Nuclear Mitotic Apparatus Research Articles

Tankyrase as a Novel Molecular Target in Cancer and Fibrotic Diseases.

Tankyrases belong to a group of enzymes called poly ADP ribosyl polymerases (PARPs). With the advent of a new class of small molecule inhibitors of PARP for clinical use like OLAPARIB; that gained accelerated approval by the USFDA in treating ovarian and breast cancers, the horizons of the PARPs as a novel target in various disease conditions has risen. Tankyrases (PARP 5) are yet another class of PARPs that perform poly ADP ribosylation on different substrate proteins aiding in progression of many diseases like cancer, fibrosis, diabetes and neurological disorders even. Few of the substrates of Tankyrases are Telomeric Repeat binding Factor protein (TRF1), Axis Inhibitory protein (AXIN 1&2), Insulin Responsive Amino Peptidase (IRAP), Nuclear Mitotic Apparatus protein (NuMa), that become aberrantly active due to the apparent overexpression of the enzyme during hyper proliferative disease conditions like cancer, fibrosis and metabolic disorders like diabetes. Tankyrases intervene in many physiological processes like cell growth and survival by affecting the Wnt signaling pathways. On the other hand, these functions are overdone during cancer and fibrosis especially. The development of novel therapies for cancer is a never ending process pertaining to several issues associated with current anticancer drugs like development of drug resistance and toxicity. A fibrotic disease like lung fibrosis is a debilitating condition with limited treatment options and survival rate. Tankyrase inhibition by specific small molecule inhibitors can therefore become a good combinatorial or single treatment strategy in treating hyper proliferative diseases and diabetes. In light of all these concerns, this article aims to brief the role of Tankyrase and the relevance of its inhibition to overcome the hurdles faced by current treatment regimens.

The Dynamic Multisite Interactions between Two Intrinsically Disordered Proteins.

Protein interactions involving intrinsically disordered proteins (IDPs) comprise a variety of binding modes, from the well-characterized folding upon binding to dynamic fuzzy complexes. To date, most studies concern the binding of an IDP to a structured protein, while the interaction between two IDPs is poorly understood. In this study, NMR, smFRET, and molecular dynamics (MD) simulation are combined to characterize the interaction between two IDPs, the C-terminal domain (CTD) of protein 4.1G and the nuclear mitotic apparatus (NuMA) protein. It is revealed that CTD and NuMA form a fuzzy complex with remaining structural disorder. Multiple binding sites on both proteins were identified by molecular dynamics and mutagenesis studies. This study provides an atomic scenario in which two IDPs bearing multiple binding sites interact with each other in dynamic equilibrium. The combined approach employed here could be widely applicable for investigating IDPs and their dynamic interactions.

The Dynamic Multisite Interactions between Two Intrinsically Disordered Proteins

AbstractProtein interactions involving intrinsically disordered proteins (IDPs) comprise a variety of binding modes, from the well‐characterized folding upon binding to dynamic fuzzy complexes. To date, most studies concern the binding of an IDP to a structured protein, while the interaction between two IDPs is poorly understood. In this study, NMR, smFRET, and molecular dynamics (MD) simulation are combined to characterize the interaction between two IDPs, the C‐terminal domain (CTD) of protein 4.1G and the nuclear mitotic apparatus (NuMA) protein. It is revealed that CTD and NuMA form a fuzzy complex with remaining structural disorder. Multiple binding sites on both proteins were identified by molecular dynamics and mutagenesis studies. This study provides an atomic scenario in which two IDPs bearing multiple binding sites interact with each other in dynamic equilibrium. The combined approach employed here could be widely applicable for investigating IDPs and their dynamic interactions.

