scholarly journals Interaction of Activator of G-protein Signaling 3 (AGS3) with LKB1, a Serine/Threonine Kinase Involved in Cell Polarity and Cell Cycle Progression

2003 ◽  
Vol 278 (26) ◽  
pp. 23217-23220 ◽  
Author(s):  
Joe B. Blumer ◽  
Michael L. Bernard ◽  
Yuri K. Peterson ◽  
Jun-ichi Nezu ◽  
Peter Chung ◽  
...  
Keyword(s):  
Cell Cycle ◽  
G Protein ◽  
Cell Polarity ◽  
Cell Cycle Progression ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
Threonine Kinase

scholarly journals Tyr198 is the Essential Autophosphorylation Site for STK16 Localization and Kinase Activity

2019 ◽  
Vol 20 (19) ◽  
pp. 4852 ◽  
Author(s):  
Junjun Wang ◽  
Juanjuan Liu ◽  
Xinmiao Ji ◽  
Xin Zhang
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Kinase Domain ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
Threonine Kinase ◽  
Cellular Processes ◽  
Activation Segment ◽  
And Function

STK16, reported as a Golgi localized serine/threonine kinase, has been shown to participate in multiple cellular processes, including the TGF-β signaling pathway, TGN protein secretion and sorting, as well as cell cycle and Golgi assembly regulation. However, the mechanisms of the regulation of its kinase activity remain underexplored. It was known that STK16 is autophosphorylated at Thr185, Ser197, and Tyr198 of the activation segment in its kinase domain. We found that STK16 localizes to the cell membrane and the Golgi throughout the cell cycle, but mutations in the auto-phosphorylation sites not only alter its subcellular localization but also affect its kinase activity. In particular, the Tyr198 mutation alone significantly reduced the kinase activity of STK16, abolished its Golgi and membrane localization, and affected the cell cycle progression. This study demonstrates that a single site autophosphorylation of STK16 could affect its localization and function, which provides insights into the molecular regulatory mechanism of STK16’s kinase activity.

Multiple Myeloma Cells Survival and Proliferation Rely on High Levels and Activity of the Serine-Threonine Kinase CK2.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 643-643 ◽  
Author(s):  
Francesco A. Piazza ◽  
Maria Ruzzene ◽  
Giovanni Di Maira ◽  
Enrico Brunetta ◽  
Luca Bonanni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Transcriptional Activity ◽  
Kinase Activity ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
Threonine Kinase ◽  
Protein Levels ◽  
Tnf Α ◽  
Ck2 Inhibitors

Abstract Survival and proliferation of Multiple Myeloma plasma cells (MMPCs) depend on the activation of signaling pathways through the interaction with the surrounding bone marrow microenvironment. CK2 is a ubiquitous cellular serine-threonine kinase, whose involvement in oncogenic transformation, apoptosis and cell cycle progression has recently become matter of intense research. Due to its connection with signaling molecules pivotal for plasma cell (PCs) survival, such as those implicated in the TNF-α/NF-κB, IGF1/PI3K/AKT and Wnt/β-catenin pathways, CK2 is likely to play a central role in MM biology. We investigated CK2 function in MMPCs survival and cell cycle progression, in the modulation of the sensitivity to chemotherapeutics and in the regulation of the I-κB/NF-κB dependent pathway. We first analysed the CK2 protein levels and specific kinase activity in MMPCs. Different cell lines and highly purified CD138+ PCs from 5 patients were used. We observed higher protein levels of the CK2 catalytic subunit αin the neoplastic MMPCs than in controls (resting peripheral blood and splenic B lymphocytes). Moreover, also the total CK2-dependent kinase activity was found significantly increased in MMPCs. We also assessed the levels and pattern of total protein phosphorylation by radioactive phosphate incorporation assay. We found that MMPCs share a similar pattern of phoshorylated proteins. The degree of phosphorylation of some of these proteins was significantly reduced in the presence of specific CK2 inhibitors. Next, using a panel of highly specific CK2 inhibitors, we studied the effects of hampering CK2 function in MMPCs. A dose-dependent cytotoxic effect was observed after the treatment with such compounds that was associated with the activation of both the extrinsic and intrinsic caspase-dependent pathways, the release from mitochondria of cytochrome c and smac/diablo and cell cycle arrest in G2-M. A possible role for CK2 inhibition in sensitising MMPCs to melphalan-induced apoptosis was also investigated. Indeed, CK2 blockade lowered the threshold of sensitivity of MMPCs to the cytotoxic effect of melphalan. We then looked at the consequences of CK2 blockade on the NF-κB dependent signaling cascade. Basal and TNF-α-dependent I-κB-αdegradation, as well as NF-κB transcriptional activity upon TNF-αstimulation, were partially impaired by CK2 blockade in MMPCs. Finally, we detected association between the endogenous αcatalytic subunit of CK2 and the NF-κB p50/p105 member by confocal microscopy and co-immunoprecipitation. Altogether, our data suggest a pivotal role for CK2 in controlling survival, proliferation and sensitivity to chemotherapeutics of MMPCs and implicate this kinase in the regulation of the NF-κB pathway in MM through the modulation of I-κB protein levels and NF-κB transcriptional activity. This latter effect is possibly exerted through physical association of CK2 with NF-κB transcription factors. Our findings also suggest that CK2 inhibition could be exploited as a novel therapeutic approach for MM.

