Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.4.4 (kinesin)
 5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The kinesin-related protein (HSET) gene belongs to the kinesin superfamily, the members of which are involved in cellular transport processes. The HSET gene product was previously characterized by partial cDNA sequencing. The gene is located on the short arm of human Chromosome 6 (6p21.3), at the centromeric end of the major histocompatibility complex. Here, we report the genomic structure of the complete HSET gene together with its flanking loci. Sequence analysis of the 40 kilobase (kb) cosmid clone containing the HSET gene also revealed the presence of several new genes not related to the kinesin superfamily. These include a 60S ribosomal protein L35A-like pseudogene (rPL35A-like) on the telomeric side and a polycomb-like gene (PHF1), a copper tolerance-like gene (CUTA1) and the 5' part of the synaptic ras-GTPase-activating protein (SynGAP) gene centromeric of HSET. In addition, a complete 60S ribosomal protein L12-like (rPL12L) gene in intron 3 of the HSET gene was identified which appears to have an open reading frame. The possible involvement of the HSET gene and a beta-tubulin gene (TUBB) in the pathogenesis of immotile cilia syndrome (ICS) was studied by screening two unrelated ICS families with microtubular defects and suspected HLA linkage for mutations within the HSET gene and the TUBB gene. Four single base substitutions were detected in the HSET gene, and none in the TUBB gene. On the basis of these data, a role of the HSET and TUBB products in the pathogenesis of ICS in the two families is unlikely.
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PMID:Genomic organization of the HSET locus and the possible association of HLA-linked genes with immotile cilia syndrome (ICS). 1036 22

Several studies indicate that spindle microtubules determine the position of the cleavage plane at the end of cell division, but their exact role in triggering the formation and ingression of the cleavage furrow is still unclear. Here we show that in Drosophila depletion of either the GAP (GTPase-activating protein) or the kinesin-like subunit of the evolutionary conserved centralspindlin complex prevents furrowing without affecting the association of astral microtubules with the cell cortex. Moreover, time-lapse imaging indicates that astral microtubules serve to deliver the centralspindlin complex to the equatorial cortex just before furrow formation. However, when the GAP-signaling component was mislocalized around the entire cortex using a membrane-tethering motif, this caused ectopic furrowing even in the absence of its motor partner. Thus, the GAP component of centralspindlin is both necessary and sufficient for furrow formation and ingression and astral microtubules provide a route for its delivery to the cleavage site.
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PMID:RacGAP50C is sufficient to signal cleavage furrow formation during cytokinesis. 1703 38

Cytokinesis in metazoan cells requires a set of antiparallel microtubules that become bundled upon anaphase onset to form a structure known as the central spindle. Bundling of these microtubules requires a protein complex, centralspindlin, that consists of the CYK-4/MgcRacGAP Rho-family GTPase-activating protein and the ZEN-4/MKLP1 kinesin-6 motor protein. Centralspindlin, but not its individual subunits, is sufficient to bundle microtubules in vitro. Here, we present a biochemical and genetic dissection of centralspindlin. We show that each of the two subunits of centralspindlin dimerize via a parallel coiled coil. The two homodimers assemble into a high-affinity heterotetrameric complex by virtue of two low-affinity interactions. Conditional mutations in the regions that mediate complex assembly can be readily suppressed by numerous second site mutations in the interacting regions. This unexpected plasticity explains the lack of primary sequence conservation of the regions critical for this essential protein-protein interaction.
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PMID:Cooperative assembly of CYK-4/MgcRacGAP and ZEN-4/MKLP1 to form the centralspindlin complex. 1794

