• Cell-cycle events are controlled by cyclin-dependent kinases (CDKs), whose periodic activation is driven by cyclins. (nature.com)
  • Brown, N. R., Noble, M. E., Endicott, J. A. & Johnson, L. N. The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases. (nature.com)
  • A relatively well understood example is the network that controls progression of the cell cycle, where cyclin-dependent kinases (CDKs) couple with various cyclins over the cell cycle to regulate critical processes [ 2 - 4 ]. (biomedcentral.com)
  • Cyclins, when bound with the dependent kinases, such as the p34/cdc2/cdk1 protein, form the maturation-promoting factor. (wikipedia.org)
  • Cyclin-dependent protein kinases (Cdks) play central roles in regulating the production, activation, inactivation and destruction of these EPs. (nih.gov)
  • Cyclin-dependent kinase 5 (Cdk5) is a member of the Cdk family of serine/threonine kinases and is abundantly expressed in the brain ( Dhavan and Tsai, 2001 ). (frontiersin.org)
  • Inhibition of Cdk5 by olomoucine enhanced phosphorylation of kinesin, suggesting that the effect was mediated by negative regulation of other kinases. (frontiersin.org)
  • Predikin now consists of two components: (i) PredikinDB, a database of phosphorylation sites that links substrates to kinase sequences and (ii) a Perl module, which provides methods to classify protein kinases, reliably identify substrate-determining residues, generate scoring matrices and score putative phosphorylation sites in query sequences. (biomedcentral.com)
  • Protein kinases, the enzymes responsible for protein phosphorylation, make up almost 2% of protein-encoding genes in the human genome [ 1 ] and an estimated 30-50% of human proteins are phosphorylated [ 2 ]. (biomedcentral.com)
  • Progression through the cell cycle is driven by the oscillating activity of Cyclin Dependent Kinases (CDKs). (intechopen.com)
  • We herein demonstrated that CADM1 interacts with Hippo pathway core kinases and enhances the phosphorylation of YAP1, and also that the membranous co-expression of CADM1 and LATS2 predicts a favorable prognosis in lung adenocarcinoma. (cancerindex.org)
  • Protein kinases that control cell cycle progression in all eukaryotes and require physical association with CYCLINS to achieve full enzymatic activity. (bvsalud.org)
  • Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events. (bvsalud.org)
  • As a biologically important example we have studied the complex formed by cyclins and cyclin-dependent kinases (CDKs), which play an essential role in the control of the eukaryotic cell cycle. (lu.se)
  • Cyclins themselves have no enzymatic activity but have binding sites for some substrates and target the Cdks to specific subcellular locations. (wikipedia.org)
  • The activity of CDKs is controlled by their binding to coactivator subunits termed Cyclins, as well as by CDK inhibitory proteins termed CKIs. (intechopen.com)
  • Identification of a cyclin-cdk2 recognition motif present in substrates and p21-like cyclin-dependent kinase inhibitors. (nature.com)
  • Cyclin-dependent kinase 2 (Cdk2)/cyclin A is a novel PR coregulator that binds the NTD and acts by phosphorylating steroid receptor coactivator-1 and modulating steroid receptor coactivator-1 interaction with PR. (nih.gov)
  • however, phosphorylation of serine 400 was not required, indicating that JDP-2 and Cdk2/cyclin A act by distinct mechanisms. (nih.gov)
  • Cyclin E/Cdk2 kinase activity is frequently deregulated in human cancers, resulting in impaired apoptosis. (oncotarget.com)
  • Here, we show that cyclin E/Cdk2 phosphorylates and stabilizes the pro-survival Bcl-2 family protein Mcl-1, a key cell death resistance determinant to the small molecule Bcl-2 family inhibitors ABT-199 and ABT-737, mimetics of the Bcl-2 homology domain 3 (BH3). (oncotarget.com)
  • Cyclin E levels were elevated and there was increased association of cyclin E/Cdk2 with Mcl-1 in ABT-737-resistant compared to parental cells. (oncotarget.com)