Functional implication of human serine/threonine kinase, hAIK, in cell cycle progression

2000 ◽  
Vol 7 (6) ◽  
pp. 484-493 ◽  
Author(s):  
Shun-Chun Yang ◽  
Chian-Hoang Huang ◽  
Nien-Jung Chen ◽  
Cheng-Kung Chou ◽  
Chi-Hung Lin
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
Functional Implication ◽  
Threonine Kinase

scholarly journals Design of Amino Acid- and Carbohydrate-Based Anticancer Drugs to Inhibit PIM kinases, an In Silico Study

2021 ◽  
Author(s):  
Sepideh Kalhor ◽  
Alireza Fattahi
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
The Novel ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
Threonine Kinase ◽  
Pim Kinases ◽  
In Silico Study ◽  
Regulation Of Cell Cycle ◽  
Cancerous Cells

PIM-1 is a serine-threonine kinase which is mainly expressed in tissues such as Thymus, spleen, bone marrow, and liver. This protein takes a role in many stages of the cell cycle, including the regulation of cell cycle progression and apoptosis. According to many studies, overexpression of PIM kinases happens in various types of human tumors; such as lymphomas, prostate cancer, and oral cancer. As a result, the design of drugs to inhibit PIM-1 in cancerous cells has attracted many attentions in recent years. This study aimed to design the alternative inhibitors for PIM-1 kinase, which are based on carbohydrates and amino acids and are expected to be non-toxic and to have the same chemotherapeutic effects as the traditional agents. The combinatorial use of quantum mechanics studies and molecular dynamic simulation (MD) has enabled us to precisely predict the mechanism of the inhibition of PIM-1 kinase by the novel designed drugs and to compare them with the recently synthesized chemotherapeutic drugs; such as DBC.

scholarly journals The Serine/Threonine Kinase Nek6 Is Required for Cell Cycle Progression through Mitosis

2003 ◽  
Vol 278 (52) ◽  
pp. 52454-52460 ◽  
Author(s):  
Min-Jean Yin ◽  
Lihua Shao ◽  
David Voehringer ◽  
Tod Smeal ◽  
Bahija Jallal
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
Threonine Kinase

scholarly journals Akt/Protein Kinase B-Dependent Phosphorylation and Inactivation of WEE1Hu Promote Cell Cycle Progression at G2/M Transition

2005 ◽  
Vol 25 (13) ◽  
pp. 5725-5737 ◽  
Author(s):  
Kazuhiro Katayama ◽  
Naoya Fujita ◽  
Takashi Tsuruo
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Phosphorylation Site ◽  
Cytoplasmic Localization ◽  
M Cell ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
M Phase ◽  
Promote Cell Cycle Progression

