Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that regulates cell cycle progression in proliferating cells. To enter the S-phase, APC/C must be inactivated by phosphorylation of its cofactor, Cdh1. In post-mitotic cells such as neurons APC/C-Cdh1 complex is highly active and responsible for the continuous degradation of mitotic cyclins. However, the specific molecular pathway that determines neuronal cell cycle blockade in post-mitotic neurons is unknown. Here, we show that activation of glutamatergic receptors in rat cortical primary neurons endogenously triggers cyclin-dependent kinase-5 (Cdk5)-mediated phosphorylation of Cdh1 leading to its cytoplasmic accumulation and disassembly from the APC3 core protein, causing APC/C inactivation. Conversely, pharmacological or genetic inhibition of Cdk5 promotes Cdh1 ubiquitination and proteasomal degradation. Furthermore, we show that Cdk5-mediated phosphorylation and inactivation of Cdh1 leads to p27 depletion, which switches on the cyclin D1-cyclin-dependent kinase-4 (Cdk4)-retinoblastoma protein (pRb) pathway to allow the S-phase entry of neurons. However, neurons do not proceed through the cell cycle and die by apoptosis. These results indicate that APC/C-Cdh1 actively suppresses an aberrant cell cycle entry and death of neurons, highlighting its critical function in neuroprotection.
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PMID:Cdk5-mediated inhibition of APC/C-Cdh1 switches on the cyclin D1-Cdk4-pRb pathway causing aberrant S-phase entry of postmitotic neurons. 2665 92

Organ growth is determined by a coordinated combination of cell proliferation and cell growth and differentiation. Endoreduplication is often coupled with cell growth and differentiation, but the genetic and molecular mechanisms that link endoreduplication with cell and organ growth are largely unknown. Here, we describe UBIQUITIN-SPECIFIC PROTEASE14 (UBP14), encoded by the DA3 gene, which functions as a negative regulator of endoreduplication. The Arabidopsis thaliana da3-1 mutant shows large cotyledons, leaves, and flowers with higher ploidy levels. UBP14 acts along with UV-B-INSENSITIVE4 (UVI4), an inhibitor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase, to repress endoreduplication. Also, UBP14 functions antagonistically with CELL CYCLE SWITCH52 A1 (CCS52A1), an activator of APC/C, to regulate endoreduplication. UBP14 physically associates with UVI4 both in vitro and in vivo but does not directly interact with CCS52A1. Further results reveal that UBP14 influences the stability of cyclin A2;3 (CYCA2;3) and cyclin-dependent kinase B1;1 (CDKB1;1), two downstream components of the APC/C Thus, our findings show how endoreduplication is linked with cell and organ growth by revealing important genetic and molecular functions for the ubiquitin-specific protease UBP14 and for the key cell cycle regulators UVI4, CCS52A1, CYCA2;3, and CDKB1;1.
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PMID:UBIQUITIN-SPECIFIC PROTEASE14 Interacts with ULTRAVIOLET-B INSENSITIVE4 to Regulate Endoreduplication and Cell and Organ Growth in Arabidopsis. 2709 60

B-type cyclin-dependent kinase activity must be turned off for mitotic exit and G1 stabilization. B-type cyclin degradation is mediated by the anaphase-promoting complex/cyclosome (APC/C); during and after mitotic exit, APC/C is dependent on Cdh1. Cdh1 is in turn phosphorylated and inactivated by cyclin-CDK at the Start transition of the new cell cycle. We developed a biosensor to assess the cell cycle dynamics of APC/C-Cdh1. Nuclear exit of the G1 transcriptional repressor Whi5 is a known marker of Start; APC/C-Cdh1 is inactivated 12 min after Whi5 nuclear exit with little measurable cell-to-cell timing variability. Multiple phosphorylation sites on Cdh1 act in a redundant manner to repress its activity. Reducing the number of phosphorylation sites on Cdh1 can to some extent be tolerated for cell viability, but it increases variability in timing of APC/C-Cdh1 inactivation. Mutants with minimal subsets of phosphorylation sites required for viability exhibit striking stochasticity in multiple responses including budding, nuclear division, and APC/C-Cdh1 activity itself. Multiple cyclin-CDK complexes, as well as the stoichiometric inhibitor Acm1, contribute to APC/C-Cdh1 inactivation; this redundant control is likely to promote rapid and reliable APC/C-Cdh1 inactivation immediately following the Start transition.
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PMID:An APC/C-Cdh1 Biosensor Reveals the Dynamics of Cdh1 Inactivation at the G1/S Transition. 2741 35

