Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Kinesin-I is essential for the transport of membrane-bound organelles in neural and nonneural cells. However, the means by which kinesin interacts with its intracellular cargoes, and the means by which kinesin-cargo interactions are regulated in response to cellular transport requirements are not fully understood. The C terminus of the Drosophila kinesin heavy chain (KHC) was used in a two-hybrid screen of a Drosophila cDNA library to identify proteins that bind specifically to the kinesin tail domain. UNC-76 is an evolutionarily conserved cytosolic protein that binds to the tail domain of KHC in two-hybrid and copurification assays, indicating that kinesin and UNC-76 form a stable complex in vivo. Loss of Drosophila Unc-76 function results in locomotion and axonal transport defects reminiscent of the phenotypes observed in kinesin mutants, suggesting that UNC-76 is required for kinesin-dependent axonal transport. Unc-76 exhibits dosage-sensitive genetic relationships with Khc and Kinesin light chain mutations, further supporting the hypothesis that UNC-76 and kinesin-I work in a common transport pathway. Given the interaction of FEZ1, the mammalian homolog of UNC-76, with protein kinase Czeta, and the role of FEZ1 in axon outgrowth, we propose that UNC-76 helps integrate kinesin activity in response to transport requirements in axons.
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PMID:The kinesin-associated protein UNC-76 is required for axonal transport in the Drosophila nervous system. 1292 68

The microtubule-based motor kinesin-I is essential for the intracellular transport of membrane-bound organelles in the Drosophila nervous system and female germ line. A number of studies have demonstrated that kinesin-I binds to its intracellular cargos through protein-protein interactions between the kinesin tail domain and proteins on the cargo surface. To identify proteins that mediate or regulate kinesin-cargo interactions, we have performed yeast two-hybrid screens of a Drosophila embryonic cDNA library, using the tetratricopeptide repeats of the kinesin light chain and amino acids 675-975 of the kinesin heavy chain as baits. One of the proteins we have identified is YETI. Interestingly, YETI has the unique ability to bind specifically to both subunits of the kinesin tail domain. An epitope-tagged YETI fusion protein, when expressed in Drosophila S2 cultured cells, binds to kinesin-I in copurification assays, suggesting that YETI-kinesin-I interactions are context-independent. Immunostaining of cultured cells expressing YETI shows that YETI accumulates in the nucleus and cytosol. YETI is evolutionarily conserved, and its yeast homolog (AOR1) may have a role in regulating cytoskeletal dynamics or intracellular transport. Collectively, these results demonstrate that YETI interacts with both kinesin subunits of the kinesin tail domain, and is potentially involved in kinesin-dependent transport pathways.
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PMID:The Drosophila kinesin-I associated protein YETI binds both kinesin subunits. 1472 Apr 62

Infection of host cells by Salmonella enterica serovar Typhimurium (S. typhimurium) leads to the formation of specialised membrane-bound compartments called Salmonella-containing vacuoles (SCVs). Bacteria remain enclosed by the vacuolar membrane as they divide, and by translocating effector proteins across the vacuolar membrane through the SPI-2 type III secretion system, they interfere with host cell processes in ways that promote bacterial growth. One such effector is SifA, which is required to maintain the integrity of the vacuolar membrane and for the formation in epithelial cells of long tubular structures called Sifs that are connected to SCVs. Unknown effector(s) mediate the assembly of a meshwork of F-actin around SCVs. We report that intracellular bacteria also cause a dramatic accumulation of microtubules around S. typhimurium microcolonies in both epithelial cells and macrophages. Although this process appears to be independent of SPI-2-mediated F-actin assembly, it does require bacterial protein synthesis. In epithelial cells, microtubule accumulation is accompanied by the recruitment of both kinesin and dynein. Inhibition of the activity of either motor prevented both Sif formation and the loss of vacuolar membrane from sifA mutant bacteria. It also resulted in morphologically abnormal vacuoles enclosing wild-type bacteria, and impaired their replication. Our experiments indicate that recruitment of dynein to SCVs is dependent on Rab7 activity. We show that the recently described Rab7 effector RILP is also recruited to SCVs in a Rab7-dependent manner. However, overexpression of RILP did not restore dynein recruitment to SCVs in cells expressing dominant negative Rab7, suggesting that RILP requires a functional Rab7 to be activated at the SCV membrane, or that dynein recruitment is mediated by an effector other than RILP. Together, these experiments indicate that microtubule motors play important roles in regulating vacuolar membrane dynamics during intracellular replication of S. typhimurium.
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PMID:Microtubule motors control membrane dynamics of Salmonella-containing vacuoles. 1497 Feb 61

