scholarly journals A cyclin-dependent kinase, CDK11/p58, represses cap-dependent translation during mitosis

2020 ◽  
Vol 77 (22) ◽  
pp. 4693-4708 ◽  
Author(s):  
Sihyeon An ◽  
Oh Sung Kwon ◽  
Jinbae Yu ◽  
Sung Key Jang
Keyword(s):  
Translational Regulation ◽  
Ectopic Expression ◽  
Translational Repression ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
C Elegans ◽  
Target Sites ◽  
M Phase ◽  
A Subunit ◽  
Cycle Dependent

Abstract During mitosis, translation of most mRNAs is strongly repressed; none of the several explanatory hypotheses suggested can fully explain the molecular basis of this phenomenon. Here we report that cyclin-dependent CDK11/p58—a serine/threonine kinase abundantly expressed during M phase—represses overall translation by phosphorylating a subunit (eIF3F) of the translation factor eIF3 complex that is essential for translation initiation of most mRNAs. Ectopic expression of CDK11/p58 strongly repressed cap-dependent translation, and knockdown of CDK11/p58 nullified the translational repression during M phase. We identified the phosphorylation sites in eIF3F responsible for M phase-specific translational repression by CDK11/p58. Alanine substitutions of CDK11/p58 target sites in eIF3F nullified its effects on cell cycle-dependent translational regulation. The mechanism of translational regulation by the M phase-specific kinase, CDK11/p58, has deep evolutionary roots considering the conservation of CDK11 and its target sites on eIF3F from C. elegans to humans.

scholarly journals Neuronal Cell Shape and Neurite Initiation Are Regulated by the Ndr Kinase SAX-1, a Member of the Orb6/COT-1/Warts Serine/Threonine Kinase Family

2000 ◽  
Vol 11 (9) ◽  
pp. 3177-3190 ◽  
Author(s):  
Jennifer A. Zallen ◽  
Erin L. Peckol ◽  
David M. Tobin ◽  
Cornelia I. Bargmann
Keyword(s):  
Cell Shape ◽  
Neuronal Cell ◽  
Neurite Growth ◽  
Dominant Negative ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
C Elegans ◽  
Calcium Calmodulin Dependent ◽  
Binding Domains ◽  
Neurite Initiation

The Caenorhabditis elegans sax-1 gene regulates several aspects of neuronal cell shape. sax-1 mutants have expanded cell bodies and ectopic neurites in many classes of neurons, suggesting that SAX-1 functions to restrict cell and neurite growth. The ectopic neurites in sensory neurons of sax-1mutants resemble the defects caused by decreased sensory activity. However, the activity-dependent pathway, mediated in part by the UNC-43 calcium/calmodulin-dependent kinase II, functions in parallel with SAX-1 to suppress neurite initiation. sax-1 encodes a serine/threonine kinase in the Ndr family that is related to the Orb6 (Schizosaccharomyces pombe), Warts/Lats (Drosophila), and COT-1 (Neurospora) kinases that function in cell shape regulation. These kinases have similarity to Rho kinases but lack consensus Rho-binding domains. Dominant negative mutations in the C. elegans RhoA GTPase cause neuronal cell shape defects similar to those ofsax-1 mutants, and genetic interactions betweenrhoA and sax-1 suggest shared functions. These results suggest that SAX-1/Ndr kinases are endogenous inhibitors of neurite initiation and cell spreading.

scholarly journals Phylogenetic Analyses of Proteins Coordinating G2 Size Control in Fission Yeast

2019 ◽  
Author(s):  
Zsófia Nagy ◽  
Anna Medgyes-Horváth ◽  
Csilla Szalay ◽  
Matthias Sipiczki ◽  
Ákos Sveiczer
Keyword(s):  
Fission Yeast ◽  
Common Ancestor ◽  
Phylogenetic Analyses ◽  
Consensus Sequence ◽  
Size Control ◽  
Model Organisms ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
M Phase ◽  
Wee1 Kinase