Novel t(5;11)(q32;q13.4) with NUMA1-PDGFRB fusion in a myeloid neoplasm with eosinophilia with response to imatinib mesylate

We report a NUMA1-PDGFRB fusion in a myeloproliferative neoplasm with eosinophilia in a 61-year old man, with response to imatinib mesylate therapy. A t(5;11) chromosome translocation involving bands 5q32 and 11q13.4 was identified by metaphase chromosome analysis, and rearrangement of the platelet-derived growth factor receptor beta (PDGFRB) gene on 5q32 was demonstrated by FISH using a PDGFRB break-apart probe set. Bacterial artificial chromosome (BAC) FISH mapping of the PDGFRB fusion partner gene narrowed the breakpoint at 11q13.4 to a 150 kb genomic region containing three genes, including NUMA1. Mate pair sequencing analysis demonstrated NUMA1-PDGFRB fusion. The fusion protein includes coiled-coil domains of nuclear mitotic apparatus protein 1 (NuMA1, involved in protein homodimerization and heteroassociation) and tyrosine kinase domains of PDGFRB. Diverse rearrangements involving the PDGFRB gene have been identified in myeloid and lymphoid neoplasms with eosinophilia, but rearrangement of the nuclear mitotic apparatus protein 1 (NUMA1) gene has previously been reported in a human malignancy in only one instance, a NUMA1-RARA fusion caused by a t(11;17) translocation in a patient with acute promyelocytic leukemia. The NUMA1-PDGFRB fusion is the second instance of rearrangement of NUMA1, encoding an element of the mitotic apparatus, in human cancer.

Katanin p80, NuMA and cytoplasmic dynein cooperate to control microtubule dynamics

Human mutations in KATNB1 (p80) cause severe congenital cortical malformations, which encompass the clinical features of both microcephaly and lissencephaly. Although p80 plays critical roles during brain development, the underlying mechanisms remain predominately unknown. Here, we demonstrate that p80 regulates microtubule (MT) remodeling in combination with NuMA (nuclear mitotic apparatus protein) and cytoplasmic dynein. We show that p80 shuttles between the nucleus and spindle pole in synchrony with the cell cycle. Interestingly, this striking feature is shared with NuMA. Importantly, p80 is essential for aster formation and maintenance in vitro. siRNA-mediated depletion of p80 and/or NuMA induced abnormal mitotic phenotypes in cultured mouse embryonic fibroblasts and aberrant neurogenesis and neuronal migration in the mouse embryonic brain. Importantly, these results were confirmed in p80-mutant harboring patient-derived induced pluripotent stem cells and brain organoids. Taken together, our findings provide valuable insights into the pathogenesis of severe microlissencephaly, in which p80 and NuMA delineate a common pathway for neurogenesis and neuronal migration via MT organization at the centrosome/spindle pole.

A chimeric protein composed of NuMA fused to the DNA binding domain of LANA is sufficient for the ori-P-dependent DNA replication

The Kaposi's sarcoma-associated herpesvirus (KSHV) genome is stably maintained in KSHV-infected PEL cell lines during cell division. We previously showed that accumulation of LANA in the nuclear matrix fraction could be important for the latent DNA replication, and that the functional significance of LANA should be its recruitment of ori-P to the nuclear matrix. Here, we investigated whether the forced localization of the LANA-DNA binding domain (DBD) to the nuclear matrix facilitated ori-P-containing plasmid replication. We demonstrated that chimeric proteins constructed by fusion of LANA DBD with the nuclear mitotic apparatus protein (NuMA), which is one of the components of the nuclear matrix, could bind with ori-P and enhance replication of an ori-P-containing plasmid, compared with that in the presence of DBD alone. These results further suggested that the ori-P recruitment to the nuclear matrix through the binding with DBD is important for latent viral DNA replication.

Nuclear Mitotic Apparatus (NuMA) Interacts with and Regulates Astrin at the Mitotic Spindle

The large nuclear mitotic apparatus (NuMA) protein is an essential player in mitotic spindle assembly and maintenance. We report here the identification of Astrin, a spindle- and kinetochore-associated protein, as a novel interactor of NuMA. We show that the C-terminal tail of NuMA can directly bind to the C terminus of Astrin and that this interaction helps to recruit Astrin to microtubules. Knockdown of NuMA by RNA interference dramatically impaired Astrin recruitment to the mitotic spindle. Overexpression of the N terminus of mammalian homologue of Drosophila Pins (LGN), which blocks the microtubule binding of NuMA and competes with Astrin for NuMA binding, also led to similar results. Furthermore, we found that cytoplasmic dynein is required for the spindle pole accumulation of Astrin, and dynein-mediated transport is important for balanced distribution of Astrin between spindle poles and kinetochores. On the other hand, if Astrin levels are reduced, then NuMA could not efficiently concentrate at the spindle poles. Our findings reveal a direct physical link between two important regulators of mitotic progression and demonstrate the critical role of the NuMA-Astrin interaction for accurate cell division.

Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells.

Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington’s disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions.

Xeno-Free and Defined Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells Functionally Integrate in a Large-Eyed Preclinical Model.

SummaryHuman embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells could replace lost tissue in geographic atrophy (GA) but efficacy has yet to be demonstrated in a large-eyed model. Also, production of hESC-RPE has not yet been achieved in a xeno-free and defined manner, which is critical for clinical compliance and reduced immunogenicity. Here we describe an effective differentiation methodology using human laminin-521 matrix with xeno-free and defined medium. Differentiated cells exhibited characteristics of native RPE including morphology, pigmentation, marker expression, monolayer integrity, and polarization together with phagocytic activity. Furthermore, we established a large-eyed GA model that allowed in vivo imaging of hESC-RPE and host retina. Cells transplanted in suspension showed long-term integration and formed polarized monolayers exhibiting phagocytic and photoreceptor rescue capacity. We have developed a xeno-free and defined hESC-RPE differentiation method and present evidence of functional integration of clinically compliant hESC-RPE in a large-eyed disease model.

Abstract 3771: Tank-binding kinase 1 associates with centrosomes and regulates microtubule dynamics and mitosis

Abstract TANK Binding Kinase 1 (TBK1) regulates interferon signaling and NFκB function by acting as a non-canonical IκB kinase. TBK1 also participates in RalB-mediated inflammatory responses and contributes to the survival of non-small cell lung cancers (NSCLC) driven by oncogenic KRAS. In addition, TBK1 could phosphorylate and activate Akt, modulate autophagy and alter the autocrine cytokine network in cancer cells indicating oncogenic roles in addition to its immune regulatory functions. Our studies reveal that TBK1 plays a novel and direct role in promoting mitotic progression of lung cancer cells by phosphorylating multiple substrates during mitosis as well as by modulating microtubule dynamics. Levels of active phospho-TBK1 are elevated in mitotic cells where it localized to centrosomes, mitotic spindles and midbody as seen by confocal microscopy. Inhibition of TBK1 by kinase inhibitors such as BX795, Amlexanox, MRT67037 or depletion of TBK1 by shRNA resulted in mitotic defects and decreased the number of mitotic cells. TBK1 could interact with the centrosomal protein CEP170 and the nuclear mitotic apparatus protein NuMA as seen by GST binding assays, immunoprecipitation-western blot assays and proximity ligation assays. In addition, TBK1 could phosphorylate CEP170 and NuMA in in vitro kinase assays; mass spectrometry analysis revealed that TBK1 phosphorylated 12 serine residues and a threonine residue of CEP170 and five serine residues of NuMA. Inhibition or depletion of TBK1 prevented the centrosomal localization of CEP170 and the association of NuMA with the spindle poles. TBK1 depletion in A549 and H1650 cells resulted in more stable microtubules; further, depletion of TBK1 inhibited the interaction of CEP170 with the microtubule depolymerase Kif2b and the binding of NuMA to Dynein, resulting in mitotic abnormalities or mitotic arrest. In addition, inhibition of specific interaction between TBK1 and CEP170 using a 13 amino acid peptide resulted in inhibition of mitosis, enhanced microtubule stability and mitotic defects. These results are paradigm shifting that suggest TBK1 plays a significant role in regulating microtubule dynamics and mitotic progression of cells and this might have significant relevance to cancer as well as innate immune response. Citation Format: Smitha R. Pillai, Jonathan Nguyen, Joseph Johnson, Eric Haura, Domenico Coppola, Srikumar Chellappan. Tank-binding kinase 1 associates with centrosomes and regulates microtubule dynamics and mitosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3771. doi:10.1158/1538-7445.AM2015-3771

The deubiquitinating enzyme complex BRISC is required for proper mitotic spindle assembly in mammalian cells.