Myosins are eukaryotic molecular motors moving along actin filaments. Only a small set of myosin classes is present in plants, in which myosins have been found to play a role in cytoplasmic streaming and chloroplast movement. Whereas most studies have been done on green algae, more recent data suggest a role of higher plant myosin at the postcytokinetic cell wall. Here we characterize a loss-of-function mutation for a myosin of plant-specific class XI and demonstrate myosin functions during plant development in Arabidopsis. T-DNA insertion in MYA2 caused pleiotropic effects, including flower sterility and dwarf growth. Elongation of epidermal cells, such as in hypocotyls and anther filaments, was reduced by up to 50% of normal length. This effect on anther filaments is responsible for flower sterility. In the meristems of root tips, it was evident that cell division was delayed and that cell plates were mislocated. Like zwichel, a kinesin-related mutation causing two-branched trichomes, the mya2 knockout causes branching defects, but here the trichomes remained unbranched. Growth was also impaired in pollen tubes and root hairs, cells that are highly dependent on vesicle transport. A failure in vesicle flow could be directly confirmed, because cytoplasmic streaming of vesicles and, more so, of large endoplasmic reticulum-based organelles was slowed. The defect in vesicle trafficking was accompanied by failures in basipetal auxin transport, measured in stem segments of inflorescences. This result strongly suggests a causal link between auxin-dependent processes and the distribution of vesicles and membrane-bound molecules by plant myosin.
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PMID:Arabidopsis myosin XI mutant is defective in organelle movement and polar auxin transport. 1828 2

Salmonella enterica causes a variety of diseases, including gastroenteritis and typhoid fever. The success of this pathogen depends on its capacity to proliferate within host cells in a membrane-bound compartment. We found that the Salmonella-containing vacuole recruited the plus-end-directed motor kinesin. Bacterial effector proteins translocated into the host cell by a type III secretion system antagonistically regulated this event. Among these effectors, SifA targeted SKIP, a host protein that down-regulated the recruitment of kinesin on the bacterial vacuole and, in turn, controlled vacuolar membrane dynamics.
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PMID:The intracellular fate of Salmonella depends on the recruitment of kinesin. 1590 2

It is well established that actin and microtubule cytoskeletal systems are involved in organelle transport and membrane trafficking in cells. This is also true for the transport of secretory vesicles in neuroendocrine cells and neurons. It was however unclear whether secretory vesicles remain free-floating, only to associate with such cytoskeletal systems when needing transport. This hypothesis was tested using live pancreatic acinar cells in physiological buffer solutions, using the photonic force microscope (PFM). When membrane-bound secretory vesicles (0.2-1.2 microm in diameter) in live pancreatic acinar cells were trapped at the laser focus of the PFM and pulled, they were all found tethered to filamentous structures. Mild exposure of cells to nocodazole and cytochalasin B, disrupts the tether. Immunoblot analysis of isolated secretory vesicles, further demonstrated the association of actin, myosin V, and kinesin. These studies demonstrate for the first time that secretory vesicles in live pancreatic acinar cells are tethered and not free-floating, suggesting that following vesicle biogenesis, they are placed on their own railroad track, ready to be transported to their final destination within the cell when required. This makes sense, since precision and regulation are the hallmarks of all cellular process, and therefore would hold true for the transport and localization of subcellular organelles such as secretory vesicles.
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PMID:Secretory vesicles in live cells are not free-floating but tethered to filamentous structures: a study using photonic force microscopy. 1671 90

Intracellular replication of Salmonella enterica occurs in membrane-bound compartments, called Salmonella-containing vacuoles (SCVs). Following invasion of epithelial cells, most SCVs migrate to a perinuclear region and replicate in close association with the Golgi network. The association of SCVs with the Golgi is dependent on the Salmonella-pathogenicity island-2 (SPI-2) type III secretion system (T3SS) effectors SseG, SseF and SifA. However, little is known about the dynamics of SCV movement. Here, we show that in epithelial cells, 2 h were required for migration of the majority of SCVs to within 5 microm from the microtubule organizing centre (MTOC), which is located in the same subcellular region as the Golgi network. This initial SCV migration was saltatory, bidirectional and microtubule-dependent. An intact Golgi, SseG and SPI-2 T3SS were dispensable for SCV migration to the MTOC, but were essential for maintenance of SCVs in that region. Live-cell imaging between 4 and 8 h post invasion revealed that the majority of wild-type SCVs displaced less than 2 microm in 20 min from their initial starting positions. In contrast, between 6 and 8 h post invasion the majority of vacuoles containing sseG, sseF or ssaV mutant bacteria displaced more than 2 microm in 20 min from their initial starting positions, with some undergoing large and dramatic movements. Further analysis of the movement of SCVs revealed that large displacements were a result of increased SCV speed rather than a change in their directionality, and that SseG influences SCV motility by restricting vacuole speed within the MTOC/Golgi region. SseG might function by tethering SCVs to Golgi-associated molecules, or by controlling microtubule motors, for example by inhibiting kinesin recruitment or promoting dynein recruitment.
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PMID:The SPI-2 type III secretion system restricts motility of Salmonella-containing vacuoles. 1757 17