  • Studies with Mcl-1 phosphorylation mutants show that cyclin E/Cdk2-dependent phosphorylation of Mcl-1 residues on its PEST domain resulted in increased Mcl-1 stability (Thr92, and Thr163) and Bim binding (Ser64). (oncotarget.com)
  • There are distinct differences between CDK9/CycT1 and the cell cycle CDK CDK2/CycA manifested by a relative rotation of 26 degrees of CycT1 with respect to the CDK, showing for the first time plasticity in CDK cyclin interactions. (ox.ac.uk)
  • Cyclin dependent-kinase 2 (CDK2) plays important functions during the mitotic cell cycle and also facilitates several key events during germ cell development. (lu.se)
  • In testis extracts from mice lacking Cdk2, there are changes in expression of PMS2, MSH2, and HEI10, which may be reflective of the loss of CDK2 phosphorylation. (lu.se)
  • A ) Quantitative PCR analysis of CDK1, cyclin A2, CDK2, cyclin E2 and CYP1B1 mRNA levels in macrophages treated with carrier (DMSO), AhR agonist or AhR antagonist. (elifesciences.org)
  • B ) Western blot analysis of HSP90 (loading control) CDK1, cyclin A2, CDK2, cyclin E2 protein levels in macrophages treated with carrier (DMSO), AhR agonist or antagonist. (elifesciences.org)
  • We hypothesize that a dynamic equilibrium between the dominant buried state and an transiently open, kinase-accessible state is present in the p27-cyclin A-CDK2 complex, and aim to test this hypothesis through the use of unbiased molecular dynamics and metadynamics simulations. (lu.se)
  • A- and B-type cyclins differentially modulate substrate specificity of cyclin-cdk complexes. (nature.com)
  • Cell changes in the cell cycle like the assembly of mitotic spindles and alignment of sister-chromatids along the spindles are induced by M cyclin- Cdk complexes. (wikipedia.org)
  • p27 regulates G1 /S transition by abrogating the activity of cyclin/CDK complexes. (umass.edu)
  • p27 is a protein that binds to and prevents the activation of different G1 and S phase cyclin-CDK complexes. (lu.se)
  • Three sequential phosphorylation events on specific residues of p27, regulate the activity of these complexes and ultimately control cell cycle proliferation or arrest. (lu.se)
  • SMAD phosphorylation by active receptors, and constitutive SMAD dephosphorylation by nuclear phosphatases, are coupled through nucleocytoplasmic shuttling of SMADs. (nature.com)
  • The model is based on a bicyclic phosphorylation-dephosphorylation cascade involving cyclin and cdc2 kinase. (ebi.ac.uk)
  • Inhibition of Cdk5 resulted in dephosphorylation of the inhibitory Ser9 site on GSK3β and an increase of activating phosphorylation at Tyr216. (frontiersin.org)
  • Two biochemical processes, protein phosphorylation/dephosphorylation and ubiquitin-mediated degradation drive cell cycle control. (benthamscience.com)
  • Endogenous regulation of the cell cycle depends on phosphorylation and dephosphorylation of the cyclin- cyclin-dependent kinase (CDK)-cyclin-dependent kinase inhibitor (CDKI) pathway. (jcancer.org)
  • The selective suppression of HIV-1 transcription by the cyclin-dependent kinase inhibitor, flavopiridol, abrogated cyclin D 1 expression, underlying the requirement for HIV-1 encoded products to induce cyclin D 1 . (biomedcentral.com)
  • We studied here phosphorylation of 5-HT 1A R by cyclin-dependent kinase 5 (Cdk5), a neuron-specific membrane-bound Ser/Thr kinase that is activated by binding of the p35 Cdk5 activator. (elsevierpure.com)
  • These results suggest that Cdk5-p35 modulates 5-HT signaling through phosphorylation-dependent degradation of 5-HT lA R. (elsevierpure.com)
  • Glutamate inputs activate cyclin-dependent kinase 5 (Cdk5), which inhibits postsynaptic dopamine signaling by phosphorylating DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa) at Thr75 in the striatum. (frontiersin.org)
  • We here report that Cdk5 with Tyr15 phosphorylation (Cdk5-pTyr15) is enriched in the mouse striatum, where dopaminergic stimulation inhibited phosphorylation of Tyr15-Cdk5 by acting through the D2 class dopamine receptors. (frontiersin.org)
