NuMA phosphorylation by CDK1 couples mitotic progression with cortical dynein function

Kotak, Sachin; Busso, Coralie; Gönczy, Pierre

doi:10.1038/emboj.2013.172

Cited by 98 publications

(169 citation statements)

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“…During the metaphase-anaphase transition, CDK1-induced phosphorylation on threonine 2055 (T2055) results in movement of NuMA from the cell membrane to the spindle poles, resulting in chromosome segregation (Kotak et al, 2013). Western analysis indicated the presence of pNuMA in control lenses (Fig.…”

Section: Relocalization Of Numa During Fiber Cell Differentiation Andmentioning

confidence: 99%

“…In proliferating cells, mitosis requires cyclin-dependent kinase 1 (CDK1) in conjunction with cyclins A or B to phosphorylate nuclear membrane lamins to destabilize the nuclear envelope (reviewed by Nigg, 1993). Activated CDK1 also aids in regulating mitotic chromatin (reviewed by Nigg, 1993;Kotak et al, 2013;Orthwein et al, 2014;Zheng et al, 2014). By contrast, post-mitotic cells rarely exhibit CDK1 and cyclin A/B expression (King et al, 1994;Tommasi and Pfeifer, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Nuclear removal during terminal lens fiber cell differentiation requires CDK1 activity: appropriating mitosis-related nuclear disassembly

et al. 2014

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Lens epithelial cells and early lens fiber cells contain the typical complement of intracellular organelles. However, as lens fiber cells mature they must destroy their organelles, including nuclei, in a process that has remained enigmatic for over a century, but which is crucial for the formation of the organelle-free zone in the center of the lens that assures clarity and function to transmit light. Nuclear degradation in lens fiber cells requires the nuclease DNase IIβ (DLAD) but the mechanism by which DLAD gains access to nuclear DNA remains unknown. In eukaryotic cells, cyclin-dependent kinase 1 (CDK1), in combination with either activator cyclins A or B, stimulates mitotic entry, in part, by phosphorylating the nuclear lamin proteins leading to the disassembly of the nuclear lamina and subsequent nuclear envelope breakdown. Although most post-mitotic cells lack CDK1 and cyclins, lens fiber cells maintain these proteins. Here, we show that loss of CDK1 from the lens inhibited the phosphorylation of nuclear lamins A and C, prevented the entry of DLAD into the nucleus, and resulted in abnormal retention of nuclei. In the presence of CDK1, a single focus of the phosphonuclear mitotic apparatus is observed, but it is not focused in CDK1-deficient lenses. CDK1 deficiency inhibited mitosis, but did not prevent DNA replication, resulting in an overall reduction of lens epithelial cells, with the remaining cells possessing an abnormally large nucleus. These observations suggest that CDK1-dependent phosphorylations required for the initiation of nuclear membrane disassembly during mitosis are adapted for removal of nuclei during fiber cell differentiation.

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Section: Relocalization Of Numa During Fiber Cell Differentiation Andmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nuclear removal during terminal lens fiber cell differentiation requires CDK1 activity: appropriating mitosis-related nuclear disassembly

et al. 2014

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“…One study revealed the role of cortical dynein and asymmetric membrane elongation in positioning the anaphase spindle [73], whereas the other one focused on the interplay between CDK1 kinase and PPP2CA phosphatase in dictating levels of cortical dynein during mitosis [74]. …”

