How protein kinases co-ordinate mitosis in animal cells

Tang, Hoi; Poon, Randy Y. C.

doi:10.1042/bj20100284

Cited by 108 publications

(83 citation statements)

References 205 publications

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“…Now, our data identify a role in mitotic progression and chromosome segregation. The distribution of GR through metaphase and anaphase overlaps with the spindle centrosome, which plays a major role in coordinating accurate chromosome segregation (28)(29)(30)(31)(32). Moreover, under conditions not permissive for GR transcriptional effects, there was a clear biological role, implying a nontranscriptional mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

Matthews

Berry

Morgan

et al. 2015

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

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The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily, which controls programs regulating cell proliferation, differentiation, and apoptosis. We have identified an unexpected role for GR in mitosis. We discovered that specifically modified GR species accumulate at the mitotic spindle during mitosis in a distribution that overlaps with Aurora kinases. We found that Aurora A was required to mediate mitosis-driven GR phosphorylation, but not recruitment of GR to the spindle. GR was necessary for mitotic progression, with increased time to complete mitosis, frequency of mitotic aberrations, and death in mitosis observed following GR knockdown. Complementation studies revealed an essential role for the GR ligand-binding domain, but no clear requirement for ligand binding in regulating chromosome segregation. The GR N-terminal domain, and specifically phosphosites S203 and S211, were not required. Reduced GR expression results in a cell cycle phenotype, with isolated cells from mouse and human subjects showing changes in chromosome content over prolonged passage. Furthermore, GR haploinsufficient mice have an increased incidence of tumor formation, and, strikingly, these tumors are further depleted for GR, implying additional GR loss as a consequence of cell transformation. We identified reduced GR expression in a panel of human liver, lung, prostate, colon, and breast cancers. We therefore reveal an unexpected role for the GR in promoting accurate chromosome segregation during mitosis, which is causally linked to tumorigenesis, making GR an authentic tumor suppressor gene.glucocorticoid receptor | mitosis | aneuploidy | DNA damage | cancer G lucocorticoids (Gcs) act through the glucocorticoid receptor (GR), a member of the nuclear hormone receptor superfamily, and a ligand-activated transcription factor (1-4). The GR is ubiquitously expressed and regulates energy metabolism, immunity, and cell fate decisions. The quiescent GR resides in the cytoplasm in a complex with heat shock proteins and immunophilins, attached to the microtubule architecture of the cell in a heat shock protein 90-dependent manner (5). Ligand binding drives GR transformation, involving N-terminal phosphorylation on S203 and S211 and rapid translocation to the nucleus requiring attachment to dynein by heat shock protein 90, immunophilins, and dynamitin (6). Once in the nucleus, GR binds directly to DNA to regulate transcription, or tethers to other DNA-bound transcription factors, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP1), to regulate their function (7-10).In mitosis, GR is phosphorylated on both S203 and S211, but in a ligand-independent manner (11), and more comprehensive phosphoproteomic analyses identify the presence of multiple N-terminal GR phosphoforms in purified mitotic spindle fractions (12). Although altered GR function in mitosis has been shown (11, 13, 14), the kinases responsible and cellular consequences have not been defined. The role of G...

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Section: Discussionmentioning

confidence: 99%

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

Matthews

Berry

Morgan

et al. 2015

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

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“…While Hrb1/Gbp2 remain bound to transcripts during translation, localization studies show that Hrb1 is predominantly nuclear at steady state and that its re-import into the nucleus is mediated by the Mtr10 karyopherin import receptor (Hacker and Krebber 2004). Both Hrb1 and Gbp2 are phosphorylated by the cytoplasmic SR-specific protein kinase Sky1 (Porat et al 2006;Ma and Poon 2011). This phosphorylation increases the affinity of Hrb1 for the mRNP.…”

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confidence: 99%

“…SR proteins are a class of small nuclear ribonucleoprotein splicing factors that harbor two distinct types of domains: RNA recognition motifs (RRMs), responsible for RNA binding, and SR domains, long repeats of serine-arginine or arginine/serine dipeptides that are extensively phosphorylated (Ma and Poon 2011). Some RRM proteins contain RGG/RG tripeptide motifs that serve as sites for arginine methylation (Thandapani et al 2013).…”