  • Moreover, in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model, dopamine deficiency caused increased phosphorylation of both Tyr15-Cdk5 and Thr75-DARPP-32 in the striatum, which could be attenuated by administration of L-3,4-dihydroxyphenylalanine and imatinib (STI-571), a selective c-Abl inhibitor. (frontiersin.org)
  • Glutamate inputs activate Cdk5, which inhibits postsynaptic dopamine D1 receptor (D1R)-mediated signaling by phosphorylating DARPP-32 at Thr75 (Thr75-DARPP-32) in the striatum, since DARPP-32 with Thr75 phosphorylation (DARPP-32-pThr75) functions as an inhibitor of cAMP-dependent protein kinase A (PKA). (frontiersin.org)
  • One of the regulatory mechanisms that modulate the Cdk5 kinase activity is phosphorylation of conserved residues ( Dhavan and Tsai, 2001 ). (frontiersin.org)
  • Here, we show that in the mouse striatum, dopamine receptor stimulation negatively regulates phosphorylation of Tyr15-Cdk5 most likely through a D2R-mediated mechanism. (frontiersin.org)
  • attenuates abnormally increased striatal phosphorylation of both Tyr15-Cdk5 and Thr75-DARPP-32, as does L-3,4-dihydroxyphenylalanine (L-dopa). (frontiersin.org)
  • Here, we investigated the mechanism by which cyclin I safeguards against apoptosis and found that cyclin I bound and activated cyclin-dependent kinase 5 (Cdk5) in isolated mouse podocytes and neurons. (jci.org)
  • Cdk5 activity was reduced in glomeruli and brain lysates from cyclin I-deficient mice, and inhibition of Cdk5 increased in vitro the susceptibility to apoptosis in response to cellular damage. (jci.org)
  • Taken together, these data suggest that a cyclin I-Cdk5 complex forms a critical antiapoptotic factor in terminally differentiated cells that functions via MAPK signaling to modulate levels of the prosurvival proteins Bcl-2 and Bcl-XL. (jci.org)
  • Cyclin I-Cdk5 preferentially phosphorylates tau. (jci.org)
  • A ) HEK293 cells were transfected with HA-Cdk5, then cotransfected with either myc-p35 or myc-cyclin I. Following an IP to the myc epitope tag on either p35 or cyclin I, in vitro kinase assays were performed using either histone H1 (HH1) or tau as substrates. (jci.org)
  • In contrast, cyclin I-Cdk5 preferentially phosphorylated tau (lane 6) rather than histone H1 (lane 2). (jci.org)
  • No kinase activity was detected in the presence of a kinase-inactive dominant negative Cdk5 mutant (HA-D145N-Cdk5, lane 3, 7) or in the absence of either Cdk5 (lanes 1, 5) or p35/cyclin I (lanes 4, 8). (jci.org)
  • B ) To compare the kinase kinetics by which cyclin I-Cdk5 phosphorylates tau in comparison with p35-Cdk5, a time-course experiment was performed in HEK293 cells cotransfected with myc-p35 and HA-Cdk5 or myc-cyclin I and HA-Cdk5. (jci.org)
  • Cyclin I-Cdk5 showed phosphorylation kinetics similar to those of p35-Cdk5. (jci.org)
  • Cdk5 is named after its structural similarity to members of the serine/threonine cyclin-dependent kinase family. (frontiersin.org)
  • Altered phosphorylation of CREB phosphopeptide, a substrate of GSK3β, suggested that GSK3β may be the mediator of Cdk5 activity in kinesin-mediated axonal transport. (frontiersin.org)
  • New features in Predikin include the use of SQL queries to PredikinDB to generate predictions, scoring of predictions, more reliable identification of substrate-determining residues and putative phosphorylation sites, extended options to handle protein kinase and substrate data and an improved web interface. (biomedcentral.com)
  • Mutation of phosphorylation sites within this region of the NTD showed that phosphorylation of serine 400 was required for the partial agonist activity of RU486 stimulated by JDP-2, but was not required for activity of hormone agonist, either in the presence or absence of JDP-2. (nih.gov)
  • We conclude that PR bound to RU486 and associated with JDP-2 adopts an active conformation in a subregion of the NTD requiring phosphorylation of serine 400 that is distinct from that promoted by progestin agonists. (nih.gov)
