Lis1 and Ndel1 influence the timing of nuclear envelope breakdown in neural stem cells

Hebbar, Sachin; Mesngon, Mariano; Guillotte, Aimee M.; Desai, Bhavim; Ayala, Ramsés; Smith, Deanna S.

doi:10.1083/jcb.200803071

Cited by 86 publications

(119 citation statements)

References 31 publications

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“…It has been reported that p150 Glued colocalized with Lis1 at the NE in nocodazoletreated cells (12). Here, we further show that p150 Glued accumulated at the NE in prophase cells under normal growth conditions (Fig.…”

Section: Accumulation Of P150 Glued At the Ne In Prophase Is Positivelysupporting

confidence: 84%

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Polo-like kinase 1 phosphorylation of p150 ^Glued facilitates nuclear envelope breakdown during prophase

Liu

Yang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear envelope breakdown (NEBD) is an essential step during the G2/M transition in higher eukaryotic cells. Increasing evidence supports the notion that both microtubules and microtubuleassociated motor proteins are critical regulators of NEBD. Although it has been described that p150 Glued , the major component of the dynein/dynactin complex, localizes in the nuclear envelope during prophase, the exact role of p150 Glued and its regulation during NEBD are largely elusive. Polo-like kinase 1 (Plk1), the best characterized Ser/Thr kinase, is involved in mitotic entry in several systems; however, the targets of Plk1 during NEBD are unknown. Herein, we show that in mammalian cells both Plk1 and p150 Glued regulate NEBD and that Plk1 interacts with and phosphoryates p150 Glued during NEBD at prophase. Using various approaches, we showed that Plk1 phosphorylates p150 Glued at Ser-179 and that the pS179 epitope is generated at the nuclear envelope of prophase cells. Significantly, Plk1-mediated phosphorylation of p150 Glued at Ser-179 positively regulates its accumulation at the nuclear envelope during prophase. Finally, we found that cells expressing the Plk1-unphosphorylatable mutant (p150 Glued -S179A) arrest at G2, as indicated by reduced NEBD, increased levels of cyclin B and phospho-H3, but a decreased level of Cdc2 kinase activity. Taking these data together, we conclude that Plk1 phosphorylation of p150 Glued might be one major pathway of NEBD regulation. mitosis | microtubule dynamics | dynactin

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Section: Accumulation Of P150 Glued At the Ne In Prophase Is Positivelysupporting

confidence: 84%

“…Immunostaining was performed as previously described (12). Briefly, HeLa and U2OS cells were plated onto 12-mm glass coverslips in sixwell plates.…”

Section: Methodsmentioning

confidence: 99%

Polo-like kinase 1 phosphorylation of p150 ^Glued facilitates nuclear envelope breakdown during prophase

Liu

Yang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Emerging evidence suggests that LIS1 and NDEL1 contribute to many dynein-related activities in neurons; reduced expression of LIS1 and NDEL1 in neural precursor cells increased average centrosome-nucleus spacing, and LIS1 interference caused inhibition of centrosomal migration (15) and somal translocation (16). Reduction of LIS1 and NDEL1 in a mitotic cell line impaired prophase nuclear envelope invagination (17). However, although many observations suggest that LIS1 and NDEL1 regulate dynein at the cellular level, the underlying mechanism remains elusive.…”

mentioning

confidence: 99%

Functional Dissection of LIS1 and NDEL1 Towards Understanding the Molecular Mechanisms of Cytoplasmic Dynein Regulation

