How protein kinases co-ordinate mitosis in animal cells

2011 ◽  
Vol 435 (1) ◽  
pp. 17-31 ◽  
Author(s):  
Hoi Tang Ma ◽  
Randy Y. C. Poon
Keyword(s):  
Protein Kinases ◽  
Feedback Loops ◽  
Cell Physiology ◽  
Animal Cells ◽  
Aurora Kinases ◽  
Cyclin Dependent Kinases ◽  
Mitotic Kinases ◽  
Mitotic Kinase ◽  
Recurrent Theme

Mitosis is associated with profound changes in cell physiology and a spectacular surge in protein phosphorylation. To accomplish these, a remarkably large portion of the kinome is involved in the process. In the present review, we will focus on classic mitotic kinases, such as cyclin-dependent kinases, Polo-like kinases and Aurora kinases, as well as more recently characterized players such as NIMA (never in mitosis in Aspergillus nidulans)-related kinases, Greatwall and Haspin. Together, these kinases co-ordinate the proper timing and fidelity of processes including centrosomal functions, spindle assembly and microtubule–kinetochore attachment, as well as sister chromatid separation and cytokinesis. A recurrent theme of the mitotic kinase network is the prevalence of elaborated feedback loops that ensure bistable conditions. Sequential phosphorylation and priming phosphorylation on substrates are also frequently employed. Another important concept is the role of scaffolds, such as centrosomes for protein kinases during mitosis. Elucidating the entire repertoire of mitotic kinases, their functions, regulation and interactions is critical for our understanding of normal cell growth and in diseases such as cancers.

scholarly journals FAM83D directs protein kinase CK1α to the mitotic spindle for proper spindle positioning

2018 ◽  
Author(s):  
Luke J. Fulcher ◽  
Zhengcheng He ◽  
Lin Mei ◽  
Thomas J. Macartney ◽  
Nicola T. Wood ◽  
...  
Keyword(s):  
Cell Division ◽  
Protein Kinases ◽  
Mitotic Spindle ◽  
Mammalian Cells ◽  
Casein Kinase 1 ◽  
Spindle Positioning ◽  
Cyclin Dependent Kinases ◽  
Mitotic Kinases ◽  
Mitotic Kinase ◽  
Endogenous Locus

SummaryThe concerted action of many protein kinases helps orchestrate the error-free progression through mitosis of mammalian cells. The roles and regulation of some prominent mitotic kinases, such as cyclin-dependent kinases, are well-established. However, these and other known mitotic kinases alone cannot account for the extent of protein phosphorylation that has been reported during mammalian mitosis. Here we demonstrate that CK1α, of the casein kinase 1 family of protein kinases, localises to the spindle and is required for proper spindle-positioning and timely cell division. CK1α is recruited to the spindle by FAM83D, and cells devoid of FAM83D, or those harbouring CK1α-binding-deficient FAM83DF283A/F283A knockin mutation, display pronounced spindle-positioning defects, and a prolonged mitosis. Restoring FAM83D at the endogenous locus in FAM83D-/- cells, or artificially delivering CK1α to the spindle in FAM83DF283A/F283A cells, rescues these defects. These findings implicate CK1α as new mitotic kinase that orchestrates the kinetics and orientation of cell division.

scholarly journals The oscillation of mitotic kinase governs cell cycle latches

2021 ◽  
Author(s):  
Bela Novak ◽  
John J Tyson
Keyword(s):  
Cell Cycle ◽  
Negative Feedback ◽  
Molecular Switches ◽  
Feedback Loops ◽  
Yeast Cells ◽  
Cyclin Dependent Kinases ◽  
Mitotic Kinase ◽  
Daughter Cells ◽  
Negative Feedback Loops ◽  
A Cell

