ReviewMitosis

Aurora-PLK1 cascades as key signaling modules in the regulation of mitosis

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Science Signaling  14 Aug 2018:
Vol. 11, Issue 543, eaar4195
DOI: 10.1126/scisignal.aar4195

Figures

  • Fig. 1 Regulation of mitosis and cytokinesis by the four complexes organized by the core Aurora cofactors.

    The complexes formed by each of the four core Aurora cofactors with Aurora A (AurA) or Aurora B (AurB) are shown in the middle of the figure along with text indicating the subcellular localization of each complex. All core Aurora cofactors, except TPX2, upon their priming phosphorylation, bind PLK1 and organize the respective Aurora kinase and PLK1 into a two-tiered kinase cascade that controls distinct events during mitotic progression, as illustrated by the diagrams of cells. Filled ovals next to each cell indicate which of the cofactors form functional complexes with Aurora at each stage of the cell cycle, and the subcellular localization of AurA (red), AurB (yellow), and PLK1 (blue) during mitotic progression is shown. Inactive AurA is shown in gray; active forms of the kinases are shown in color. Phosphate groups are depicted as solid black dots. Kinase-activating phosphate groups on the T-loop of AurA, AurB, and PLK1 are depicted as black dots with a yellow center.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALINGCREDIT: A. KITTERMAN/SCIENCE SIGNALINGCREDIT: A. KITTERMAN/SCIENCE SIGNALINGCREDIT: A. KITTERMAN/SCIENCE SIGNALINGCREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 2 Mechanism of action of the core AurA cofactors.

    In G2 phase, the pericentrin (PCNT)–mediated recruitment of CEP192 complexes initiates the AurA-PLK1 kinase cascade that culminates in the PLK1 phosphorylation-dependent docking of γ-TuRC and CKAP5 onto CEP192 and drives centrosome maturation and separation. In parallel with this cascade, another AurA-PLK1 cascade organized by Bora begins to operate in G2 phase and activates the bulk of PLK1 in the cytoplasm (middle). Before mitotic entry, active PLK1 promotes SCFβTrCP-mediated proteasomal degradation of Bora, thus making itself and AurA available to other mitotic partner proteins and substrates. Upon mitotic entry and nuclear envelope breakdown (M phase), the RanGTP that is produced by the chromatin-associated GEF RCC1 releases TPX2 from its inhibitory interaction with importin α/β (Imp α/β). TPX2 then binds to and activates AurA in a phosphorylation-independent manner. The TPX2-AurA complex oligomerizes (not shown) and interacts with the RHAMM–γ-TuRC complex to form an MT-nucleating TPX2–AurA–RHAMM–γ-TuRC complex, which, after its phosphorylation by AurA, becomes competent for MT nucleation. These processes underlie the chromatin-driven spindle assembly pathway (1). In addition, TPX2 works together with the Augmin complex and γ-TuRC to enable MT-driven spindle assembly (2). CKAP5 cooperates with γ-TuRC in promoting MT nucleation. Inactive forms of AurA and PLK1 are shown in gray; active forms are shown in color. Phosphate groups are depicted as solid black dots. Kinase-activating phosphate groups on the T-loop of AurA and PLK1 are depicted as black dots with a yellow center. The associated adaptor subunit of the γ-TuRC, NEDD1, is not shown for simplicity.

  • Fig. 3 Regulation of the Aurora-PLK1 cascades at spindle poles and kinetochores.

    (A) AurA-PLK1 signaling is facilitated at spindle poles through multiple PLK1-mediated positive feedback loops. The active PLK1 in CEP192 complexes may (i) phosphorylate PCNT, thereby promoting CEP192 recruitment (double-headed arrow) (87); (ii) phosphorylate CEP215, thereby facilitating expansion of the PCM (as inferred from studies in Drosophila) and the interdependent recruitment of CEP215 and PCNT (double-headed arrow) (88, 151, 152); (iii) abrogate the CEP192-PP1 interaction by phosphorylating the PP1-docking motif of CEP192 (115); and (iv) cooperate with cytoplasmic PLK1 in phosphorylating and inactivating PP6 (112), which may enable activation loop autophosphorylation of the MT-bound AurA in TPX2 complexes (109). (B) The CPC, comprising AurB, INCENP, Borealin, and Survivin, organizes a network of proteins that drives the formation and function of the outer kinetochore. Only a portion of the functional protein interactions occurring at the centromere and kinetochore are shown, without depicting the distinction between these two structures or the kinetochore-MT attachment status. The recruitment of CPCs to centromeres and kinetochores promotes CPC oligomerization and trans-autophosphorylation of AurB, which then phosphorylates multiple substrates, including PLK1. It was proposed that, after the initial CDK1-dependent CPC recruitment and AurB activation at the inner kinetochore, AurB promotes the recruitment of the kinase BUB1, which phosphorylates H2A histone at Thr120 to generate a binding site for SGO1 or SGO2 (SGO1/2) [(158); reviewed in (141)]. SGO1/2 recruits the CPC in a manner that depends on Borealin dimerization and phosphorylation by CDK1 (427429). In a positive feedback loop, active AurB, PLK1, and CDK1 phosphorylate and activate Haspin, thereby triggering the main mechanism of CPC recruitment to centromeres (154158, 430432). This mechanism is counteracted by the PP1 regulatory subunit Repo-Man, which is recruited to chromatin and dephosphorylates histone H3 at Thr3 (256258). See text for further details. Red arrows, phosphorylation events; black arrows, activating effects; black lines ending with a T-bar, inhibitory effects; dashed lines, protein-protein interactions. Phosphate groups are depicted as solid black dots. Kinase-activating phosphate groups on the T-loop of AurA, AurB, and PLK1 are depicted as black dots with a yellow center.