Deubiquitinating enzymes (DUBs) negatively regulate protein ubiquitination and play an important role in diverse physiological processes, including mitotic division. The BRCC36 isopeptidase complex (BRISC) is a DUB that is specific for lysine 63-linked ubiquitin hydrolysis; however, its biological function remains largely undefined. Here, we identify a critical role for BRISC in the control of mitotic spindle assembly in cultured mammalian cells. BRISC is a microtubule (MT)-associated protein complex that predominantly localizes to the minus ends of K-fibers and spindle poles and directly binds to MTs; importantly, BRISC promotes the assembly of functional bipolar spindle by deubiquitinating the essential spindle assembly factor nuclear mitotic apparatus (NuMA). The deubiquitination of NuMA regulates its interaction with dynein and importin-β, which are required for its function in spindle assembly. Collectively, these results uncover BRISC as an important regulator of the mitotic spindle assembly and cell division, and have important implications for the development of anticancer drugs targeting BRISC.

Nuclear mitotic apparatus changes as a sign of cervical neoplasia associated with high-risk human papillomavirus

Nuclear mitotic apparatus changes as a sign of cervical neoplasia associated with high-risk human papillomavirus

Identification and characterization of novel NuMA isoforms

The large nuclear mitotic apparatus (NuMA) has been investigated for over 30years with functions related to the formation and maintenance of mitotic spindle poles during mitosis. However, the existence and functions of NuMA isoforms generated by alternative splicing remains unclear. In the present work, we show that at least seven NuMA isoforms (categorized into long, middle and short groups) generated by alternative splicing from a common NuMA mRNA precursor were discovered in HeLa cells and these isoforms differ mainly at the carboxyl terminus and the coiled-coil domains. Two “hotspot” exons with molecular mass of 3366-nt and 42-nt tend to be spliced during alternative splicing in long and middle groups. Furthermore, full-length coding sequences of long and middle NuMA obtained by using fusion PCR were constructed into GFP-tagged vector to illustrate their cellular localization. Long NuMA mainly localized in the nucleus with absence from nucleoli during interphase and translocated to the spindle poles in mitosis. Middle NuMA displayed the similar cell cycle-dependent distribution pattern as long NuMA. However, expression of NuMA short isoforms revealed a distinct subcellular localization. Short NuMA were present in the cytosol during the whole cycle, without colocalization with mitotic apparatus. These results have allowed us tentatively to explore a new research direction for NuMA’s various functions.

SLK-dependent activation of ERMs controls LGN–NuMA localization and spindle orientation

Mitotic spindle orientation relies on a complex dialog between the spindle microtubules and the cell cortex, in which F-actin has been recently implicated. Here, we report that the membrane-actin linkers ezrin/radixin/moesin (ERMs) are strongly and directly activated by the Ste20-like kinase at mitotic entry in mammalian cells. Using microfabricated adhesive substrates to control the axis of cell division, we found that the activation of ERMs plays a key role in guiding the orientation of the mitotic spindle. Accordingly, impairing ERM activation in apical progenitors of the mouse embryonic neocortex severely disturbed spindle orientation in vivo. At the molecular level, ERM activation promotes the polarized association at the mitotic cortex of leucine-glycine-asparagine repeat protein (LGN) and nuclear mitotic apparatus (NuMA) protein, two essential factors for spindle orientation. We propose that activated ERMs, together with Gαi, are critical for the correct localization of LGN-NuMA force generator complexes and hence for proper spindle orientation.