Torisawa

Nakayama

Furuta

et al. 2011

Journal of Biological Chemistry

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LIS1 and NDEL1 are known to be essential for the activity of cytoplasmic dynein in living cells. We previously reported that LIS1 and NDEL1 directly regulated the motility of cytoplasmic dynein in an in vitro motility assay. LIS1 suppressed dynein motility and inhibited the translocation of microtubules (MTs), while NDEL1 dissociated dynein from MTs and restored dynein motility following suppression by LIS1. However, the molecular mechanisms and detailed interactions of dynein, LIS1, and NDEL1 remain unknown. In this study, we dissected the regulatory effects of LIS1 and NDEL1 on dynein motility using full-length or truncated recombinant fragments of LIS1 or NDEL1. The C-terminal fragment of NDEL1 dissociated dynein from MTs, whereas its N-terminal fragment restored dynein motility following suppression by LIS1, demonstrating that the two functions of NDEL1 localize to different parts of the NDEL1 molecule, and that restoration from LIS1 suppression is caused by the binding of NDEL1 to LIS1, rather than to dynein. The truncated monomeric form of LIS1 had little effect on dynein motility, but an artificial dimer of truncated LIS1 suppressed dynein motility, which was restored by the N-terminal fragment of NDEL1. This suggests that LIS1 dimerization is essential for its regulatory function. These results shed light on the molecular interactions between dynein, LIS1, and NDEL1, and the mechanisms of cytoplasmic dynein regulation.Cytoplasmic dynein is a multi-subunit protein complex that moves along microtubules. It is involved in various cellular and subcellular activities, such as cell migration, vesicle transport, and organelle positioning (1, 2). Dynein interacts with several accessory proteins to accomplish this wide range of activities throughout the cell cycle (3). The best-characterized of these accessory proteins is dynactin, a multiprotein complex that is almost universally associated with dynein-dependent functions (4). Platelet-activating factor acetylhydrolase, isoform 1b, subunit 1 (PAFAH1B1; commonly known as lissencephaly 1, LIS1) 3 and its binding partner nuclear distribution gene E homolog (A. nidulans)-like 1 (NDEL1) also contribute to many dynein functions involving nuclear and spindle positioning and centrosomal movement (3).LIS1 was first identified as a protein associated with the smooth brain disease, lissencephaly (5, 6). Homozygous loss of Lis1 or Ndel1 is lethal in mice (7, 8). The C terminus of LIS1 binds to cytoplasmic dynein (9), whereas the N terminus contains a LisH homodimerization domain (10). Between these domains is a coiled-coil region that imparts flexibility to the LIS1 dimer (11), suggesting that LIS1 can alter its conformation between an "open state," in which the coiled-coil regions form a random helix, and a "closed state," in which the coiled-coil regions form a superhelix (12). NDEL1 contains an N-terminal coiled-coil domain that interacts with LIS1, and an unstructured C terminus that directly binds to dynein (13,14). LIS1 and NDEL1 are thought to associate with cytoplas...

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“…NDEL1 is differentially phosphorylated by CDK1 (Yan et al, 2003) and CDK5 (Niethammer et al, 2000). Interestingly, NDEL1 double phosphorylation by CDK1 and CDK5 reduced the amount of NDEL1 and LIS1 that coimmunoprecipitated with dynein, suggesting that phosphorylation not only strengthens NDEL1 binding to LIS1 but promotes the release of LIS1-pNDEL1 complexes from dynein (Hebbar et al, 2008). In contrast, phosphorylation by either kinase alone was insufficient to reduce dynein binding.…”

Section: Novel Role Of Mitotic Kinase In Neuronal Migrationmentioning

confidence: 98%

Activation of Aurora-A Is Essential for Neuronal Migration via Modulation of Microtubule Organization

et al. 2012

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Neuronal migration is a critical feature to ensure proper location and wiring of neurons during cortical development. Postmitotic neurons migrate from the ventricular zone into the cortical plate to establish neuronal lamina in an “inside-out” gradient of maturation. Here, we report that the mitotic kinase Aurora-A is critical for the regulation of microtubule organization during neuronal migration via an Aurora-A–NDEL1 pathway in the mouse. Suppression of Aurora-A activity by inhibitors or siRNA resulted in severe impairment of neuronal migration of granular neurons. In addition,in uteroinjection of the Aurora-A kinase-dead mutant provoked defective migration of cortical neurons. Furthermore, we demonstrated that suppression of Aurora-A impaired microtubule modulation in migrating neurons. Interestingly, suppression of CDK5 by an inhibitor or siRNA reduced Aurora-A activity and NDEL1 phosphorylation by Aurora-A, which led to defective neuronal migration. We found that CDK5RAP2 is a key molecule that mediates functional interaction and is essential for centrosomal targeting of Aurora-A. Our observations demonstrated novel and surprising cross talk between Aurora-A and CDK5 during neuronal migration.

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Lis1 and Ndel1 influence the timing of nuclear envelope breakdown in neural stem cells

Cited by 86 publications

References 31 publications

Polo-like kinase 1 phosphorylation of p150 ^Glued facilitates nuclear envelope breakdown during prophase

Polo-like kinase 1 phosphorylation of p150 ^Glued facilitates nuclear envelope breakdown during prophase

Functional Dissection of LIS1 and NDEL1 Towards Understanding the Molecular Mechanisms of Cytoplasmic Dynein Regulation

Activation of Aurora-A Is Essential for Neuronal Migration via Modulation of Microtubule Organization

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Lis1 and Ndel1 influence the timing of nuclear envelope breakdown in neural stem cells

Cited by 86 publications

References 31 publications

Polo-like kinase 1 phosphorylation of p150 Glued facilitates nuclear envelope breakdown during prophase

Polo-like kinase 1 phosphorylation of p150 Glued facilitates nuclear envelope breakdown during prophase

Functional Dissection of LIS1 and NDEL1 Towards Understanding the Molecular Mechanisms of Cytoplasmic Dynein Regulation

Activation of Aurora-A Is Essential for Neuronal Migration via Modulation of Microtubule Organization

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Polo-like kinase 1 phosphorylation of p150 ^Glued facilitates nuclear envelope breakdown during prophase

Polo-like kinase 1 phosphorylation of p150 ^Glued facilitates nuclear envelope breakdown during prophase