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confidence: 99%

Restraint of the G2/M Transition by the SR/RRM Family mRNA Shuttling Binding Protein SNXAHRB1 in Aspergillus nidulans

et al. 2014

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Control of the eukaryotic G2/M transition by CDC2/CYCLINB is tightly regulated by protein-protein interactions, protein phosphorylations, and nuclear localization of CDC2/CYCLINB. We previously reported a screen, in Aspergillus nidulans, for extragenic suppressors of nimX2 cdc2 that resulted in the identification of the cold-sensitive snxA1 mutation. We demonstrate here that snxA1 suppresses defects in regulators of the CDK1 mitotic induction pathway, including nimX2 cdc2 , nimE6 cyclinB , and nimT23 cdc25 , but does not suppress G2-arresting nimA1/nimA5 mutations, the S-arresting nimE10 cyclinB mutation, or three other G1/S phase mutations. snxA encodes the A. nidulans homolog of Saccharomyces cerevisiae Hrb1/Gbp2; nonessential shuttling messenger RNA (mRNA)-binding proteins belonging to the serine-arginine-rich (SR) and RNA recognition motif (RRM) protein family; and human heterogeneous ribonucleoprotein-M, a spliceosomal component involved in pre-mRNA processing and alternative splicing. snxA Hrb1 is nonessential, its deletion phenocopies the snxA1 mutation, and its overexpression rescues snxA1 and DsnxA mutant phenotypes. snxA1 and a second allele isolated in this study, snxA2, are hypomorphic mutations that result from decreased transcript and protein levels, suggesting that snxA acts normally to restrain cell cycle progression. SNXA HRB1 is predominantly nuclear, but is not retained in the nucleus during the partially closed mitosis of A. nidulans. We show that the snxA1 mutation does not suppress nimX2 by altering NIMX2 CDC2 /NIME CYCLINB kinase activity and that snxA1 or DsnxA alter localization patterns of NIME CYCLINB at the restrictive temperatures for snxA1 and nimX2. Together, these findings suggest a novel and previously unreported role of an SR/RRM family protein in cell cycle regulation, specifically in control of the CDK1 mitotic induction pathway. CONTROL of the eukaryotic G2/M transition by protein kinases has been widely studied and is highly conserved among all eukaryotes from the budding and fission yeasts and filamentous fungi to metazoans (for review, see Ma and Poon 2011). The CDK1/CYCLINB protein kinase complex is a major regulator of this transition in all eukaryotes and is responsible for the phosphorylations of numerous proteins, leading to massive nuclear and cytoplasmic reorganizations that regulate mitosis (for review, see Lindqvist et al. 2009). The complex itself is tightly regulated, both temporally and spatially, to allow mitotic entry.Although CDK1/CYCLINB activity is essential for mitotic entry in all eukaryotes, structural differences in the nucleus in various organisms result in "open" mitosis (more complex eukaryotes) or "closed" mitosis (budding yeasts); these differences likely affect the temporo-spatial functioning of CDK1/ CYCLINB. The partially closed mitosis of the filamentous fungus Aspergillus nidulans is an evolutionary intermediate between open and closed mitoses and provides a system for studying mitotic entry in organisms intermediate between budding ...

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“…39 Globally, a large number of phosphorylation events are up-regulated upon mitotic entry. 40 Several large scale proteomics analyses have identified >40 phosphorylation sites on human IQGAP1.…”

Section: Introductionmentioning

confidence: 99%

IQGAP1 is associated with nuclear envelope reformation and completion of abscission

et al. 2015

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The final stage of mitosis is cytokinesis, which results in 2 independent daughter cells. Cytokinesis has 2 phases: membrane ingression followed by membrane abscission. IQGAP1 is a scaffold protein that interacts with proteins implicated in mitosis, including F-actin, myosin and CaM. IQGAP1 in yeast recruits actin and myosin II filaments to the contractile ring for membrane ingression. In contrast, we show that mammalian IQGAP1 is not required for ingression, but coordinates nuclear pore complex (NPC) reassembly and completion of abscission. Depletion of IQGAP1 disrupts Nup98 and mAb414 nuclear envelope localization and delays abscission timing. IQGAP1 phosphorylation increases 15-fold upon mitotic entry at S86, S330 and T1434, with the latter site being targeted by CDK2/Cyclin A and CDK1/Cyclin A/ B in vitro. Expressing the phospho-deficient mutant IQGAP1-S330A impairs NPC reassembly in cells undergoing abscission. Thus, mammalian IQGAP1 functions later in mitosis than its yeast counterpart to regulate nuclear pore assembly in a S330 phosphorylation-dependent manner during the abscission phase of cytokinesis.

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How protein kinases co-ordinate mitosis in animal cells

Cited by 108 publications

References 205 publications

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

Restraint of the G2/M Transition by the SR/RRM Family mRNA Shuttling Binding Protein SNXAHRB1 in Aspergillus nidulans

IQGAP1 is associated with nuclear envelope reformation and completion of abscission

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