  • SKP2 overexpression is associated with increased serine 10 phosphorylation of p27 (pSer10p27) in triple-negative breast cancer. (umass.edu)
  • p27 can undergo phosphorylation at serine 10 (pSer10p27). (umass.edu)
  • The oscillations of the cyclins, namely fluctuations in cyclin gene expression and destruction by the ubiquitin mediated proteasome pathway, induce oscillations in Cdk activity to drive the cell cycle. (wikipedia.org)
  • The ubiquitin-mediated proteolysis of cyclin E plays a central role in cell-cycle progression, and cyclin E accumulation is a common event in cancer. (rcsb.org)
  • Furthermore, we found that levels of phosphorylated MEK1/2 and ERK1/2 were decreased in cyclin I-deficient podocytes and that inhibition of MEK1/2 restored Bcl2 and Bcl-XL protein levels. (jci.org)
  • Interestingly, inhibition of FAK signaling pathway attenuated the phosphorylation of AKT, but inhibition of AKT signaling pathway did not affect the phosphorylation of FAK. (oncotarget.com)
  • Here we compare the specificity of two budding yeast cyclins, the S-phase cyclin Clb5 and the M-phase cyclin Clb2, in the phosphorylation of 150 Cdk1 (Cdc28) substrates. (nature.com)
  • Although we did not identify any highly Clb2-specific substrates, we found that Clb2-Cdk1 possessed higher intrinsic kinase activity than Clb5-Cdk1, enabling efficient phosphorylation of a broad range of mitotic Cdk1 targets. (nature.com)
  • Thus, Clb5 and Clb2 use distinct mechanisms to enhance the phosphorylation of S-phase and M-phase substrates. (nature.com)
  • There are several different cyclins that are active in different parts of the cell cycle and that cause the Cdk to phosphorylate different substrates. (wikipedia.org)
  • S-phase kinase-associated protein 2 (SKP2) is an important cell cycle regulator, targeting the cyclin-dependent kinase (CDK) inhibitor p27 for degradation, and is frequently overexpressed in breast cancer. (umass.edu)
  • Incorporation of both FAK inhibitor and AKT inhibitor counteracted the upregulating expression of Cyclin A2, CyclinB1, and Snail, and downregulating expression of E-cadherin expression induced by Lasp1 overexpression. (oncotarget.com)
  • Roscovitine is a cyclin-dependent kinase (cdk) inhibitor. (tocris.com)
  • The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). (thermofisher.com)
  • Targets of the cyclin-dependent kinase Cdk1. (nature.com)
  • Previously, we found that eukaryotic initiation factor (eIF) 4A interacts with cyclin dependent kinase A (CDKA), the plant ortholog of mammalian CDK1. (aber.ac.uk)
  • From genome-scale data sets of budding yeast, we identify 126 EPs that are regulated by Cdk1 both through direct phosphorylation of the EP and through phosphorylation of the transcription factors that control expression of the EP, so that each of these EPs is regulated by a feed-forward loop (FFL) from Cdk1. (nih.gov)
  • S cyclins bind to Cdk and the complex directly induces DNA replication. (wikipedia.org)
  • Here, we ask whether the expression of HIV-1 genes in infected podocytes induces cyclin D 1 and phospho-pRb (Ser780) expression, hallmarks of cyclin D1-mediated G 1 → S phase progression. (biomedcentral.com)
  • HIV-1 expression induces cyclin D 1 and phospho-pRb (Ser780) expression in infected podocytes, suggesting that HIV-1 activates cyclin D1-dependent cell-cycle mechanisms to promote proliferation of infected renal epithelium. (biomedcentral.com)
  • The positive transcription elongation factor b (P-TEFb) (CDK9/cyclin T (CycT)) promotes mRNA transcriptional elongation through phosphorylation of elongation repressors and RNA polymerase II. (ox.ac.uk)
  • Phosphorylation of Clb5-specific targets during S phase was reduced by replacing Clb5 with Clb2 or by mutating the substrate RXL motif, confirming the importance of Clb5 specificity in vivo . (nature.com)
  • Figure 3: Clb5-specific substrate phosphorylation occurs in vivo . (nature.com)