ABSTRACT The serine/threonine kinase Akt is known to promote cell growth by regulating the cell cycle in G1 phase through activation of cyclin/Cdk kinases and inactivation of Cdk inhibitors. However, how the G2/M phase is regulated by Akt remains unclear. Here, we show that Akt counteracts the function of WEE1Hu. Inactivation of Akt by chemotherapeutic drugs or the phosphatidylinositide-3-OH kinase inhibitor LY294002 induced G2/M arrest together with the inhibitory phosphorylation of Cdc2. Because the increased Cdc2 phosphorylation was completely suppressed by wee1hu gene silencing, WEE1Hu was associated with G2/M arrest induced by Akt inactivation. Further analyses revealed that Akt directly bound to and phosphorylated WEE1Hu during the S to G2 phase. Serine-642 was identified as an Akt-dependent phosphorylation site. WEE1Hu kinase activity was not affected by serine-642 phosphorylation. We revealed that serine-642 phosphorylation promoted cytoplasmic localization of WEE1Hu. The nuclear-to-cytoplasmic translocation was mediated by phosphorylation-dependent WEE1Hu binding to 14-3-3θ but not 14-3-3β or -σ. These results indicate that Akt promotes G2/M cell cycle progression by inducing phosphorylation-dependent 14-3-3θ binding and cytoplasmic localization of WEE1Hu.

scholarly journals Compartmentalized nodes control mitotic entry signaling in fission yeast

2013 ◽  
Vol 24 (12) ◽  
pp. 1872-1881 ◽  
Author(s):  
Lin Deng ◽  
James B. Moseley
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Fission Yeast ◽  
Cell Polarity ◽  
Cell Cycle Progression ◽  
Interaction Network ◽  
Yeast Cells ◽  
Cell Cortex ◽  
Cycle Progression ◽  
Mitotic Entry

Cell cycle progression is coupled to cell growth, but the mechanisms that generate growth-dependent cell cycle progression remain unclear. Fission yeast cells enter into mitosis at a defined size due to the conserved cell cycle kinases Cdr1 and Cdr2, which localize to a set of cortical nodes in the cell middle. Cdr2 is regulated by the cell polarity kinase Pom1, suggesting that interactions between cell polarity proteins and the Cdr1-Cdr2 module might underlie the coordination of cell growth and division. To identify the molecular connections between Cdr1/2 and cell polarity, we performed a comprehensive pairwise yeast two-hybrid screen. From the resulting interaction network, we found that the protein Skb1 interacted with both Cdr1 and the Cdr1 inhibitory target Wee1. Skb1 inhibited mitotic entry through negative regulation of Cdr1 and localized to both the cytoplasm and a novel set of cortical nodes. Skb1 nodes were distinct structures from Cdr1/2 nodes, and artificial targeting of Skb1 to Cdr1/2 nodes delayed entry into mitosis. We propose that the formation of distinct node structures in the cell cortex controls signaling pathways to link cell growth and division.

scholarly journals G Protein Coupled‐Receptor Kinase 5 is Localized to Centrosomes and Regulates Cell Cycle Progression

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Christopher H. So ◽  
Allison M. Michal ◽  
Neil Beeharry ◽  
Haripriya Shankar ◽  
Rouzbeh Mashayekhi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
G Protein ◽  
Cell Cycle Progression ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Cycle Progression ◽  
G Protein Coupled

scholarly journals Cell Cycle Progression and Cell Polarity Require Sphingolipid Biosynthesis in Aspergillus nidulans

2001 ◽  
Vol 21 (18) ◽  
pp. 6198-6209 ◽  
Author(s):  
Jijun Cheng ◽  
Tae-Sik Park ◽  
Anthony S. Fischl ◽  
Xiang S. Ye
Keyword(s):  
Cell Cycle ◽  
Actin Cytoskeleton ◽  
Aspergillus Nidulans ◽  
Cell Polarity ◽  
Cell Cycle Progression ◽  
Polarized Growth ◽  
Serine Palmitoyltransferase ◽  
Cycle Progression ◽  
Marked Accumulation ◽  
Sphingolipid Biosynthesis

ABSTRACT Sphingolipids are major components of the plasma membrane of eukaryotic cells and were once thought of merely as structural components of the membrane. We have investigated effects of inhibiting sphingolipid biosynthesis, both in germinating spores and growing hyphae of Aspergillus nidulans. In germinating spores, genetic or pharmacological inactivation of inositol phosphorylceramide (IPC) synthase arrests the cell cycle in G1 and also prevents polarized growth during spore germination. However, inactivation of IPC synthase not only eliminates sphingolipid biosynthesis but also leads to a marked accumulation of ceramide, its upstream intermediate. We therefore inactivated serine palmitoyltransferase, the first enzyme in the sphingolipid biosynthesis pathway, to determine effects of inhibiting sphingolipid biosynthesis without an accumulation of ceramide. This inactivation also prevented polarized growth but did not affect nuclear division of germinating spores. To see if sphingolipid biosynthesis is required to maintain polarized growth, and not just to establish polarity, we inhibited sphingolipid biosynthesis in cells in which polarity was already established. This inhibition rapidly abolished normal cell polarity and promoted cell tip branching, which normally never occurs. Cell tip branching was closely associated with dramatic changes in the normally highly polarized actin cytoskeleton and found to be dependent on actin function. The results indicate that sphingolipids are essential for the establishment and maintenance of cell polarity via control of the actin cytoskeleton and that accumulation of ceramide is likely responsible for arresting the cell cycle in G1.