Section: Note Added In Proofmentioning

confidence: 99%

Mechanisms of spindle positioning: cortical force generators in the limelight

Kotak

Gönczy

2013

Current Opinion in Cell Biology

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156

138

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Correct positioning of the spindle governs placement of the cytokinesis furrow and thus plays a crucial role in the partitioning of fate determinants and the disposition of daughter cells in a tissue. Converging evidence indicates that spindle positioning is often dictated by interactions between the plus-end of astral microtubules that emanate from the spindle poles and an evolutionary conserved cortical machinery that serves to pull on them. At the heart of this machinery lies a ternary complex (LIN-5/GPR-1/2/Ga in Caenorhabditis elegans and NuMA/LGN/Gai in Homo sapiens) that promotes the presence of the motor protein dynein at the cell cortex. In this review, we discuss how the above components contribute to spindle positioning and how the underlying mechanisms are precisely regulated to ensure the proper execution of this crucial process in metazoan organisms IntroductionThe mitotic spindle is a diamond-shaped microtubulebased structure that faithfully segregates sister chromatids during cell division. Several types of microtubules emanate from the spindle poles, including astral microtubules that reach out to the actin rich cortex located beneath the plasma membrane ( Figure 1a). Pulling forces exerted on the plus-end of astral microtubules at the cell cortex are critical for accurately positioning the spindle with respect to cell-intrinsic or cell-extrinsic spatial cues. In turn, correct spindle positioning dictates placement of the cytokinesis furrow and is thus essential for determining the relative size and spatial disposition of the resulting daughter cells [2]. Accurate spindle positioning also ensures that cell fate determinants are appropriately segregated into daughter cells during development and in stem cell lineages [3].What features of the cell cortex allow interactions with astral microtubules to orchestrate spindle positioning? Specialized cortical sites are key. Their importance has been suggested for instance by elegant experiments in Chaetopterus oocytes, in which the meiotic spindle pulled away from its cortical attachment site using a micro-needle returns to that location once released (Figure 1b). Such experiments illustrate the existence of a mechanical link between the spindle and specialized cortical regions [4,5]. Laser microsurgery experiments in Fusarium solani or C. elegans suggested that this link corresponds to astral microtubules connecting the spindle poles with the cell cortex [6,7,8,9,10 ]. Although not the focus of this review, there are instances where pulling forces are exerted along the length of astral microtubules instead of at their plusend located at the cell cortex [11,12,13]. Work in several systems in recent years has increased our understanding of the basic principles governing spindle positioning and identified core molecular players and aspects of their mechanism of action. In this brief review, we will focus on cortically driven spindle positioning in one-cell C. elegans embryos and mammalian cells in culture. In doing so, we will discuss the nature of the t...

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“…CDK-1 phosphorylation possibly activates PKC-3 or might prime LIN-5 for subsequent phosphorylation by PKC-3. Direct phosphorylation of NuMA by CDK-1 has been implicated in dynein localization in mammalian cells grown in culture (Kiyomitsu and Cheeseman 2013;Kotak et al 2013). NuMA phosphorylation by CDK-1 during metaphase negatively affects cortical Galli et al (2011) dynein levels and is antagonized by the continuously active protein phosphatase PPP2CA.…”

Section: Lin-5 Regulatorsmentioning

confidence: 99%

Polarity Control of Spindle Positioning in the C. elegans Embryo

Fielmich

Heuvel

2015

Cell Polarity 2

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Cell and tissue polarity guides a large variety of developmental processes, including the choice between symmetric and asymmetric cell division. Asymmetric divisions create cell diversity and are needed for the maintenance of tissue-specific stem cells. Symmetric divisions, on the other hand, promote exponential cell proliferation. Polarized cells often divide symmetrically by cleaving along the axis of polarity. Alternatively, cell cleavage in a plane perpendicular to the polarity axis results in asymmetric division. To control this decision, developmental cues position the mitotic spindle, which instructs the plane of cell cleavage. In animal cells, the positioning of the spindle depends on evolutionarily conserved interactions between a heterotrimeric G-protein alpha subunit, TPR-GoLoco domain protein, and NuMA-related coiled-coil protein. This trimeric complex recruits the dynein microtubule motor and captures astral microtubules at the cortex. The interplay between dynein movement and depolymerizing microtubules generates cortical pulling forces that promote aster movement and spindle positioning. Through mechanisms that are poorly understood, cell polarity and other developmental signals control the microtubule-pulling forces to instruct the orientation and plane of cell division. In this chapter, we review the current understanding of the connection between cell polarity and spindle positioning, with a focus on studies of the early C. elegans embryo. The nematode C. elegans develops through a highly reproducible division pattern and has proven to be a powerful model for studying the regulation and execution of asymmetric cell division.

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NuMA phosphorylation by CDK1 couples mitotic progression with cortical dynein function

Cited by 98 publications

References 55 publications

Nuclear removal during terminal lens fiber cell differentiation requires CDK1 activity: appropriating mitosis-related nuclear disassembly

Nuclear removal during terminal lens fiber cell differentiation requires CDK1 activity: appropriating mitosis-related nuclear disassembly

Mechanisms of spindle positioning: cortical force generators in the limelight

Polarity Control of Spindle Positioning in the C. elegans Embryo

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