Interaction between RB protein and NuMA is required for proper alignment of spindle microtubules

Retinoblastoma protein (pRB) controls cell cycle progression and cell cycle exit through interactions with cellular proteins. Many pRB-binding proteins, which function in gene transcription or modulation of chromatin structure, harbor LXCXE motifs in their binding domain for pRB. In this study, we found that nuclear mitotic apparatus protein (NuMA), a mitotic spindle organizer, interacts with pRB through LSCEE sequences located in its C-terminal region. siRNA-mediated down-regulation of pRB caused aberrant distribution of NuMA and alignment of spindle microtubules in mitotic cells. Abnormal organization of spindle microtubules was also accompanied by misalignment of an over-expressed NuMA mutant (mut-NuMA) with a defect in pRB binding caused by an LSGEK mutation. The mut-NuMA-over-expressing cells showed lower potency for survival than wild-type NuMA (wt-NuMA)-over-expressing cells during 2 weeks of culture. Interestingly, knockdown of pRB reduced the population of wt-NuMA-over-expressing cells to the same level as mut-NuMA cells after 2 weeks. Taken together, pRB may have a novel function in regulating the mitotic function of NuMA and spindle organization, which are required for proper cell cycle progression.

Par1b Induces Asymmetric Inheritance of Plasma Membrane Domains via LGN-Dependent Mitotic Spindle Orientation in Proliferating Hepatocytes

Author SummaryThe development and maintenance of the polarized epithelial architecture and function of organs that form tubular “lumen” structures is important for normal physiology and, when deregulated, gives rise to disease. Recent studies have highlighted the importance of a strict coordination of the orientation of mitotic divisions relative to an internal axis of asymmetry in proliferating epithelial cells during this process. Hepatocytes are the predominant epithelial cells of the liver. Hepatocytes display a unique lumen-forming architecture and cellular asymmetry, but the molecular basis for this special polarized architecture is not well understood. Our study now reveals an unexpected mode of plasma membrane domain inheritance that is coupled to a cellular axis of asymmetry in proliferating mammalian hepatocytes. We show that mitotic hepatocytes asymmetrically segregate their apical plasma membrane (the membrane facing the lumen structure) along with the lumen to their daughter cells. We demonstrate that the coordinated action of two proteins, Par1b and LGN, constitutes a fundamental part of the underlying molecular mechanism. This coupling of cell division and polarity in hepatocytes is distinct from that established in other epithelial cell types. These findings are important for understanding the unique polarized tissue architecture in the developing liver.

Cell cycle-dependent SUMO-1 conjugation to nuclear mitotic apparatus protein (NuMA)

Covalent conjugation of proteins with small ubiquitin-like modifier 1 (SUMO-1) plays a critical role in a variety of cellular functions including cell cycle control, replication, and transcriptional regulation. Nuclear mitotic apparatus protein (NuMA) localizes to spindle poles during mitosis, and is an essential component in the formation and maintenance of mitotic spindle poles. Here we show that NuMA is a target for covalent conjugation to SUMO-1. We find that the lysine 1766 residue is the primary NuMA acceptor site for SUMO-1 conjugation. Interestingly, SUMO modification of endogenous NuMA occurs at the entry into mitosis and this modification is reversed after exiting from mitosis. Knockdown of Ubc9 or forced expression of SENP1 results in impairment of the localization of NuMA to mitotic spindle poles during mitosis. The SUMOylation-deficient NuMA mutant is defective in microtubule bundling, and multiple spindles are induced during mitosis. The mitosis-dependent dynamic SUMO-1 modification of NuMA might contribute to NuMA-mediated formation and maintenance of mitotic spindle poles during mitosis.

