JAK2-CHK2 signaling safeguards the integrity of the mitotic spindle assembly checkpoint and genome stability
Ontology highlight
ABSTRACT:
INSTRUMENT(S): LTQ Orbitrap Elite
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Sheau-Yann Shieh
PROVIDER: MSV000087138 | MassIVE | Wed Mar 31 19:22:00 BST 2021
SECONDARY ACCESSION(S): PXD025136
REPOSITORIES: MassIVE
Similar Datasets
Project description:Checkpoint kinase 2 (CHK2) plays an important role in safeguarding the mitotic progression, specifically the spindle assembly, though the mechanism of regulation remains poorly understood. Here, we identified a novel mitotic phosphorylation site on CHK2 Tyr156, and its responsible kinase JAK2. Expression of a phospho-deficient mutant CHK2 Y156F or treatment with JAK2 inhibitor IV compromised mitotic spindle assembly, leading to genome instability. In contrast, a phospho-mimicking mutant CHK2 Y156E restored mitotic normalcy in JAK2-inhibited cells. Mechanistically, we show that this phosphorylation is required for CHK2 interaction with and phosphorylation of the spindle assembly checkpoint (SAC) kinase Mps1, and failure of which results in impaired Mps1 kinetochore localization and defective SAC. Concordantly, analysis of clinical cancer datasets revealed that deletion of JAK2 is associated with increased genome alteration; and alteration in CHEK2 and JAK2 is linked to preferential deletion or amplification of cancer-related genes. Thus, our findings not only reveal a novel JAK2-CHK2 signaling axis that maintains genome integrity through SAC but also highlight the potential impact on genomic stability with clinical JAK2 inhibition.
2024-10-16 | PXD056821 | Pride
Project description:Ibrahim2008 - Mitotic Spindle Assembly Checkpoint - Dissociation variant
The Mitotic Spindle Assembly Checkpoint ((M)SAC) is an evolutionary conserved mechanism. This model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. MCC:APC dissociation is described by two alternatives models, namely the "Dissociation" and the "Convey" model variants. Both these model are available in BioModels Database. This model corresponds to the "Dissociation" variant.
This model is described in the article:
In-silico modeling of the mitotic spindle assembly checkpoint.
Ibrahim B, Diekmann S, Schmitt E, Dittrich P
PLoS One. 2008 Feb 6;3(2):e1555.
Abstract:
BACKGROUND: The Mitotic Spindle Assembly Checkpoint ((M)SAC) is an evolutionary conserved mechanism that ensures the correct segregation of chromosomes by restraining cell cycle progression from entering anaphase until all chromosomes have made proper bipolar attachments to the mitotic spindle. Its malfunction can lead to cancer.
PRINCIPLE FINDINGS: We have constructed and validated for the human (M)SAC mechanism an in silico dynamical model, integrating 11 proteins and complexes. The model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. Originating from the biochemical reactions for the underlying molecular processes, non-linear ordinary differential equations for the concentrations of 11 proteins and complexes of the (M)SAC are derived. Most of the kinetic constants are taken from literature, the remaining four unknown parameters are derived by an evolutionary optimization procedure for an objective function describing the dynamics of the APC:Cdc20 complex. MCC:APC dissociation is described by two alternatives, namely the "Dissociation" and the "Convey" model variants. The attachment of the kinetochore to microtubuli is simulated by a switching parameter silencing those reactions which are stopped by the attachment. For both, the Dissociation and the Convey variants, we compare two different scenarios concerning the microtubule attachment dependent control of the dissociation reaction. Our model is validated by simulation of ten perturbation experiments.
CONCLUSION: Only in the controlled case, our models show (M)SAC behaviour at meta- to anaphase transition in agreement with experimental observations. Our simulations revealed that for (M)SAC activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding.
This model describes the controlled dissociation variant of the mitotic spindle assembly checkpoint. If the tool you use has problems with events, you can uncomment the assignment rules for u and u_prime and comment out the list of events.
In accordance with the authors due to typos in the original publication some initial conditions and parameters were slightly changed in the model:
article
model
[O-Mad2]
1.5e-7 M
1.3e-7 M
[BubR1:Bub3]
1.30e-7 M
1.27e-7 M
k -4
0.01 M -1
s -1
0.02 M -1
s -1
k -5
0.1 M -1
s -1
0.2 M -1
s -1
This model is hosted on BioModels Database
and identified by: MODEL6655615431
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
2024-09-02 | BIOMD0000000186 | BioModels
Project description:Ibrahim2008 - Mitotic Spindle Assembly Checkpoint - Convey variant
The Mitotic Spindle Assembly Checkpoint ((M)SAC) is an evolutionary conserved mechanism. This model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. MCC:APC dissociation is described by two alternatives models, namely the "Dissociation" and the "Convey" model variants. Both these model are available in BioModels Database. This model corresponds to the "Convey" variant.