Recently, recycling endosomes have emerged as a key components required for the successful completion of cytokinesis. Furthermore, FIP3 (family of Rab11-interacting protein 3), a Rab11 GTPase-binding protein, has been implicated in targeting the recycling endosomes to the midbody of dividing cells. Previously, we have shown that FIP3/Rab11-containing endosomes associate with centrosomes until anaphase, at which time they translocate to the cleavage furrow. At telophase, FIP3/Rab11-containing endosomes move from the furrow into the midbody, and this step is required for abscission. While several other proteins were implicated in regulating FIP3 targeting to the cleavage furrow, the mechanisms regulating the dynamics of FIP3-containing endosomes during mitosis have not been defined. To identify the factors regulating FIP3 targeting to the furrow, we used a combination of siRNA (small interfering RNA) screens and proteomic analysis to identify Cyk-4/MgcRacGAP (GTPase-activating protein) and kinesin I as FIP3-binding proteins. Furthermore, kinesin I mediates the transport of FIP3-containing endosomes to the cleavage furrow. Once in the furrow, FIP3 binds to Cyk-4 as part of centralspindlin complex and accumulates at the midbody. Finally, we demonstrated that ECT2 regulates FIP3 association with the centralspindlin complex. Thus we propose that kinesin I, in concert with centralspindlin complex, plays a role in temporal and spatial regulation of endosome transport to the cleavage furrow during cytokinesis.
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PMID:Mechanisms regulating targeting of recycling endosomes to the cleavage furrow during cytokinesis. 1848 66

Membrane trafficking and cytoskeletal dynamics are important cellular processes that drive tip growth in root hairs. These processes interact with a multitude of signaling pathways that allow for the efficient transfer of information to specify the direction in which tip growth occurs. Here, we show that AGD1, a class I ADP ribosylation factor GTPase-activating protein, is important for maintaining straight growth in Arabidopsis (Arabidopsis thaliana) root hairs, since mutations in the AGD1 gene resulted in wavy root hair growth. Live cell imaging of growing agd1 root hairs revealed bundles of endoplasmic microtubules and actin filaments extending into the extreme tip. The wavy phenotype and pattern of cytoskeletal distribution in root hairs of agd1 partially resembled that of mutants in an armadillo repeat-containing kinesin (ARK1). Root hairs of double agd1 ark1 mutants were more severely deformed compared with single mutants. Organelle trafficking as revealed by a fluorescent Golgi marker was slightly inhibited, and Golgi stacks frequently protruded into the extreme root hair apex of agd1 mutants. Transient expression of green fluorescent protein-AGD1 in tobacco (Nicotiana tabacum) epidermal cells labeled punctate bodies that partially colocalized with the endocytic marker FM4-64, while ARK1-yellow fluorescent protein associated with microtubules. Brefeldin A rescued the phenotype of agd1, indicating that the altered activity of an AGD1-dependent ADP ribosylation factor contributes to the defective growth, organelle trafficking, and cytoskeletal organization of agd1 root hairs. We propose that AGD1, a regulator of membrane trafficking, and ARK1, a microtubule motor, are components of converging signaling pathways that affect cytoskeletal organization to specify growth orientation in Arabidopsis root hairs.
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PMID:A class I ADP-ribosylation factor GTPase-activating protein is critical for maintaining directional root hair growth in Arabidopsis. 1853 80

Regulation of Rho GTPase signaling is critical for cell shape determination and polarity. Here, we investigated the role of LRG1, a novel member of the GTPase-activating proteins (GAPs) of Neurospora crassa. LRG1 is essential for apical tip extension and to restrict excessive branch formation in subapical regions of the hypha and is involved in determining the size of the hyphal compartments. LRG1 localizes to hyphal tips and sites of septation via its three LIM domains. The accumulation of LRG1 as an apical cap is dependent on a functional actin cytoskeleton and active growth, and is influenced by the opposing microtubule-dependent motor proteins dynein and kinesin-1. Genetic evidence and in vitro GTPase assays identify LRG1 as a RHO1-specific GAP affecting several output pathways of RHO1, based on hyposensitivity to the glucan inhibitor caspofungin, synthetic lethality with a hyperactive beta1,3-glucan synthase mutant, altered PKC/MAK1 pathway activities, and hypersensitivity to latrunculin A. The morphological defects of lrg-1 are highly reminiscent to the Ndr kinase/RAM pathway mutants cot-1 and pod-6, and genetic evidence suggests that RHO1/LRG1 function in parallel with COT1 in coordinating apical tip growth.
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PMID:The RHO1-specific GTPase-activating protein LRG1 regulates polar tip growth in parallel to Ndr kinase signaling in Neurospora. 1871 60