Smk1 is a meiosis-specific MAP kinase (MAPK) in budding yeast that is required for spore formation. It is localized to prospore membranes (PSMs), the structures that engulf haploid cells during meiosis II (MII). Similar to canonically activated MAPKs, Smk1 is controlled by phosphorylation of its activation-loop threonine (T) and tyrosine (Y). However, activation loop phosphorylation occurs via a noncanonical two-step mechanism in which 1) the cyclin-dependent kinase activating kinase Cak1 phosphorylaytes T207 during MI, and 2) Smk1 autophosphorylates Y209 as MII draws to a close. Autophosphorylation of Y209 and catalytic activity for substrates require Ssp2, a meiosis-specific protein that is translationally repressed until anaphase of MII. Ama1 is a meiosis-specific targeting subunit of the anaphase-promoting complex/cyclosome that regulates multiple steps in meiotic development, including exit from MII. Here, we show that Ama1 activates autophosphorylation of Smk1 on Y209 by promoting formation of the Ssp2/Smk1 complex at PSMs. These findings link meiotic exit to Smk1 activation and spore wall assembly.
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PMID:The meiosis-specific Cdc20 family-member Ama1 promotes binding of the Ssp2 activator to the Smk1 MAP kinase. 2911 76

The cell division cycle culminates in mitosis when two daughter cells are born. As cyclin-dependent kinase (Cdk) activity reaches its peak, the anaphase-promoting complex/cyclosome (APC/C) is activated to trigger sister chromatid separation and mitotic spindle elongation, followed by spindle disassembly and cytokinesis. Degradation of mitotic cyclins and activation of Cdk-counteracting phosphatases are thought to cause protein dephosphorylation to control these sequential events. Here, we use budding yeast to analyze phosphorylation dynamics of 3,456 phosphosites on 1,101 proteins with high temporal resolution as cells progress synchronously through mitosis. This reveals that successive inactivation of S and M phase Cdks and of the mitotic kinase Polo contributes to order these dephosphorylation events. Unexpectedly, we detect as many new phosphorylation events as there are dephosphorylation events. These correlate with late mitotic kinase activation and identify numerous candidate targets of these kinases. These findings revise our view of mitotic exit and portray it as a dynamic process in which a range of mitotic kinases contribute to order both protein dephosphorylation and phosphorylation.
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PMID:Phosphoproteome dynamics during mitotic exit in budding yeast. 3017 9

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and key regulator of cell cycle progression. Since APC/C promotes the degradation of mitotic cyclins, it controls cell cycle-dependent oscillations in cyclin-dependent kinase (CDK) activity. Both CDKs and APC/C control a large number of substrates and are regulated by analogous mechanisms, including cofactor-dependent activation. However, whereas substrate dephosphorylation is known to counteract CDK, it remains largely unknown whether deubiquitinating enzymes (DUBs) antagonize APC/C substrate ubiquitination during mitosis. Here, we demonstrate that Cezanne/OTUD7B is a cell cycle-regulated DUB that opposes the ubiquitination of APC/C targets. Cezanne is remarkably specific for K11-linked ubiquitin chains, which are formed by APC/C in mitosis. Accordingly, Cezanne binds established APC/C substrates and reverses their APC/C-mediated ubiquitination. Cezanne depletion accelerates APC/C substrate degradation and causes errors in mitotic progression and formation of micronuclei. These data highlight the importance of tempered APC/C substrate destruction in maintaining chromosome stability. Furthermore, Cezanne is recurrently amplified and overexpressed in numerous malignancies, suggesting a potential role in genome maintenance and cancer cell proliferation.
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PMID:Cezanne/OTUD7B is a cell cycle-regulated deubiquitinase that antagonizes the degradation of APC/C substrates. 2997 62

In nature, cells and in particular unicellular microorganisms are exposed to a variety of nutritional environments. Fission yeast cells cultured in nitrogen-rich media grow fast, divide with a large size and show a short G1 and a long G2. However, when cultured in nitrogen-poor media, they exhibit reduced growth rate and cell size and a long G1 and a short G2. In this study, we compared the phenotypes of cells lacking the highly conserved cyclin-dependent kinase (Cdk) inhibitor Rum1 and the anaphase-promoting complex/cyclosome (APC/C) activator Ste9 in nitrogen-rich and nitrogen-poor media. Rum1 and Ste9 are dispensable for cell division in nitrogen-rich medium. However, in nitrogen-poor medium they are essential for generating a proper wave of MluI cell-cycle box binding factor (MBF)-dependent transcription at the end of G1, which is crucial for promoting a successful S phase. Mutants lacking Rum1 and Ste9 showed premature entry into S phase and a reduced wave of MBF-dependent transcription, leading to replication stress, DNA damage and G2 cell cycle arrest. This work demonstrates how reprogramming the cell cycle by changing the nutritional environment may reveal new roles for cell cycle regulators.
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PMID:Nutritional cell cycle reprogramming reveals that inhibition of Cdk1 is required for proper MBF-dependent transcription. 3015 12