This model is described in the article:
In-silico modeling of the mitotic spindle assembly checkpoint.
Ibrahim B, Diekmann S, Schmitt E, Dittrich P
PLoS One. 2008 Feb 6;3(2):e1555.
Abstract:
BACKGROUND: The Mitotic Spindle Assembly Checkpoint ((M)SAC) is an evolutionary conserved mechanism that ensures the correct segregation of chromosomes by restraining cell cycle progression from entering anaphase until all chromosomes have made proper bipolar attachments to the mitotic spindle. Its malfunction can lead to cancer.
PRINCIPLE FINDINGS: We have constructed and validated for the human (M)SAC mechanism an in silico dynamical model, integrating 11 proteins and complexes. The model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. Originating from the biochemical reactions for the underlying molecular processes, non-linear ordinary differential equations for the concentrations of 11 proteins and complexes of the (M)SAC are derived. Most of the kinetic constants are taken from literature, the remaining four unknown parameters are derived by an evolutionary optimization procedure for an objective function describing the dynamics of the APC:Cdc20 complex. MCC:APC dissociation is described by two alternatives, namely the "Dissociation" and the "Convey" model variants. The attachment of the kinetochore to microtubuli is simulated by a switching parameter silencing those reactions which are stopped by the attachment. For both, the Dissociation and the Convey variants, we compare two different scenarios concerning the microtubule attachment dependent control of the dissociation reaction. Our model is validated by simulation of ten perturbation experiments.
CONCLUSION: Only in the controlled case, our models show (M)SAC behaviour at meta- to anaphase transition in agreement with experimental observations. Our simulations revealed that for (M)SAC activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding.
This model describes the controlled dissociation variant of the mitotic spindle assembly checkpoint. If the tool you use has problems with events, you can uncomment the assignment rules for u and u_prime and comment out the list of events.
In accordance with the authors due to typos in the original publication some initial conditions and parameters were slightly changed in the model:
article
model
[O-Mad2]
1.5e-7 M
1.3e-7 M
[BubR1:Bub3]
1.30e-7 M
1.27e-7 M
k -4
0.01 M -1
s -1
0.02 M -1
s -1
k -5
0.1 M -1
s -1
0.2 M -1
s -1
This model is hosted on BioModels Database
and identified by: MODEL6655578762
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
2024-09-02 | BIOMD0000000187 | BioModels
Project description:Accurate chromosome segregation is coordinated by the spindle assembly checkpoint (SAC) through its effector the mitotic checkpoint complex (MCC), to inhibit the anaphase-promoting complex or cyclosome (APC/C). Cdc20 is an essential mitotic regulator since it promotes mitotic exit through activating the APC/C and monitors kinetochore-microtubule attachment through activating the SAC. The proper functioning of Cdc20 requires multiple interactions with APC/C and MCC subunits. To functionally assess each of these interactions within cells requires efficient depletion of endogenous Cdc20, which is highly difficult to achieve by RNAi. Here we generated Cdc20 RNAi sensitive cell lines by CRISPR/Cas9 which display a penetrant metaphase arrest phenotype by a single RNAi treatment. In this null background, we accurately measured the contribution of each known motif of Cdc20 on APC/C and SAC activation. The CRY box, a previously identified degron was found to be critical for the SAC by promoting theMCC formation and stabilizing the interaction between the MCC and APC/C. These data reveal additionalregulatory components within the SAC and establish a novel method to interrogate Cdc20 function.