Regulation of G2 phase is based on inhibition of MPF (M-phase Promoting Factor) through phosphorylation by Wee1-like kinases. Removal of the inhibiting phosphate group requires Cdc25-like phosphatases. In fission yeast, size control is achieved by monitoring cell length via interactions of Pom1, Nif1, Cdr1 and Cdr2 proteins, regulating MPF via the Wee1 kinase. Here, a search for homologues of these key proteins was performed in the genomes of several model organisms to analyze the evolution of G2 size control. Both the known upstream pathways regulating Wee1 protein (Pom1 → Cdr2, and Nif1 → Cdr1) have been found to be characteristic only in fission yeasts. Mik1, a backup copy of Wee1 kinase probably appeared in the common ancestor of the fission yeasts. The duplication resulting in Wee1A and Wee1B isoforms probably happened in a common ancestor of higher animals, while the Myt1 protein (found only in animals) could be a variant between an ancient serine / threonine kinase and the Wee1 tyrosine kinase. Probably both the ancestors of plants and that of fungi may have lost the myt1 gene. In fission yeasts, Pyp3 is a backup phosphatase of Cdc25, also activating MPF in late G2. Interestingly, we found that the small Ibp1 phosphatase appeared to be a closer homologue of Cdc25, although its function is different. Moreover, Cdc25 homologues identified in plants were found to be more closely related to Ibp1 rather than to Cdc25 of fission yeast. In the Cdc25-like proteins, a novel conserved region was found with the consensus sequence LxxG(Y/F).

The C. elegans par-4 gene encodes a putative serine-threonine kinase required for establishing embryonic asymmetry

Development ◽  
2000 ◽  
Vol 127 (7) ◽  
pp. 1467-1475 ◽  
Author(s):  
J.L. Watts ◽  
D.G. Morton ◽  
J. Bestman ◽  
K.J. Kemphues
Keyword(s):  
Cell Cycle ◽  
Kinase Domain ◽  
Missense Mutations ◽  
Serine Threonine Kinase ◽  
Cell Stage ◽  
Threonine Kinase ◽  
C Elegans ◽  
Human Kinase ◽  
Early Embryos ◽  
Peutz Jeghers Syndrome

During the first cell cycle of Caenorhabditis elegans embryogenesis, asymmetries are established that are essential for determining the subsequent developmental fates of the daughter cells. The maternally expressed par genes are required for establishing this polarity. The products of several of the par genes have been found to be themselves asymmetrically distributed in the first cell cycle. We have identified the par-4 gene of C. elegans, and find that it encodes a putative serine-threonine kinase with similarity to a human kinase associated with Peutz-Jeghers Syndrome, LKB1 (STK11), and a Xenopus egg and embryo kinase, XEEK1. Several strong par-4 mutant alleles are missense mutations that alter conserved residues within the kinase domain, suggesting that kinase activity is essential for PAR-4 function. We find that the PAR-4 protein is present in the gonads, oocytes and early embryos of C. elegans, and is both cytoplasmically and cortically distributed. The cortical distribution begins at the late 1-cell stage, is more pronounced at the 2- and 4-cell stages and is reduced at late stages of embryonic development. We find no asymmetry in the distribution of PAR-4 protein in C. elegans embryos. The distribution of PAR-4 protein in early embryos is unaffected by mutations in the other par genes.

scholarly journals Molecular Basis of the Mechanisms Controlling MASTL

2019 ◽  
Vol 19 (2) ◽  
pp. 326-343 ◽  
Author(s):  
Dario Hermida ◽  
Gulnahar B. Mortuza ◽  
Anna-Kathrine Pedersen ◽  
Irina Pozdnyakova ◽  
Tam T. T. N. Nguyen ◽  
...  
Keyword(s):  
Kinase Domain ◽  
Order Structure ◽  
Middle Region ◽  
Activation Model ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
M Phase ◽  
Key Factor ◽  
Hydrogen Deuterium ◽  
Exchange Data

The human MASTL (Microtubule-associated serine/threonine kinase-like) gene encodes an essential protein in the cell cycle. MASTL is a key factor preventing early dephosphorylation of M-phase targets of Cdk1/CycB. Little is known about the mechanism of MASTL activation and regulation. MASTL contains a non-conserved insertion of 550 residues within its activation loop, splitting the kinase domain, and making it unique. Here, we show that this non-conserved middle region (NCMR) of the protein is crucial for target specificity and activity. We performed a phosphoproteomic assay with different MASTL constructs identifying key phosphorylation sites for its activation and determining whether they arise from autophosphorylation or exogenous kinases, thus generating an activation model. Hydrogen/deuterium exchange data complements this analysis revealing that the C-lobe in full-length MASTL forms a stable structure, whereas the N-lobe is dynamic and the NCMR and C-tail contain few localized regions with higher-order structure. Our results indicate that truncated versions of MASTL conserving a cryptic C-Lobe in the NCMR, display catalytic activity and different targets, thus establishing a possible link with truncated mutations observed in cancer-related databases.

