Mechanism and Regulation of Cytoplasmic Dynein

Cianfrocco, Michael A.; DeSantis, Morgan E.; Leschziner, Andres E.; Reck-Peterson, Samara L.

doi:10.1146/annurev-cellbio-100814-125438

Cited by 225 publications

(247 citation statements)

References 193 publications

(326 reference statements)

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“…This transport is accomplished through activation of motor proteins. Generally speaking, kinesin motor proteins transport cargo toward the plus ends of MTs, whereas cytoplasmic dynein moves cargo toward the minus ends of MTs (Verhey et al , 2011; Cianfrocco et al , 2015). …”

Section: Dynamic Microtubules In Neuronal Dendritesmentioning

confidence: 99%

Of microtubules and memory: implications for microtubule dynamics in dendrites and spines

Dent

2017

MBoC

118

104

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Microtubules (MTs) are cytoskeletal polymers composed of repeating subunits of tubulin that are ubiquitously expressed in eukaryotic cells. They undergo a stochastic process of polymerization and depolymerization from their plus ends termed dynamic instability. MT dynamics is an ongoing process in all cell types and has been the target for the development of several useful anticancer drugs, which compromise rapidly dividing cells. Recent studies also suggest that MT dynamics may be particularly important in neurons, which develop a highly polarized morphology, consisting of a single axon and multiple dendrites that persist throughout adulthood. MTs are especially dynamic in dendrites and have recently been shown to polymerize directly into dendritic spines, the postsynaptic compartment of excitatory neurons in the CNS. These transient polymerization events into dendritic spines have been demonstrated to play important roles in synaptic plasticity in cultured neurons. Recent studies also suggest that MT dynamics in the adult brain function in the essential process of learning and memory and may be compromised in degenerative diseases, such as Alzheimer’s disease. This raises the possibility of targeting MT dynamics in the design of new therapeutic agents.

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Section: Dynamic Microtubules In Neuronal Dendritesmentioning

confidence: 99%

Of microtubules and memory: implications for microtubule dynamics in dendrites and spines

Dent

2017

MBoC

118

104

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“…Dynein is a 1.4 MDa protein complex consisting of two copies of six different subunits that assemble into a tail domain from which two motor domains protrude (Vallee et al , 1988; Vale, 2003; Pfister et al , 2006). The motile properties of metazoan dynein depend strongly on its interaction with a variety of regulatory proteins whose mechanisms of action and their combinatorial interplay are poorly understood (Vallee et al , 2012; Cianfrocco et al , 2015). …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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Cytoplasmic dynein is involved in a multitude of essential cellular functions. Dynein's activity is controlled by the combinatorial action of several regulatory proteins. The molecular mechanism of this regulation is still 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 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 Lissencephaly‐1 (Lis1). BicD2 and Lis1 together control the overall efficiency of motility initiation. Remarkably, dynactin can bias motility initiation locally from microtubule plus ends by autonomous plus‐end recognition. This bias is further enhanced by EBs and Lis1. Our study provides insight into the mechanism of dynein regulation by dissecting the distinct functional contributions of the individual members of a dynein regulatory network.

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“…Alternative models of MTOC translocation posit either a dynein- or actin-dependent mechanism for driving MTOC movements. Dynein is a minus end-directed microtubule motor protein that if anchored at the IS could reel in microtubules and pull the MTOC up to the IS (16). Variants of the Dynein-based models either propose that dynein causes microtubules to loop through the IS and continue to slide rearward (11, 17, 18) or that microtubule plus ends depolymerized as they move towards the IS (19), perhaps similar to the model for chromosome-to-pole movements.…”

Section: Introductionmentioning

confidence: 99%

Dynein Separately Partners with NDE1 and Dynactin To Orchestrate T Cell Focused Secretion

Nath

Christian

Tan

et al. 2016

The Journal of Immunology

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Helper and cytotoxic T cells accomplish focused secretion through the clustering of vesicles around the MTOC and translocation of the MTOC to the target contact site. Here, using Jurkat cells and OT-I T cell receptor (TcR) transgenic primary murine CTLs, we show that the dynein-binding proteins NDE1 and dynactin (as represented by p150Glued) form mutually exclusive complexes with dynein, exhibit non-overlapping distributions in target-stimulated cells, and mediate different transport events. When Jurkat cells expressing a dominant negative form of NDE1 (NDE1-EGFP fusion) were activated by SEE-coated Raji cells, NDE1 and dynein failed to accumulate at the immunological synapse (IS) and MTOC translocation was inhibited. Knockdown of NDE1 in Jurkat cells or primary mouse CTLs also inhibited MTOC translocation and CTL-mediated killing. In contrast to NDE1, knockdown of p150Glued, which depleted the alternative dynein-dynactin complex, resulted in impaired accumulation of CTLA-4 and granzyme-B containing intracellular vesicles at the IS, while MTOC translocation was not affected. Depletion of p150Glued in CTLs also inhibited CTL-mediated lysis. We conclude that the NDE1/Lis1 and dynactin complexes separately mediate two key components of T cell focused secretion, namely translocation of the MTOC and lytic granules to the IS, respectively.

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Mechanism and Regulation of Cytoplasmic Dynein

Cited by 225 publications

References 193 publications

Of microtubules and memory: implications for microtubule dynamics in dendrites and spines

Of microtubules and memory: implications for microtubule dynamics in dendrites and spines

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

Dynein Separately Partners with NDE1 and Dynactin To Orchestrate T Cell Focused Secretion

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