Matrix metalloproteinases (MMPs) are endopeptidases that cleave matrix, soluble and membrane-bound proteins and are regulated by their endogenous inhibitors the tissue inhibitors of MMPs (TIMPs). Nothing is known about MMP/TIMP trafficking and secretion in neuronal cells. We focussed our attention on the gelatinases MMP-2 and MMP-9, and their inhibitor TIMP-1. MMPs and TIMP-1 fused to GFP were expressed in N2a neuroblastoma and primary neuronal cells to study trafficking and secretion using real time video-microscopy, imaging, electron microscopy and biochemical approaches. We show that MMPs and TIMP-1 are secreted in 160-200 nm vesicles in a Golgi-dependent pathway. These vesicles distribute along microtubules and microfilaments, co-localise differentially with the molecular motors kinesin and myosin Va and undergo both anterograde and retrograde trafficking. MMP-9 retrograde transport involves the dynein/dynactin molecular motor. In hippocampal neurons, MMP-2 and MMP-9 vesicles are preferentially distributed in the somato-dendritic compartment and are found in dendritic spines. Non-transfected hippocampal neurons also demonstrate vesicular secretion of MMP-2 in both its pro- and active forms and gelatinolytic activity localised within dendritic spines. Our results show differential trafficking of MMP and TIMP-1-containing vesicles in neuronal cells and suggest that these vesicles could play a role in neuronal and synaptic plasticity.
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PMID:Vesicular trafficking and secretion of matrix metalloproteinases-2, -9 and tissue inhibitor of metalloproteinases-1 in neuronal cells. 1881 73

Kinesin-3 motors drive the transport of synaptic vesicles and other membrane-bound organelles in neuronal cells. In the absence of cargo, kinesin motors are kept inactive to prevent motility and ATP hydrolysis. Current models state that the Kinesin-3 motor KIF1A is monomeric in the inactive state and that activation results from concentration-driven dimerization on the cargo membrane. To test this model, we have examined the activity and dimerization state of KIF1A. Unexpectedly, we found that both native and expressed proteins are dimeric in the inactive state. Thus, KIF1A motors are not activated by cargo-induced dimerization. Rather, we show that KIF1A motors are autoinhibited by two distinct inhibitory mechanisms, suggesting a simple model for activation of dimeric KIF1A motors by cargo binding. Successive truncations result in monomeric and dimeric motors that can undergo one-dimensional diffusion along the microtubule lattice. However, only dimeric motors undergo ATP-dependent processive motility. Thus, KIF1A may be uniquely suited to use both diffuse and processive motility to drive long-distance transport in neuronal cells.
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PMID:Mammalian Kinesin-3 motors are dimeric in vivo and move by processive motility upon release of autoinhibition. 1933 88

Novel nanoscale microscopic technologies are driving dramatic advances in the knowledge of cytoskeleton structure and dynamics. Cytoskeleton, that is organized into microtubules, actin meshwork and intermediate filaments, besides providing cells with important mechanical properties, allows, within the cell, not only the molecule cargo transport, but also the charged particle/biophoton transmission, so that the cell signaling might be considered as consisting of both molecule/chemically- and charged particle/physically-addressed systems. Molecular motors that drive molecule cargo translocation along the cytoskeletal highway, either through endocytic or secretory-exocytic mechanisms, include kinesin and cytoplasmic dynein, traveling on microtubule, and myosin family members, traveling along actin meshwork. The membrane-bound organelles and protein complexes are sorted with high specificity to their various destinations. In the field of highly structured cell signaling machinery, the endocytosis appears to play an important role with following specific changes in gene expression. In the opposite direction, the exocytosis involves many intracellular steps toward the vesicle fusion with the plasma membrane. Insights into cytoskeletal structure and dynamics are providing important progress in identifying proper targets for cancer therapy. Taxane and Vinca alkaloids, by stabilizing the polymerized microtubules, are able to suppress their dynamic behaviour with subsequent cell death. Epithelones, by acting in same way, are emerging as a new class of anticancer drugs, moreover their toxicity resulting unaffected also towards taxane-resistant cancer cells. Even the alkylating agent nitrogen mustard exerts some cytotoxic effects at the level of the microtubule, whereas azaspiracid-1 induces cytoskeletal actin disorganization without affecting microtubule architecture. Regarding the influences of extracellular mechanical forces on changes in cell adhesion gene expression, the iatrogenic pressure-induced tumor cell implantation within surgical wounds may be prevented by perioperative administration of microtubule/actin inhibitors. Even though, among the different cancer therapy strategies, the chemotherapy could appear to be conceptually outclassed because of its low cancer cell-selectivity in comparison with novel molecular mechanism-based agents. However "combo-strategies", that combine the chemotherapeutic high killing potential with new molecule targeted agents, may be an effective curative measure. Some anticytoskeleton agents are under evaluation for their applications in tumor chemotherapy; benomyl, griseofulvin, sulfonamides, that are used as antimycotic and antimicrobial drugs, appear to have a powerful antitumor potential by targeting microtubule assembly dinamics, together with exhibiting, in comparison with taxane and Vinca alkaloids, a more limited toxicity. An exciting challenge for the next future will be to properly define the cytoskeleton structure and dynamic behaviour to design more effective drugs for cancer chemotherapy.
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PMID:Cytoskeleton structure and dynamic behaviour: quick excursus from basic molecular mechanisms to some implications in cancer chemotherapy. 1936 82


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