma cells increase their proliferation, migration and invasion in response to Hepatocyte Growth Factor (HGF). One of the well-known adaptor-proteins belonging to c-MET signaling cascade is c-Src. Activation of c-Src is related to the increase of aggressiveness of many cancers. For this reason, we focused on the role of c-Src in c-MET-triggered and HGF-dependent NT2D1 cell activities. In the present paper, we have elucidated that this adaptor-protein is involved in HGF-dependent NT2D1 cell proliferation, migration and invasion, since Src inhibitor-1 administration abrogates these responses. Despite these biological evidences western blot analyses have not revealed the increase of c-Src activation because of HGF administration. However, notably, immunofluorescence analyses revealed that cytoplasmic and membrane-associated localization of c-Src shifted to the nuclear compartment after HGF stimulation. These results shed new light in the modality of HGF-dependent c-Src recruitment, and put the basis for novel investigations on the relationship between c-Src, and TGCT aggressiveness.

scholarly journals Role of adaptor protein p66Shc in renal pathologies

2018 ◽  
Vol 314 (2) ◽  
pp. F143-F153 ◽  
Author(s):  
Kevin D. Wright ◽  
Alexander Staruschenko ◽  
Andrey Sorokin
Keyword(s):  
Reactive Oxygen Species ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Review Article ◽  
Oxygen Species ◽  
Kidney Physiology ◽  
Signaling Mechanisms ◽  
Wide Range ◽  
Key Questions

p66Shc is one of the three adaptor proteins encoded by the Shc1 gene, which are expressed in many organs, including the kidney. Recent studies shed new light on several key questions concerning the signaling mechanisms mediated by p66Shc. The central goal of this review article is to summarize recent findings on p66Shc and the role it plays in kidney physiology and pathology. This article provides a review of the various mechanisms whereby p66Shc has been shown to function within the kidney through a wide range of actions. The mitochondrial and cytoplasmic signaling of p66Shc, as it relates to production of reactive oxygen species (ROS) and renal pathologies, is further discussed.

scholarly journals The Role of LNK (SH2B3) in the Regulation of JAK-STAT Signalling in Haematopoiesis

2021 ◽  
Vol 15 (1) ◽  
pp. 24
Author(s):  
Rhiannon Morris ◽  
Liesl Butler ◽  
Andrew Perkins ◽  
Nadia J. Kershaw ◽  
Jeffrey J. Babon
Keyword(s):  
Inflammatory Diseases ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Janus Kinase ◽  
Target Cells ◽  
Signal Transducer ◽  
Pathway Activation ◽  
Specific Receptors ◽  
Stat Pathway

LNK is a member of the SH2B family of adaptor proteins and is a non-redundant regulator of cytokine signalling. Cytokines are secreted intercellular messengers that bind to specific receptors on the surface of target cells to activate the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signalling pathway. Activation of the JAK-STAT pathway leads to proliferative and often inflammatory effects, and so the amplitude and duration of signalling are tightly controlled. LNK binds phosphotyrosine residues to signalling proteins downstream of cytokines and constrains JAK-STAT signalling. Mutations in LNK have been identified in a range of haematological and inflammatory diseases due to increased signalling following the loss of LNK function. Here, we review the regulation of JAK-STAT signalling via the adaptor protein LNK and discuss the role of LNK in haematological diseases.

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