scholarly journals Akt Inhibits Apoptosis Downstream of BID Cleavage via a Glucose-Dependent Mechanism Involving Mitochondrial Hexokinases

2004 ◽  
Vol 24 (2) ◽  
pp. 730-740 ◽  
Author(s):  
Nathan Majewski ◽  
Veronique Nogueira ◽  
R. Brooks Robey ◽  
Nissim Hay
Keyword(s):  
Ectopic Expression ◽  
Glucose Deprivation ◽  
Hexokinase Ii ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Amino Terminal ◽  
Growth Factor Deprivation ◽  
Catalytically Active ◽  
Induced Apoptosis ◽  
Dependent Mechanism

ABSTRACT The serine/threonine kinase Akt/protein kinase B inhibits apoptosis induced by a variety of stimuli, including overexpression or activation of proapoptotic Bcl-2 family members. The precise mechanisms by which Akt prevents apoptosis are not completely understood, but Akt may function to maintain mitochondrial integrity, thereby preventing cytochrome c release following an apoptotic insult. This effect may be mediated, in part, via promotion of physical and functional interactions between mitochondria and hexokinases. Here we show that growth factor deprivation induced proteolytic cleavage of the proapoptotic Bcl-2 family member BID to yield its active truncated form, tBID. Activated Akt inhibited mitochondrial cytochrome c release and apoptosis following BID cleavage. Akt also antagonized tBID-mediated BAX activation and mitochondrial BAK oligomerization, two downstream events thought to be critical for tBID-induced apoptosis. Glucose deprivation, which impaired the ability of Akt to maintain mitochondrion-hexokinase association, prevented Akt from inhibiting BID-mediated apoptosis. Interestingly, tBID independently elicited dissociation of hexokinases from mitochondria, an effect that was antagonized by activated Akt. Ectopic expression of the amino-terminal half of hexokinase II, which is catalytically active and contains the mitochondrion-binding domain, consistently antagonized tBID-induced apoptosis. These results suggest that Akt inhibits BID-mediated apoptosis downstream of BID cleavage via promotion of mitochondrial hexokinase association and antagonism of tBID-mediated BAX and BAK activation at the mitochondria.

scholarly journals Proteomic Investigation Uncovers Potential Targets and Target Sites of Pneumococcal Serine-Threonine Kinase StkP and Phosphatase PhpP

2020 ◽  
Vol 10 ◽  
Author(s):  
Claudia Hirschfeld ◽  
Alejandro Gómez-Mejia ◽  
Jürgen Bartel ◽  
Christian Hentschker ◽  
Manfred Rohde ◽  
...  
Keyword(s):  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Target Sites ◽  
Proteomic Investigation

scholarly journals Downregulation of an Aim-1 Kinase Couples with Megakaryocytic Polyploidization of Human Hematopoietic Cells

2001 ◽  
Vol 152 (2) ◽  
pp. 275-288 ◽  
Author(s):  
Akira Kawasaki ◽  
Itaru Matsumura ◽  
Jun-ichiro Miyagawa ◽  
Sachiko Ezoe ◽  
Hirokazu Tanaka ◽  
...  
Keyword(s):  
Late Phase ◽  
K562 Cells ◽  
Dominant Negative ◽  
Serine Threonine Kinase ◽  
Induced Expression ◽  
Threonine Kinase ◽  
Polyploid Formation ◽  
M Phase ◽  
Dependent Cell ◽  
Normal Human