scholarly journals A Localized Complex of Two Protein Oligomers Controls the Orientation of Cell Polarity

mBio ◽  
2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Adam M. Perez ◽  
Thomas H. Mann ◽  
Keren Lasker ◽  
Daniel G. Ahrens ◽  
Michael R. Eckart ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Polarity ◽  
Histidine Kinase ◽  
Bacterial Cell ◽  
Cell Cycle Progression ◽  
Caulobacter Crescentus ◽  
Cycle Progression ◽  
Self Assembling ◽  
Membrane Bound ◽  
Ordered Assembly

ABSTRACT Signaling hubs at bacterial cell poles establish cell polarity in the absence of membrane-bound compartments. In the asymmetrically dividing bacterium Caulobacter crescentus, cell polarity stems from the cell cycle-regulated localization and turnover of signaling protein complexes in these hubs, and yet the mechanisms that establish the identity of the two cell poles have not been established. Here, we recapitulate the tripartite assembly of a cell fate signaling complex that forms during the G1-S transition. Using in vivo and in vitro analyses of dynamic polar protein complex formation, we show that a polymeric cell polarity protein, SpmX, serves as a direct bridge between the PopZ polymeric network and the cell fate-directing DivJ histidine kinase. We demonstrate the direct binding between these three proteins and show that a polar microdomain spontaneously assembles when the three proteins are coexpressed heterologously in an Escherichia coli test system. The relative copy numbers of these proteins are essential for complex formation, as overexpression of SpmX in Caulobacter reorganizes the polarity of the cell, generating ectopic cell poles containing PopZ and DivJ. Hierarchical formation of higher-order SpmX oligomers nucleates new PopZ microdomain assemblies at the incipient lateral cell poles, driving localized outgrowth. By comparison to self-assembling protein networks and polar cell growth mechanisms in other bacterial species, we suggest that the cooligomeric PopZ-SpmX protein complex in Caulobacter illustrates a paradigm for coupling cell cycle progression to the controlled geometry of cell pole establishment. IMPORTANCE Lacking internal membrane-bound compartments, bacteria achieve subcellular organization by establishing self-assembling protein-based microdomains. The asymmetrically dividing bacterium Caulobacter crescentus uses one such microdomain to link cell cycle progression to morphogenesis, but the mechanism for the generation of this microdomain has remained unclear. Here, we demonstrate that the ordered assembly of this microdomain occurs via the polymeric network protein PopZ directly recruiting the polarity factor SpmX, which then recruits the histidine kinase DivJ to the developing cell pole. Further, we find that overexpression of the bridge protein SpmX in Caulobacter disrupts this ordered assembly, generating ectopic cell poles containing both PopZ and DivJ. Together, PopZ and SpmX assemble into a cooligomeric network that forms the basis for a polar microdomain that coordinates bacterial cell polarity. IMPORTANCE Lacking internal membrane-bound compartments, bacteria achieve subcellular organization by establishing self-assembling protein-based microdomains. The asymmetrically dividing bacterium Caulobacter crescentus uses one such microdomain to link cell cycle progression to morphogenesis, but the mechanism for the generation of this microdomain has remained unclear. Here, we demonstrate that the ordered assembly of this microdomain occurs via the polymeric network protein PopZ directly recruiting the polarity factor SpmX, which then recruits the histidine kinase DivJ to the developing cell pole. Further, we find that overexpression of the bridge protein SpmX in Caulobacter disrupts this ordered assembly, generating ectopic cell poles containing both PopZ and DivJ. Together, PopZ and SpmX assemble into a cooligomeric network that forms the basis for a polar microdomain that coordinates bacterial cell polarity.

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