  • Fig. 4 The Aurora-PLK1 cascades organized by CEP192 and INCENP operate at the opposite ends of spindle MTs.

    (A) The CEP192 complex at centrosomes and the chromosomal passenger complex (CPC) at centromeres and kinetochores promote Aurora and PLK1 phosphorylation-dependent formation of the mitotic outer PCM layer and the outer kinetochore, respectively. (B) By serving as a γ-TuRC anchor, CEP192 localizes exclusively to the minus ends of spindle MTs. INCENP, as a scaffold protein for the CPC, functions in prometaphase and metaphase at the interface between chromatin and spindle MTs. In anaphase, the CPC relocates from chromosomes to MTs of the central spindle and to the actomyosin ring, where it promotes the formation of the central spindle and cleavage furrow and the ingression of the cleavage furrow during cytokinesis. Only a few nonbranched MTs of the anaphase asters are shown for simplicity. Note that, in both metaphase and anaphase, CEP192 complexes and CPCs localize to the spindle poles and the cell equator, respectively.

  • Fig. 5 Examples of the AurB-PLK1 activity switches at kinetochores.

    (A) In the CPC at kinetochores, AurB may perform the activating T-loop phosphorylation of PLK1 that is docked onto the phosphorylated PBD-binding motif of either INCENP or a neighboring protein (X), leading to signal amplification and to the formation of a mixed AurB and PLK1 activity field (green). (B) The balance of the local kinase activities can be shifted toward AurB (blue) through the inactivation of PLK1 or its removal from INCENP or X by either a protein phosphatase (PPase) that dephosphorylates PLK1 and its docking proteins or by CUL3, which promotes degradation-independent PLK1 dissociation from kinetochores. (C) The balance of the local kinase activities can be shifted toward PLK1 (yellow) through PPase-mediated inactivation of AurB (1), stripping of the CPC from kinetochores (2), or degradation of INCENP (3). Red arrows, protein phosphorylation; black arrows, protein dephosphorylation, inactivation, or stripping; gray arrows, protein dislocation. Inactive forms of AurB are shown in gray; active forms of AurB and PLK1 are shown in color. For simplicity, the CPC components Borealin and Survivin are omitted, and the CPC is not shown in its oligomerized state. Note that in the mitotic cytoplasm, PLK1 is active because it is phosphorylated at Thr210 in the T-loop by the Bora-AurA complex. Phosphate groups are depicted as solid black dots. Kinase-activating phosphate groups on the T-loop of AurB and PLK1 are depicted as black dots with a yellow center.

  • Fig. 6 The PLK1 module of the G2-M checkpoint.

    The PLK1 activity sensor (blue shading) of the mitotic entry network may have been co-opted by the G2-M DNA damage checkpoint. Red arrows, protein phosphorylation events; black arrows, activating effects; black lines ending with a T-bar, inhibitory effects. Phosphate groups are depicted as solid black dots. Activating phosphorylation of PLK1 at Thr210 in the T-loop is shown as a black dot with a yellow center. In positive feedback loops, the cyclin B (Cyc B)–CDK1 complex cooperates with PLK1 to inactivate WEE1 and MYT1 and activate CDC25C (not shown).

Tables

  • Table 1 Properties of the major Aurora complexes.
    Scaffold
    protein
    Other
    core
    subunits
    Catalytic
    subunit
    Aurora kinase
    activation
    mechanism
    Downstream
    kinase
    Localization
    to mitotic
    structures
    Spindle
    assembly
    pathway and
    mechanism
    Function of the
    complex
    References
    BoraAurASubstrate preference
    for PLK1
    PLK1CytoplasmPLK1 activation in
    the cytoplasm
    before and during
    mitosis, mitotic
    entry control
    (41, 42, 71, 132, 137)
    CEP192AurAOligomerization-
    dependent T-loop
    autophosphorylation
    PLK1*CentrosomesCentrosome-
    driven; MT
    nucleation and
    anchoring
    Centrosome
    maturation and
    separation,
    generation of
    astral and spindle
    MTs
    (39, 47, 48, 75, 76)
    TPX2AurABinding-mediated
    allostery
    Spindle MTsChromatin-driven
    and MT-driven;
    MT nucleation
    and bundling
    Generation and
    amplification of
    spindle MTs
    (3, 53, 54, 5760, 65,
    426)
    INCENPSurvivin,
    Borealin
    AurB or
    AurC
    Oligomerization-
    dependent T-loop
    autophosphorylation
    PLK1*Chromosome
    arms,
    centromeres,
    kinetochores,
    central
    spindle,
    midbody
    Kinetochore-
    driven; MT
    stabilization and
    bundling
    Chromosome
    dynamics and
    cohesion,
    kinetochore-MT
    attachments,
    spindle assembly
    checkpoint,
    cytokinesis
    (25, 40, 4446, 145,
    160, 193)

    *CEP192 and INCENP recruit most of the cognate Aurora kinase associated with the indicated mitotic structures. In contrast, PLK1 is recruited to the corresponding mitotic structures not only by CEP192 and INCENP but also by other proteins.

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