  • Schulman, B. A., Lindstrom, D. L. & Harlow, E. Substrate recruitment to cyclin-dependent kinase 2 by a multipurpose docking site on cyclin A. (nature.com)
  • Finally, we examine co-clustering of the CDK consensus motifs with the 'cy' or RXL motif [ 17 ], which is known to be important in determining which CDK-cyclin complex will phosphorylate a given substrate. (biomedcentral.com)
  • The method, named Predikin, identifies key conserved substrate-determining residues in the kinase catalytic domain that contact the substrate in the region of the phosphorylation site and so determine the sequence surrounding the phosphorylation site. (biomedcentral.com)
  • Compared to controls, cultured podocytes expressing HIV-1 genes, and podocytes and tubular epithelium from hyperplastic nephrons in Tg26 kidneys, had increased levels of phospho-pRb (Ser780), a target of active cyclin D 1 /cyclin-dependent kinase-4/6 known to promote G 1 → S phase progression. (biomedcentral.com)
  • In comparison to the two general alternative mechanisms utilized by known transforming viruses to promote cell-cycle progression, namely, by activating or bypassing endogenous D-type cyclins (herein, referred to as "cyclin D"), it has not been established whether HIV-1 gene products trigger either cyclin D-dependent or cyclin D-independent proliferation in non-lymphoid tissues [ 15 ]. (biomedcentral.com)
  • A multitude of pathways control cyclin-dependent kinase activities as the major event for cell cycle progression. (benthamscience.com)
  • Cyclin-dependent kinase (CDK) 10, is reported to play an essential role in the progression from the G2 to M phase of the cell cycle. (jcancer.org)
  • Donaldson, A. D. The yeast mitotic cyclin Clb2 cannot substitute for S phase cyclins in replication origin firing. (nature.com)
  • Cyclin E depletion in various human tumor cell-lines and cyclin E -/- mouse embryo fibroblasts showed decreased levels of Mcl-1 protein, with no change in Mcl-1 mRNA levels. (oncotarget.com)
  • M cyclin concentrations rise as the cell begins to enter mitosis and the concentrations peak at metaphase. (wikipedia.org)
  • The destruction of M cyclins during metaphase and anaphase, after the Spindle Assembly Checkpoint is satisfied, causes the exit of mitosis and cytokinesis. (wikipedia.org)
  • The protein is phosphorylated in a cell-cycle dependent manner, with late prophase phosphorylation remaining through metaphase. (cancerindex.org)
  • The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. (ox.ac.uk)
  • A model that explains the role of multiple cyclin E/Sic1 degrons is provided by the findings that Fbw7 and Cdc4 dimerize, that Fbw7 dimerization enhances the turnover of a weakly associated cyclin E in vivo, and that Cdc4 dimerization increases the rate and processivity of Sic1 ubiquitination in vitro. (rcsb.org)
  • The phosphorylation stimulated the degradation of 5-HT 1A R by the proteasome, resulting in neutralization of the inhibitory action of 5-HT 1A R on intracellular cAMP concentration. (elsevierpure.com)
  • Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT 1A receptor via phosphorylation Biochemical and Biophysical Research Communications , 510 (3), 370-375. (elsevierpure.com)
  • This phosphorylation event is associated with increased cell proliferation and poor prognosis in patients with glioma. (umass.edu)
  • We previously showed that cyclin I does not regulate proliferation, but rather controls survival of podocytes, terminally differentiated epithelial cells that are essential for the structural and functional integrity of kidney glomeruli. (jci.org)
  • In conclusion, Lasp1 facilitated tumor proliferation and invasion of NSCLC through directly binding to FAK and enhancing the phosphorylation of FAK (Tyr397) and AKT (Ser473). (oncotarget.com)
  • A cyclin forms a complex with Cdk, which begins to activate but the complete activation requires phosphorylation, as well. (wikipedia.org)
  • We show that CDK9/CycT1 autophosphorylates on Thr186 in the activation segment and three C-terminal phosphorylation sites. (ox.ac.uk)