The central spindle regulates cleavage furrow formation and cytokinesis and is composed of antiparallel microtubules bundled by microtubule-associated proteins and kinesin motors. One key protein in the central spindle is a Rho family GTPase-activating protein, CYK-4/MgcRacGAP, whose target is the subject of two new studies that arrive at divergent models.
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PMID:Cytokinesis: GAP gap. 1766 50

Cytokinesis in animal cells requires the central spindle and midbody, which contain prominent microtubule bundles. Centralspindlin, a heterotetrameric complex consisting of kinesin-6 and RhoGAP (Rho-family GTPase-activating protein) subunits, is essential for the formation of these structures. Centralspindlin becomes precisely localized to the central spindle, where it promotes the equatorial recruitment of important cytokinetic regulators. These include ECT2, the activator of the small GTPase RhoA, which controls cleavage furrow formation and ingression. Centralspindlin's own RhoGAP domain also contributes to furrow ingression. Finally, centralspindlin facilitates recruitment of the chromosome passenger complex and factors that control abscission. Despite the importance of localized accumulation of centralspindlin, the mechanism by which this motor protein complex suddenly concentrates to the center of interpolar microtubule bundles during anaphase is unclear. Here, we show that centralspindlin travels along central spindle microtubules as higher-order clusters. Clustering of centralspindlin is critical for microtubule bundling and motility along microtubules in vitro and for midbody formation in vivo. These data support a positive feedback loop of centralspindlin clustering and microtubule organization that may underlie its distinctive localization during cytokinesis.
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PMID:Clustering of centralspindlin is essential for its accumulation to the central spindle and the midbody. 1996 7

Migrating neurons are bipolar, with a leading process and a trailing process [1]. The proximal region of the leading process displays a concentration of F-actin that contributes to the advance of the soma and the centrosome [2-7]. Here, we show that kinesin-6, a microtubule-based motor protein best known for its role in cytokinesis, also concentrates in this region. Depletion of kinesin-6 results in multipolar neurons that either are stationary or continuously change their direction of movement. In such neurons, F-actin no longer concentrates in a single process. During cytokinesis, kinesin-6 forms a complex with a Rho-family GTPase-activating protein called MgcRacGAP to signal to the actin cytoskeleton so that cortical movements are concentrated in the cleavage furrow [8-13]. During neuronal migration, MgcRacGap also concentrates in the proximal region of the leading process, and inhibition of its activity results in a phenotype similar to kinesin-6 depletion. We conclude that neuronal migration utilizes a cytoskeletal pathway analogous to cytokinesis, with kinesin-6 signaling through MgcRacGap to the actin cytoskeleton to constrain process number and restrict protrusive activity to a single leading process, thus resulting in a bipolar neuron able to move in a directed fashion.
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PMID:Polarity in migrating neurons is related to a mechanism analogous to cytokinesis. 2379 25

Cytokinesis requires activation of the GTPase RhoA. ECT-2, the exchange factor responsible for RhoA activation, is regulated to ensure spatiotemporal control of contractile ring assembly. Centralspindlin, composed of the Rho family GTPase-activating protein (RhoGAP) MgcRacGAP/CYK-4 and the kinesin MKLP1/ZEN-4, is known to activate ECT-2, but the underlying mechanism is not understood. We report that ECT-2-mediated RhoA activation depends on the ability of CYK-4 to localize to the plasma membrane, bind RhoA, and promote GTP hydrolysis by RhoA. Defects resulting from loss of CYK-4 RhoGAP activity can be rescued by activating mutations in ECT-2 or depletion of RGA-3/4, which functions as a conventional RhoGAP for RhoA. Consistent with CYK-4 RhoGAP activity contributing to GEF activation, the catalytic domains of CYK-4 and ECT-2 directly interact. Thus, counterintuitively, CYK-4 RhoGAP activity promotes RhoA activation. We propose that the most active form of the cytokinetic RhoGEF involves complex formation between ECT-2, centralspindlin and RhoA.
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PMID:The RhoGAP activity of CYK-4/MgcRacGAP functions non-canonically by promoting RhoA activation during cytokinesis. 2625 13


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