During the late phase of megakaryopoiesis, megakaryocytes undergo polyploidization, which is characterized by DNA duplication without concomitant cell division. However, it remains unknown by which mechanisms this process occurs. AIM-1 and STK15 belong to the Aurora/increase-in-ploidy (Ipl)1 serine/threonine kinase family and play key roles in mitosis. In a human interleukin-3–dependent cell line, F-36P, the expressions of AIM-1 and STK15 mRNA were specifically observed at G2/M phase of the cell cycle during proliferation. In contrast, the expressions of AIM-1 and STK15 were continuously repressed during megakaryocytic polyploidization of human erythro/megakaryocytic cell lines (F-36P, K562, and CMK) treated with thrombopoietin, activated ras (H-rasG12V), or phorbol ester. Furthermore, their expressions were suppressed during thrombopoietin-induced polyploidization of normal human megakaryocytes. Activation of AIM-1 by the induced expression of AIM-1(wild-type) canceled TPA-induced polyploidization of K562 cells significantly, whereas that of STK15 did not. Moreover, suppression of AIM-1 by the induced expression of AIM-1 (K/R, dominant-negative type) led to polyploidization in 25% of K562 cells, whereas STK15(K/R) showed no effect. Also, the induced expression of AIM-1(K/R) in CMK cells provoked polyploidization up to 32N. These results suggested that downregulation of AIM-1 at M phase may be involved in abortive mitosis and polyploid formation of megakaryocytes.

scholarly journals Casein kinase-1γ1 and 3 stimulate tumor necrosis factor-induced necroptosis through RIPK3

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Song-Yi Lee ◽  
Hyunjoo Kim ◽  
Cathena Meiling Li ◽  
Jaemin Kang ◽  
Ayaz Najafov ◽  
...  
Keyword(s):  
Ectopic Expression ◽  
Specific Inhibitor ◽  
Casein Kinase ◽  
In Vitro Assays ◽  
Serine Threonine Kinase ◽  
Casein Kinase 1 ◽  
Threonine Kinase ◽  
Necrosis Factor

AbstractUpon necroptosis activation, receptor interacting serine/threonine kinase (RIPK)1 and RIPK3 form a necrosome complex with pseudokinase mixed lineage kinase-like (MLKL). Although protein phosphorylation is a key event for RIPK1 and RIPK3 activation in response to a necroptosis signal, relatively little is known about other factors that might regulate the activity of these kinases or necrosome formation. Through a gain-of-function screen with 546 kinases and 127 phosphatases, we identified casein kinase 1 gamma (CK1γ) as a candidate necroptosis-promoting factor. Here, we show that the decreased activity or amounts of CK1γ1 and CK1γ3, either by treatment with a chemical inhibitor or knockdown in cells, reduced TNFα-induced necroptosis. Conversely, ectopic expression of CK1γ1 or CK1γ3 exacerbated necroptosis, but not apoptosis. Similar to RIPK1 and RIPK3, CK1γ1 was also cleaved at Asp343 by caspase-8 during apoptosis. CK1γ1 and CK1γ3 formed a protein complex and were recruited to the necrosome harboring RIPK1, RIPK3 and MLKL. In particular, an autophosphorylated form of CK1γ3 at Ser344/345 was detected in the necrosome and was required to mediate the necroptosis. In addition, in vitro assays with purified proteins showed that CK1γ phosphorylated RIPK3, affecting its activity, and in vivo assays showed that the CK1γ-specific inhibitor Gi prevented abrupt death in mice with hypothermia in a model of TNFα-induced systemic inflammatory response syndrome. Collectively, these data suggest that CK1γ1 and CK1γ3 are required for TNFα-induced necroptosis likely by regulating RIPK3.

scholarly journals A Mouse Serine/Threonine Kinase Homologous to C. elegans UNC51 Functions in Parallel Fiber Formation of Cerebellar Granule Neurons

Neuron ◽  
1999 ◽  
Vol 24 (4) ◽  
pp. 833-846 ◽  
Author(s):  
Toshifumi Tomoda ◽  
Rupal S Bhatt ◽  
Hidehito Kuroyanagi ◽  
Takuji Shirasawa ◽  
Mary E Hatten
Keyword(s):  
Fiber Formation ◽  
Parallel Fiber ◽  
Cerebellar Granule Neurons ◽  
Granule Neurons ◽  
Serine Threonine Kinase ◽  
Cerebellar Granule ◽  
Threonine Kinase ◽  
C Elegans

scholarly journals Human Prk Is a Conserved Protein Serine/Threonine Kinase Involved in Regulating M Phase Functions

1997 ◽  
Vol 272 (45) ◽  
pp. 28646-28651 ◽  
Author(s):  
Bin Ouyang ◽  
Huiqi Pan ◽  
Luo Lu ◽  
Jian Li ◽  
Peter Stambrook ◽  
...  
Keyword(s):  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
M Phase ◽  
Phase Functions
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