  • Cyclin Y phosphorylation- and 14-3-3-binding-dependent activation of PCTAIRE-1/CDK16. (mpg.de)
  • Activation of CDK4 requires binding of a D-type Cyclin and phosphorylation of Thr172 by the CAK kinase complex. (rndsystems.com)
  • Reduced CDK/cyclin, phospho-SAMHD1 and dTNP levels in macrophages following activation of AhR. (elifesciences.org)
  • Structures of the Skp1-Fbw7 complex bound to cyclin E peptides identify a doubly phosphorylated pThr380/pSer384 cyclin E motif as an optimal, high-affinity degron and a singly phosphorylated pThr62 motif as a low-affinity one. (rcsb.org)
  • HIV-1-infected podocytes showed markedly elevated cyclin D 1 mRNA and cyclin D 1 protein, the latter of which did not down-regulate during cell-cell contact or differentiation, suggesting post-transcriptional stabilization of cyclin D 1 protein levels by HIV-1. (biomedcentral.com)
  • Kaposi sarcoma herpesvirus (KSHV) encodes a D-type cyclin (ORF72) that binds CDK6 and is likely to contribute to KSHV-related cancers. (wikipedia.org)
  • The N-terminal region of the protein binds CDC2 to form a complex showing reduced H1 histone kinase activity, indicating a role as a negative regulator of CDC2/cyclin A. In addition, the C-terminal kinase domain binds to its own N-terminal region, suggesting potential negative regulation through interference with complex formation via intramolecular binding. (cancerindex.org)
  • Cyclins can be divided into four classes based on their behaviour in the cell cycle of vertebrate somatic cells and yeast cells: G1 cyclins, G1/S cyclins, S cyclins, and M cyclins. (wikipedia.org)
  • Expression of cyclins detected immunocytochemically in individual cells in relation to cellular DNA content (cell cycle phase), or in relation to initiation and termination of DNA replication during S-phase, can be measured by flow cytometry. (wikipedia.org)
  • Cyclin E knock-down restored ABT-737 sensitivity to acquired and inherently resistant Mcl-1-dependent tumor cells. (oncotarget.com)
  • Cyclin I is an atypical cyclin because it is most abundant in postmitotic cells. (jci.org)
  • and (v) pRb phosphorylation and cyclin D1 expression are reduced in K10-transfected cells and increased in K16-transfected cells. (exposed-skin-care.net)
  • In the absence of cyclin E, Mcl-1 ubiquitination was enhanced, leading to decreased protein stability. (oncotarget.com)
  • The Cdk- G1/S cyclin complex begins to induce the initial processes of DNA replication, primarily by arresting systems that prevent S phase Cdk activity in G1. (wikipedia.org)
  • Indeed, HIV-1 virus deleted of nef failed to induce cyclin D 1 mRNA to the level of other single gene mutant viruses. (biomedcentral.com)
  • We assessed cyclin D 1 and phospho-pRb (Ser780) expression in two well-characterized models of HIV-associated nephropathy pathogenesis: HIV-1 infection of cultured podocytes and HIV-1 transgenic mice (Tg26). (biomedcentral.com)
  • Collectively, our findings identify a novel mechanism of cyclin E-mediated Mcl-1 regulation that provides a rationale for clinical use of Bcl-2 family and Cdk inhibitors for Mcl-1-dependent tumors. (oncotarget.com)
  • CpG methylation of the FHIT, FANCF, cyclin-D2, BRCA2 and RUNX3 genes in Granulosa cell tumors (GCTs) of ovarian origin. (cancercentrum.se)
  • These observations suggest a mechanism whereby CDK phosphorylation has the potential to down regulate eIF4A activity and thereby affect translation. (aber.ac.uk)
  • To understand the regulation of a transcriptional CDK by its cognate cyclin, we have determined the structures of the CDK9/CycT1 and free cyclin T2. (ox.ac.uk)
  • Subsequent western blot results revealed that Lasp1 promoted the expression of Cyclin A2, CyclinB1, and Snail, and inhibited the expression of E-cadherin. (oncotarget.com)
  • Co-transcriptional pre-mRNA processing relies on reversible phosphorylation of the carboxyl-terminal domain (CTD) of Rpb1, the largest subunit of RNA polymerase II (RNAP II). (cipsm.de)