SummaryIn order to transmit a eukaryotic cell’s genome accurately from mother cell to daughter cells, it is essential that the basic events of the cell division cycle (DNA synthesis and mitosis) occur once and only once per cycle, i.e., that a cell progresses irreversibly from G1 to S to G2 to M and back to G1. Irreversible progression through the cell cycle is assured by a sequence of ‘latching’ molecular switches, based on molecular interactions among cyclin-dependent kinases and their auxiliary partners. Positive feedback loops (++ or −−) create bistable switches with latching properties, and negative feedback loops drive progression from one stage to the next. In budding yeast (Saccharomyces cerevisiae) these events are coordinated by double-negative feedback loops between Clb-dependent kinases (Clb1-6) and their antagonists (APC:Cdh1 and Sic1). If the coordinating signal is compromised, either by deletion of Clb1-5 proteins or expression of non-degradable Clb2, then irreversibility is lost and yeast cells exhibit multiple rounds of DNA replication or mitotic exit events (Cdc14 endocycles). Using mathematical modelling of a stripped-down control network, we show how endocycles arise because the switches fail to latch, and the gates swing back and forth by the action of the negative feedback loops.

scholarly journals Cyclin A2 localises in the cytoplasm at the S/G2 transition to activate PLK1

2017 ◽  
Author(s):  
Helena Silva Cascales ◽  
Kamila Burdova ◽  
Anna Middleton ◽  
Vladislav Kuzin ◽  
Erik Müllers ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Feedback Loops ◽  
List Type ◽  
Kinase Activation ◽  
Mitotic Kinases ◽  
Mitotic Kinase ◽  
Transition Functions ◽  
G2 Phase ◽  
Cyclin A2

AbstractCyclin A2 is a key regulator of the cell cycle, implicated both in DNA replication and mitotic entry. Cyclin A2 participates in feedback loops that activate mitotic kinases in G2-phase, but why active Cyclin A2-CDK2 during S phase does not trigger mitotic kinase activation remains unclear. Here we describe a change in localisation of Cyclin A2 from being only nuclear to both nuclear and cytoplasmic at the S/G2 border. We find that Cyclin A2-CDK2 can activate the mitotic kinase PLK1 through phosphorylation of Bora, and that only cytoplasmic Cyclin A2 interacts with Bora and PLK1. Expression of predominately cytoplasmic Cyclin A2 or phospho-mimicking PLK1 T210D can partially rescue a G2 arrest caused by Cyclin A2 depletion. Cytoplasmic presence of Cyclin A2 is restricted by p21, in particular after DNA damage. Cyclin A2 chromatin association during DNA replication and additional mechanisms contribute to Cyclin A2 localisation change in G2 phase. We find no evidence that such mechanisms involve G2 feedback loops and suggest that cytoplasmic appearance of Cyclin A2 at the S/G2 transition functions as a trigger for mitotic kinase activation.SynopsisMain mitotic kinases as PLK1 are activated at the S/G2 transition. A change in Cyclin A2 localisation at the S/G2 transition enables activation of PLK1.Main points-Cyclin A2 appears in the cytoplasm at the S/G2 transition-Association with replicating chromatin and p21 restricts Cyclin A2 to the nucleus-DNA damage ensures nuclear Cyclin A2 through p21-Cytoplasmic Cyclin A2 initiates PLK1 activationGraphical abstract

The structural mechanisms that underpin mitotic kinase activation

2013 ◽  
Vol 41 (4) ◽  
pp. 1037-1041 ◽  
Author(s):  
Charlotte A. Dodson ◽  
Tamanna Haq ◽  
Sharon Yeoh ◽  
Andrew M. Fry ◽  
Richard Bayliss
Keyword(s):  
Protein Phosphorylation ◽  
Protein Kinases ◽  
Rational Design ◽  
Significant Proportion ◽  
Small Subset ◽  
Kinase Activation ◽  
Mitotic Kinases ◽  
Mitotic Kinase ◽  
Almost All ◽  
Structural Mechanisms