Perturbation Of Gpsm2/Lgn Enhances Haematopoietic Stem Cell Function

A gain of function screen of candidate cell polarity genes identified the gene, Gpsm2 (G protein signaling modulator 2) also known as LGN or Pins, as an enhancer of haematopoietic stem cell (HSC) function. Mammalian Gpsm2 comprises an N-terminal domain composed of ten Leucine–Glycine–Asparagine (LGN) repeats within seven to eight tetratricopeptide motifs, which functions to bind NuMA (Nuclear Mitotic Apparatus) and a C-terminal domain containing four GoLoco repeats that modulates guanine nucleotide exchange via Gai interaction. In effect, Gpsm2 is an integral component that coordinates G protein signalling to mitotic spindle orientation during cell division. In multiple independent experiments, Gpsm2-transduced HSCs and cultured for 7 days in vitro compared to vector-transduced HSCs showed enhanced HSC repopulation out to 20 weeks-plus post transplant. At these time points, bone marrow and thymic DNA from multiple recipient mice were analysed via Southern blots with a GFP probe. This showed Gpsm2-transduced HSCs retained multipotency but that only one out of a minimum of 12 clones had undergone in vitro symmetrical expansion. Current limiting dilution assay will assess quantitatively this relative absence of HSC expansion. Although in vitro assays with Gpsm2-transduced bone marrow cells showed reduced colony formation and slightly attenuated cell proliferation, limiting dilution assays in secondary transplants showed Gpsm2-transduced HSCs maintained self-renewal ability together with a significant (p=0.009) 4-fold increase in HSC frequency compared to vector-transduced HSCs. This presumably reflects the importance of the interaction between Gpsm2-transduced HSCs within the niche in vivo. A mouse mutant lacking all GoLoco repeats of the C-terminal domain (LGN deltaC) is viable, where analyses of the neuroprogenitors of this mouse revealed altered asymmetrical versus symmetrical cell divisions without a detrimental effect on neuronal production (Konno et al. Nat Cell Biol 2008). A subsequent study of the role of LGN in epidermal development identified that a significant (>80%) knockdown of LGN via shRNA also altered asymmetrical cell divisions of epidermal stem-progenitor cells, however with a functional loss of skin barrier (Williams et al. Nature 2011). This defect could be partially rescued by the LGN N-terminal protein suggesting the LGN deltaC mouse still has functional, albeit, incomplete LGN/Gpsm2 function. We have analysed haematopoiesis in the LGN deltaC mouse. There were no significant differences in wild-type versus homozygous LGN deltaC LSK numbers, in vitro colony formation or in vivo CFU-spleen assays. However, limiting dilution assays showed a 7-fold increase (p=0.02) in HSC frequency in the LGN deltaC mouse, and competitive CD45.2/CD45.1 transplantations analysed at 16 weeks post transplant showed CD45.2 LGN deltaC HSCs reconstituted significantly (p=0.015) better compared to CD45.2 wild-type HSCs. On the premise that the Gpsm2 function of controlling somatic stem cell fate is conserved, we are investigating the hypothesise that the mechanism of perturbation of Gpsm2 enhancement of HSC function is through altered HSC asymmetric and symmetric divisional fate. Disclosures:No relevant conflicts of interest to declare.

NuMA localization, stability, and function in spindle orientation involve 4.1 and Cdk1 interactions

The epidermis is a multilayered epithelium that requires asymmetric divisions for stratification. A conserved cortical protein complex, including LGN, nuclear mitotic apparatus (NuMA), and dynein/dynactin, plays a key role in establishing proper spindle orientation during asymmetric divisions. The requirements for the cortical recruitment of these proteins, however, remain unclear. In this work, we show that NuMA is required to recruit dynactin to the cell cortex of keratinocytes. NuMA's cortical recruitment requires LGN; however, LGN interactions are not sufficient for this localization. Using fluorescence recovery after photobleaching, we find that the 4.1-binding domain of NuMA is important for stabilizing its interaction with the cell cortex. This is functionally important, as loss of 4.1/NuMA interaction results in spindle orientation defects, using two distinct assays. Furthermore, we observe an increase in cortical NuMA localization as cells enter anaphase. Inhibition of Cdk1 or mutation of a single residue in NuMA mimics this effect. NuMA's anaphase localization is independent of LGN and 4.1 interactions, revealing two distinct mechanisms responsible for NuMA cortical recruitment at different stages of mitosis. This work highlights the complexity of NuMA localization and reveals the importance of NuMA cortical stability for productive force generation during spindle orientation.

Nuclear mitotic apparatus protein, NuMA, modulates p53-mediated transcription in cancer cells

Nuclear mitotic apparatus protein, NuMA, modulates p53-mediated transcription in cancer cells