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 On the molecular mechanisms of mitotic kinase activation

Open Biology ◽  
2012 ◽  
Vol 2 (11) ◽  
pp. 120136 ◽  
Author(s):  
Richard Bayliss ◽  
Andrew Fry ◽  
Tamanna Haq ◽  
Sharon Yeoh
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Significant Proportion ◽  
Structural Basis ◽  
Kinase Activation ◽  
Mitotic Kinases ◽  
Mitotic Kinase ◽  
Disease Biology ◽  
Activation Mechanisms

During mitosis, human cells exhibit a peak of protein phosphorylation that alters the behaviour of a significant proportion of proteins, driving a dramatic transformation in the cell's shape, intracellular structures and biochemistry. These mitotic phosphorylation events are catalysed by several families of protein kinases, including Auroras, Cdks, Plks, Neks, Bubs, Haspin and Mps1/TTK. The catalytic activities of these kinases are activated by phosphorylation and through protein–protein interactions. In this review, we summarize the current state of knowledge of the structural basis of mitotic kinase activation mechanisms. This review aims to provide a clear and comprehensive primer on these mechanisms to a broad community of researchers, bringing together the common themes, and highlighting specific differences. Along the way, we have uncovered some features of these proteins that have previously gone unreported, and identified unexplored questions for future work. The dysregulation of mitotic kinases is associated with proliferative disorders such as cancer, and structural biology will continue to play a critical role in the development of chemical probes used to interrogate disease biology and applied to the treatment of patients.

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

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 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.

A role for tyrosine kinase activation in interleukin-1β induced nitric oxide production in the insulin producing cell line RINm-5F

1994 ◽  
Vol 14 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Nils Welsh
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Protein Phosphorylation ◽  
Protein Kinases ◽  
Interleukin 1Β ◽  
High Concentration ◽  
Kinase Activation ◽  
Insulin Producing Cells ◽  
Nitrite Production ◽  
Induced Signal

The aim of this investigation was to study the putative role of protein phosphorylation in interleukin-1β (IL-1β) induced signal transduction in insulin producing cells. For this purpose, insulin producing RINm-5F cells were exposed to IL-1β for 7 hours with or without different agonists and antagonists to protein kinases and phosphatases and the production of nitrite was subsequently determined. It has been shown earlier that IL-1β will stimulate the production of nitrite in such cells. It was found that EDTA, TPA and staurosporine did not affect IL-1β induced nitrite production. However, the tyrosine kinase antagonist tyrphostin inhibited, whereas sodium orthovanadate, okadaic acid and cyclosporin A, all inhibitors of protein phosphatases, potentiated IL-1β induced nitrite release to the medium. The tyrosine kinase antagonist genistein potentiated at a low concentration and inhibited at a high concentration the IL-1β effect. It is concluded that protein phosphorylation events, mediated either by protein kinases or phosphatases on both tyrosine and serine/threonine residues, may mediate or antagonize IL-1 induced signal transduction in insulin producing cells.

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 Targeting RB1 Loss in Cancers

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3737
Author(s):  
Paing Linn ◽  
Susumu Kohno ◽  
Jindan Sheng ◽  
Nilakshi Kulathunga ◽  
Hai Yu ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Suppressor Gene ◽  
Therapeutic Approaches ◽  
Neighboring Gene ◽  
Genomic Aberration ◽  
Cycle Progression ◽  
Synthetic Lethal ◽  
Mitotic Kinases ◽  
Promote Cell Cycle Progression ◽  
Almost All

Retinoblastoma protein 1 (RB1) is encoded by a tumor suppressor gene that was discovered more than 30 years ago. Almost all mitogenic signals promote cell cycle progression by braking on the function of RB1 protein through mono- and subsequent hyper-phosphorylation mediated by cyclin-CDK complexes. The loss of RB1 function drives tumorigenesis in limited types of malignancies including retinoblastoma and small cell lung cancer. In a majority of human cancers, RB1 function is suppressed during tumor progression through various mechanisms. The latter gives rise to the acquisition of various phenotypes that confer malignant progression. The RB1-targeted molecules involved in such phenotypic changes are good quarries for cancer therapy. Indeed, a variety of novel therapies have been proposed to target RB1 loss. In particular, the inhibition of a number of mitotic kinases appeared to be synthetic lethal with RB1 deficiency. A recent study focusing on a neighboring gene that is often collaterally deleted together with RB1 revealed a pharmacologically targetable vulnerability in RB1-deficient cancers. Here we summarize current understanding on possible therapeutic approaches targeting functional or genomic aberration of RB1 in cancers.

Characteristics and attitudes of family planners in Khartoum, Sudan

1982 ◽  
Vol 14 (1) ◽  
pp. 7-16 ◽  
Author(s):  
M. A. Khalifa
Keyword(s):  
Family Planning ◽  
Birth Control ◽  
Early Stage ◽  
Significant Proportion ◽  
Large Family ◽  
Capital City ◽  
Age Group ◽  
African Countries ◽  
The Mean ◽  
Almost All

SummaryIn a survey of 1475 urban Moslem wives in the age group 15–49 living in the capital city of the Sudan, knowledge of birth control was reported by almost all respondents while a significant proportion had used contraception at least once. The mean age of the users was 32·8 years, their duration of marriage was 15·1 years and their mean number of surviving children was 4·6. Those who had never used contraception had a higher mean age, a longer duration of marriage and more surviving children. Most of the users had an urban residential background and belonged to the high socioeconomic class. They held favourable attitudes to family planning. Although they thought that having a large family (more than five children) was not desirable, their mean preferred family size was no different from that of the never users.The results indicate that contraception is used for the purpose of spacing births rather than limiting their ultimate number. At this early stage of contraceptive adoption in Sudan, the characteristics of the pioneer acceptors are similar to those observed in other African countries.

scholarly journals Protein phosphatase 6 regulates mitotic spindle formation by controlling the T-loop phosphorylation state of Aurora A bound to its activator TPX2

2010 ◽  
Vol 191 (7) ◽  
pp. 1315-1332 ◽  
Author(s):  
Kang Zeng ◽  
Ricardo Nunes Bastos ◽  
Francis A. Barr ◽  
Ulrike Gruneberg
Keyword(s):  
Protein Phosphatase ◽  
Aurora A ◽  
Spindle Formation ◽  
Regulatory Subunits ◽  
Kinase Activation ◽  
Activator Proteins ◽  
Mitotic Kinase ◽  
General Importance ◽  
The Stability

Many protein kinases are activated by a conserved regulatory step involving T-loop phosphorylation. Although there is considerable focus on kinase activator proteins, the importance of specific T-loop phosphatases reversing kinase activation has been underappreciated. We find that the protein phosphatase 6 (PP6) holoenzyme is the major T-loop phosphatase for Aurora A, an essential mitotic kinase. Loss of PP6 function by depletion of catalytic or regulatory subunits interferes with spindle formation and chromosome alignment because of increased Aurora A activity. Aurora A T-loop phosphorylation and the stability of the Aurora A–TPX2 complex are increased in cells depleted of PP6 but not other phosphatases. Furthermore, purified PP6 acts as a T-loop phosphatase for Aurora A–TPX2 complexes in vitro, whereas catalytically inactive mutants cannot dephosphorylate Aurora A or rescue the PPP6C depletion phenotype. These results demonstrate a hitherto unappreciated role for PP6 as the T-loop phosphatase regulating Aurora A activity during spindle formation and suggest the general importance of this form of regulation.

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