Microcephalin-1 (MCPH1) exists as 2 isoforms that regulate cyclin-dependent kinase-1 activation and chromosome condensation during mitosis, with MCPH1 mutations causing primary microcephaly. MCPH1 is also a tumor suppressor protein, with roles in DNA damage repair/checkpoints. Despite these important roles, there is little information on the cellular regulation of MCPH1. We show that both MCPH1 isoforms are phosphorylated in a cyclin-dependent kinase-1-dependent manner in mitosis and identify several novel phosphorylation sites. Upon mitotic exit, MCPH1 isoforms were degraded by the anaphase-promoting complex/cyclosome-CDH1 E3 ligase complex. Anaphase-promoting complex/cyclosome-CDH1 target proteins generally have D-Box or KEN-Box degron sequences. We found that MCPH1 isoforms are degraded independently, with the long isoform degradation being D-Box dependent, whereas the short isoform was KEN-Box dependent. Our research identifies several novel mechanisms regulating MCPH1 and also highlights important issues with several commercial MCPH1 antibodies, with potential relevance to previously published data.-Meyer, S. K., Dunn, M., Vidler, D. S., Porter, A., Blain, P. G., Jowsey, P. A. Phosphorylation of MCPH1 isoforms during mitosis followed by isoform-specific degradation by APC/C-CDH1.
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PMID:Phosphorylation of MCPH1 isoforms during mitosis followed by isoform-specific degradation by APC/C-CDH1. 3030 38

Cell division cycle (Cdc) kinase subunit (CKS) proteins bind cyclin-dependent kinases (CDKs) and play important roles in cell division control and development, though their precise molecular functions are not fully understood. Mammals express two closely related paralogs called CKS1 and CKS2, but only CKS2 is expressed in the germ line, indicating that it is solely responsible for regulating CDK functions in meiosis. Using cks2^-/- knockout mice, we show that CKS2 is a crucial regulator of maturation-promoting factor (MPF; CDK1-cyclin A/B) activity in meiosis. cks2^-/- oocytes display reduced and delayed MPF activity during meiotic progression, leading to defects in germinal vesicle breakdown (GVBD), anaphase-promoting complex/cyclosome (APC/C) activation, and meiotic spindle assembly. cks2^-/- germ cells express significantly reduced levels of the MPF components CDK1 and cyclins A1/B1. Additionally, injection of MPF plus CKS2, but not MPF alone, restored normal GVBD in cks2^-/- oocytes, demonstrating that GVBD is driven by a CKS2-dependent function of MPF. Moreover, we generated cks2^cks1/cks1 knock-in mice and found that CKS1 can compensate for CKS2 in meiosis in vivo, but homozygous embryos arrested development at the 2- to 5-cell stage. Collectively, our results show that CKS2 is a crucial regulator of MPF functions in meiosis and that its paralog, CKS1, must be excluded from the germ line for proper embryonic development.
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PMID:CKS1 Germ Line Exclusion Is Essential for the Transition from Meiosis to Early Embryonic Development. 3098 59

Cell cycle regulation is essential for the development of multicellular organisms, but many cells in adulthood, including neurons, exit from cell cycle. Although cell cycle-related proteins are suppressed after cell cycle exit in general, recent studies have revealed that growth arrest triggers extra-cell cycle regulatory function (EXCERF) in some cell cycle proteins, such as p27(kip1), p57(kip2), anaphase-promoting complex/cyclosome (APC/C), and cyclin E. While p27 is known to control G1 length and cell cycle exit via inhibition of cyclin-dependent kinase (CDK) activities, p27 acquires additional cytoplasmic functions in growth-arrested neurons. Here, we introduce the EXCERFs of p27 in post-mitotic neurons, mainly focusing on its actin and microtubule regulatory functions. We also show that a small amount of p27 is associated with the Golgi apparatus positive for Rab6, p115, and GM130, but not endosomes positive for Rab5, Rab7, Rab8, Rab11, SNX6, or LAMTOR1. p27 is also colocalized with Dcx, a microtubule-associated protein. Based on these results, we discuss here the possible role of p27 in membrane trafficking and microtubule-dependent transport in post-mitotic cortical neurons. Collectively, we propose that growth arrest leads to two different fates in cell cycle proteins; either suppressing their expression or activating their EXCERFs. The latter group of proteins, including p27, play various roles in neuronal migration, morphological changes and axonal transport, whereas the re-activation of the former group of proteins in post-mitotic neurons primes for cell death.
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PMID:Growth Arrest Triggers Extra-Cell Cycle Regulatory Function in Neurons: Possible Involvement of p27^kip1 in Membrane Trafficking as Well as Cytoskeletal Regulation. 3108 Aug 1


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