The dynein cortical anchor Num1 activates dynein motility by relieving Pac1/LIS1-mediated inhibition

Lammers, Lindsay G.; Markus, Steven M.

doi:10.1083/jcb.201506119

Cited by 69 publications

(108 citation statements)

References 51 publications

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“…This scenario suggests a potentially simple competition‐based explanation for why overexpression of the BicD2‐N fragment in human cells abolished plus‐end tracking of dynein (Splinter et al , 2012). A similar mechanism for down‐regulating dynein end tracking by adapter proteins appears to exist in budding yeast where the expression of the cortical adaptor Num1 also removed dynein from microtubule plus ends (Lammers & Markus, 2015). …”

Section: Discussionmentioning

confidence: 90%

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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Section: Discussionmentioning

confidence: 90%

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

et al. 2017

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“…This is an intriguing possibility as mitochondria and dynein both interact with the CC domain of Num1 [10–12]. In addition, Num1 is proposed to directly activate dynein [18,19,28]. Thus, the mitochondria-dependent arrangement of Num1 within a cluster may also impact the ability of Num1 to activate dynein.…”

Section: Discussionmentioning

confidence: 99%

“…Cluster formation has been proposed to enhance the interaction between Num1 and its membrane and protein binding partners and, consequently, the ability of Num1 to robustly tether mitochondria and dynein to the cell cortex [10,11]. In addition, Num1 is proposed to directly activate dynein [18,19]. Thus, increasing the effective concentration of Num1 via cluster formation may also enhance dynein activation at sites of anchoring.…”

Section: Introductionmentioning

confidence: 99%

The role of mitochondria in anchoring dynein to the cell cortex extends beyond clustering the anchor protein

et al. 2018

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Organelle distribution is regulated over the course of the cell cycle to ensure that each of the cells produced at the completion of division inherits a full complement of organelles. In yeast, the protein Num1 functions in the positioning and inheritance of two essential organelles, mitochondria and the nucleus. Specifically, Num1 anchors mitochondria as well as dynein to the cell cortex, and this anchoring activity is required for proper mitochondrial distribution and dynein-mediated nuclear inheritance. The assembly of Num1 into clusters at the plasma membrane is critical for both of its anchoring functions. We have previously shown that mitochondria drive the assembly of Num1 clusters and that these mitochondria-assembled Num1 clusters serve as cortical attachment sites for dynein. Here we further examine the role for mitochondria in dynein anchoring. Using a GFP-αGFP nanobody targeting system, we synthetically clustered Num1 on eisosomes to bypass the requirement for mitochondria in Num1 cluster formation. Utilizing this system, we found that mitochondria positively impact the ability of synthetically clustered Num1 to anchor dynein and support dynein function even when mitochondria are no longer required for cluster formation. Thus, the role of mitochondria in regulating dynein function extends beyond simply concentrating Num1; mitochondria likely promote an arrangement of Num1 within a cluster that is competent for dynein anchoring. This functional dependency between mitochondrial and nuclear positioning pathways likely serves as a mechanism to order and integrate major cellular organization systems over the course of the cell cycle.

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“…As in S. cerevisiae, dynein localizes at the growing end of cMTs (Grava et al, 2011) and Num1 patches form at the cortex (Schmitz and Landmann, unpublished data). Therefore dynein can be captured at the cortex by Num1, which initiates pulling on the cMT, thereby moving the nucleus, essentially as described for pulling of the anaphase spindle in S. cerevisiae by the dynein off-loading model (Lee et al, 2003(Lee et al, , 2005Sheeman et al, 2003;Lammers and Markus, 2015). The cMT continues to grow during the pulling (Grava and Philippsen, 2010) until it eventually starts depolymerizing if its plus end undergoes a catastrophe.…”

Section: Introductionmentioning

confidence: 99%

“…Dynein is transported as an inactive complex with Pac1 (Lis1 homologue) at the plus ends of cMTs (not shown), searching the bud cortex and later also the mother cell cortex . When the immobile cortical Num1 captures dynein (light green dot), Pac1 is released, and the activated dynein, still bound to the cMT, starts pulling the anaphase spindle through the bud neck (Lammers and Markus, 2015). The pulled cMT glides along the bud cortex.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Nuclear Movements in a Multinucleated Cell

Gibeaux

Politi

Philippsen

et al. 2016

Preprint

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Multinucleated cells are important in many organisms, but the mechanisms governing the movements of nuclei sharing a common cytoplasm are not understood. In the hyphae of the plant pathogenic fungus Ashbya gossypii, nuclei move back and forth, occasionally bypassing each other, preventing the formation of nuclear clusters. This is essential for genetic stability. These movements depend on cytoplasmic microtubules emanating from the nuclei that are pulled by dynein motors anchored at the cortex. Using three-dimensional stochastic simulations with parameters constrained by the literature, we predict the cortical anchor density from the characteristics of nuclear movements. The model accounts for the complex nuclear movements seen in vivo, using a minimal set of experimentally determined ingredients. Of interest, these ingredients power the oscillations of the anaphase spindle in budding yeast, but in A. gossypii, this system is not restricted to a specific nuclear cycle stage, possibly as a result of adaptation to hyphal growth and multinuclearity. INTRODUCTIONPositioning of the nucleus and mitotic spindle appropriately within the cell is critical in eukaryotes during many processes, ranging from simple growth to tissue development (Morris, 2002;Dupin and Etienne-Manneville, 2011;Gundersen and Worman, 2013;Kiyomitsu, 2015). Accordingly, cells have evolved various strategies to place their nucleus or spindle in suitable locations. In most systems, this process is driven by dynein pulling on nuclei-associated cytoplasmic microtubules (cMTs). Dynein is a minus end-directed motor that can act primarily in two ways. End-on pulling occurs when cortex-anchored dynein captures a growing cMT plus end, thereby initiating its shrinkage while maintaining the attachment. Lateral or side-on pulling occurs when cortex-anchored dynein walks on cMTs toward the minus end using its motor activity. This mode of action is independent of cMT shrinkage and may result in cMT sliding parallel to the cortex (Kotak and Gönczy, 2013;McNally, 2013;Akhmanova and van den Heuvel, 2016).A detailed mechanistic view for directing nuclei during the cell cycle is known in the budding yeast Saccharomyces cerevisiae, as outlined in Figure 1 and references therein. In contrast to most eukaryotic cells, the site of the cleavage plane in S. cerevisiae is selected early in the cell cycle by generating a ring structure (future bud neck) at the mother cell cortex at which the daughter cell (bud) will emerge. In addition, in budding yeast the nuclear envelope does not disassemble during mitosis, and nuclei are always attached to the minus end of cMTs via spindle pole bodies (SPBs) embedded in the nuclear envelope. The two pathways elucidated in S. cerevisiae involve cortical pulling, but only the second pathway relies on dynein. During the Kar9-Bim1-Myo2 pathway, the nucleus is directed toward the bud neck by transporting cMT plus ends first along bud neck-emerging actin cables, followed by depolymerization of the transported cMT. In metaphase, cMTs ...

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The dynein cortical anchor Num1 activates dynein motility by relieving Pac1/LIS1-mediated inhibition

Abstract: Upon offloading to Num1 cortical receptor sites in budding yeast, cytoplasmic dynein motility is switched “on” by a mechanism that likely involves Num1-mediated dissociation of the Pac1 inhibitor, a homologue of human LIS1.

Cited by 69 publications

References 51 publications

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

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

The role of mitochondria in anchoring dynein to the cell cortex extends beyond clustering the anchor protein

Mechanism of Nuclear Movements in a Multinucleated Cell

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