In eukaryotic cells, the peak of protein phosphorylation occurs during mitosis, switching the activities of a significant proportion of proteins and orchestrating a wholesale reorganization of cell shape and internal architecture. Most mitotic protein phosphorylation events are catalysed by a small subset of serine/threonine protein kinases. These include members of the Cdk (cyclin-dependent kinase), Plk (Polo-like kinase), Aurora, Nek (NimA-related kinase) and Bub families, as well as Haspin, Greatwall and Mps1/TTK. There has been steady progress in resolving the structural mechanisms that regulate the catalytic activities of these mitotic kinases. From structural and biochemical perspectives, kinase activation appears not as a binary process (from inactive to active), but as a series of states that exhibit varying degrees of activity. In its lowest activity state, a mitotic kinase may exhibit diverse autoinhibited or inactive conformations. Kinase activation proceeds via phosphorylation and/or association with a binding partner. These remodel the structure into an active conformation that is common to almost all protein kinases. However, all mitotic kinases of known structure have divergent features, many of which are key to understanding their specific regulatory mechanisms. Finally, mitotic kinases are an important class of drug target, and their structural characterization has facilitated the rational design of chemical inhibitors.

scholarly journals Cyclin A2 localises in the cytoplasm at the S/G2 transition to activate PLK1

2021 ◽  
Vol 4 (3) ◽  
pp. e202000980
Author(s):  
Helena Silva Cascales ◽  
Kamila Burdova ◽  
Anna Middleton ◽  
Vladislav Kuzin ◽  
Erik Müllers ◽  
...  
Keyword(s):  
Dna Replication ◽  
Feedback Loops ◽  
Kinase Activation ◽  
Mitotic Entry ◽  
Mitotic Kinases ◽  
Mitotic Kinase ◽  
Transition Functions ◽  
G2 Phase ◽  
Cyclin A2 ◽  
Plk1 Expression

Cyclin A2 is a key regulator of the cell cycle, implicated both in DNA replication and mitotic entry. Cyclin A2 participates in feedback loops that activate mitotic kinases in G2 phase, but why active Cyclin A2-CDK2 during the S phase does not trigger mitotic kinase activation remains unclear. Here, we describe a change in localisation of Cyclin A2 from being only nuclear to both nuclear and cytoplasmic at the S/G2 border. We find that Cyclin A2-CDK2 can activate the mitotic kinase PLK1 through phosphorylation of Bora, and that only cytoplasmic Cyclin A2 interacts with Bora and PLK1. Expression of predominately cytoplasmic Cyclin A2 or phospho-mimicking PLK1 T210D can partially rescue a G2 arrest caused by Cyclin A2 depletion. Cytoplasmic presence of Cyclin A2 is restricted by p21, in particular after DNA damage. Cyclin A2 chromatin association during DNA replication and additional mechanisms contribute to Cyclin A2 localisation change in the G2 phase. We find no evidence that such mechanisms involve G2 feedback loops and suggest that cytoplasmic appearance of Cyclin A2 at the S/G2 transition functions as a trigger for mitotic kinase activation.

scholarly journals CDC6 regulates mitotic CDK1 via cyclin B and not cyclin A and acts through a bona fide CDK inhibitor Xic1

2020 ◽  
Author(s):  
Mohammed El Dika ◽  
Lisa Wechselberger ◽  
Bilal Djeghout ◽  
Djamel Eddine Benouareth ◽  
Krystyna Jęderka ◽  
...  
Keyword(s):  
Critical Role ◽  
Cyclin A ◽  
Cyclin B ◽  
Cyclin Dependent Kinases ◽  
Mitotic Kinase ◽  
M Phase ◽  
Bona Fide ◽  
Phase Progression ◽  
Dependent Mechanism