2023-12-06 | PXD045411 | Pride
Project description:Treating ICB-resistant glioma with anti-CD40 and mitotic spindle checkpoint controller BAL101553 (lisavanbulin)
| PRJNA773260 | ENA
Project description:Upregulation of the proto-oncogene TCL1A is causally implicated in various B- and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, molecular and cell-biological consequences of TCL1A dysregulation are not fully elucidated. To analyze if TCL1A’s oncogenic activity depends on its subcellular localization, we transduced murine hematopoietic stem cells and progenitor cells (HSC/HPC) with three different human TCL1A variants, being wild type, membrane-localized myristoylated (myr) TCL1A, and TCL1A fused to a nuclear localization signal (nls). All three groups developed mostly B-cell leukemias/lymphomas and less frequently CD4/CD8 double-positive or double-negative T-cell leukemia/lymphomas. Mice transplanted with cells expressing nls-hTCL1A had a significantly shorter survival in comparison to mice harboring wt TCL1A. Gene set enrichment analysis of gene expression profiling data from B-cell tumors identified nuclear pathways including DNA repair, cell cycle, and mitotic spindle to be enriched in the nls-hTCL1A over the hTCL1A cohort.
2022-11-14 | GSE192409 | GEO
Project description:The spindle checkpoint is a mitotic surveillance system which ensures equal segregation of sister chromatids. It delays anaphase onset by inhibiting the action of the E3 ubiquitin ligase known as the anaphase promoting complex or cyclosome (APC/C). Mads/BubR1 is a key component of the mitotic checkpoint complex (MCC) which binds and inhibits the APC/C early in mitosis. Mps1Mph1 kinase is critical for checkpoint signalling and MCC-APC/C inhibition, yet few substrates have been identified. Here we identify Mad3 as a substrate of fission yeast Mps1Mph1 kinase. We map and mutate phosphorylation sites in Mad3, producing mutants that are targeted to kinetochores and assembled into MCC, yet display reduced APC/C binding and are unable to maintain checkpoint arrests. We chow biochemically that Mad3 phospho-mimics are potent APC/C inhibitors in vitro, demonstrating that Mad3p modification can directly influence Cdc20Slp1-APC/C activity. This genetic dissection of APC/C inhibition demonstrates that Mps1Mph1 kinase-dependant modification of Mad3 and Mad2 act in a concerted manner to maintain spindle checkpoint arrests.
2016-03-31 | PXD003806 | Pride
Project description:SUMMARY Mps1 protein kinase is required for accurate chromosome segregation during the mitotic checkpoint. The molecular chaperone Heat Shock Protein 90 (Hsp90) has been linked to Mps1 activity, however the molecular mechanismsunderlying this regulatory process remain elusive. We report that Mps1 directly phosphorylates a conserved threonine residue (T101 in yeast Hsp90 and T115 in human Hsp90) in the N domain of Hsp90. This phosphorylation regulates chaperone function by reducingHsp90 ATPase activity andfosteringits association with kinase client proteins including Mps1. Phosphorylation of T101is also essential for the mitotic checkpoint because it confers Mps1 stability and activity.Additionally,Mps1 phosphorylation of Hsp90 sensitizes cells to Hsp90 inhibitors and elevated Mps1 levels confer tumor selectivity on Hsp90 drugs.Finally,we identified Cdc14 as the phosphatasethat dephosphorylatesT101 and disruptsthe Mps1-Hsp90 interaction. This leads to degradation of Mps1,thusproviding a mechanism for its inactivation and mitotic exit.
2016-01-27 | PXD001969 | Pride
Project description:The proto-oncogene TCL1A deregulates mitotic checkpoint transition and genomic stability in CLL
| PRJNA791361 | ENA
Project description:During metaphase, in response to improper kinetochore-microtubule attachments, the spindle assembly checkpoint (SAC) activates the mitotic checkpoint complex (MCC) to inhibit the anaphase-promoting complex/cyclosome (APC/C). The Mad1-Mad2 complex provides a catalytic platform for MCC assembly. Mad1-bound Mad2 recruits open-Mad2 through asymmetric dimerization and Mad1 phosphorylation by Mps1 promotes conversion of Mad2 from an open (O-Mad2) to closed (C-Mad2) state, which binds Cdc20 to form the MCC. How Mad1 phosphorylation catalytically activates MCC formation is poorly understood. This study characterises Mad1 phosphorylation by Mps1 and provides structural and biochemical insights into a phosphorylation-specific Mad1-Cdc20 interaction, which allows for a tripartite assembly of Bub1-Mad1-Cdc20 on the C-terminal domain of Mad1. We also identify a folded state of Mad1-Mad2 complex, suggesting a model by which the Cdc20-Mad1 interaction brings the Cdc20 MIM motif near Mad2. The Cdc20 MIM motif is then entrapped by the Mad2 safety belt to form a stable complex, allowing spontaneous MCC assembly.
2023-03-11 | PXD031872 | Pride