AbstractThe timing of the M-phase entry and its progression are precisely controlled by a CDC6-dependent mechanism that inhibits the major mitotic kinase CDK1, and, thus, regulates the dynamic of CDK1 during the M-phase. In this paper, we describe the differential regulation of the mitotic CDK1 dynamics by exogenous cyclin A or a non-degradable cyclin B added to the Xenopus laevis embryo cycling extracts. We showed that the variations in the level of cyclin B modify both CDK1 activity and the timing of the M-phase progression, while the cyclin A levels modify only CDK1 activity without changing the timing of the M-phase events. In consequence, CDC6 regulates the M-phase through endogenous cyclin B, but not cyclin A, which we demonstrated directly by the depletion of cyclin A, and the addition of CDC6 to the cycling extracts. Further, we showed, by p9 precipitation (p9 protein associates with Cyclin-Dependent Kinases, CDK), followed by the Western blotting that CDC6, and the bona fide CDK1 inhibitor Xic1, associate with CDK1 and/or another CDK present in Xenopus embryos, the CDK2. Finally, we demonstrated that the Xic1 temoprarily separates from the mitotic CDK complexes during the peak of CDK1 activity. These data show the differential coordination of the M-phase progression by CDK1/cyclin A and CDK1/cyclin B, confirm the critical role of the CDC6-dependent CDK1 inhibition in this process and show that CDC6 acts through the cyclin B- and not cyclin A/CDK complexes. This CDC6- and cyclin B-dependent mechanism may also depend on the precisely regulated association of Xic1 with the CDK complexes. We postulate that the dissociation of Xic1 from the CDK complexes allows the maximal activation of CDK1 during the M-phase.

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

Biological Role of CDK 11 and 12 in Cell Cycle and its Function in Tumorigenesis

2020 ◽  
Author(s):  
Shamim Mushtaq
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Web Of Science ◽  
The Body ◽  
Main Role ◽  
Hallmarks Of Cancer ◽  
Cyclin Dependent Kinases ◽  
Tumor Studies ◽  
Cycle Regulation

Uninhibited proliferation and abnormal cell cycle regulation are the hallmarks of cancer. The main role of cyclin dependent kinases is to regulate the cell cycle and cell proliferation. These protein kinases are frequently down regulated or up regulated in various cancers. Two CDK family members, CDK 11 and 12, have contradicting views about their roles in different cancers. For example, one study suggests that the CDK 11 isoforms, p58, inhibits growth of breast cancer whereas, the CDK 11 isoform, p110, is highly expressed in breast tumor. Studies regarding CDK 12 show variation of opinion towards different parts of the body, however there is a consensus that upregulation of cdk12 increases the risk of breast cancer. Hence, CDK 11 and CDK 12 need to be analyzed to confirm their mechanism and their role regarding therapeutics, prognostic value, and ethnicity in cancer. This article gives an outline on both CDKs of information known up to date from Medline, PubMed, Google Scholar and Web of Science search engines, which were explored and thirty relevant researches were finalized.

Aurora Kinase Inhibitors in Head and Neck Cancer

2018 ◽  
Vol 18 (3) ◽  
pp. 199-213
Author(s):  
Guangying Qi ◽  
Jing Liu ◽  
Sisi Mi ◽  
Takaaki Tsunematsu ◽  
Shengjian Jin ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Cancer Therapy ◽  
Kinase Inhibitors ◽  
Biological Function ◽  
Aurora Kinase ◽  
Aurora Kinases ◽  
Related Research ◽  
Chemotherapy Drugs ◽  
Aurora Kinase Inhibitors

Aurora kinases are a group of serine/threonine kinases responsible for the regulation of mitosis. In recent years, with the increase in Aurora kinase-related research, the important role of Aurora kinases in tumorigenesis has been gradually recognized. Aurora kinases have been regarded as a new target for cancer therapy, resulting in the development of Aurora kinase inhibitors. The study and application of these small-molecule inhibitors, especially in combination with chemotherapy drugs, represent a new direction in cancer treatment. This paper reviews studies on Aurora kinases from recent years, including studies of their biological function, their relationship with tumor progression, and their inhibitors.

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