Dataset Information

JAK2-CHK2 signaling safeguards the integrity of the mitotic spindle assembly checkpoint and genome stability

ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Fu-An Li

LAB HEAD: Sheau-Yann Shieh

PROVIDER: PXD056821 | Pride | 2024-10-16

REPOSITORIES: Pride

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JAK2-CHK2 signaling safeguards the integrity of the mitotic spindle assembly checkpoint and genome stability.

Chowdhury Md Al Nayem MAN Wang Shih-Wei SW Suen Ching-Shu CS Hwang Ming-Jing MJ Hsueh Yi-An YA Shieh Sheau-Yann SY

Cell death & disease 20220718 7

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 Y15 ...[more]

PMID: 35851582

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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.

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.

			Action	DRS
	160118-1-1-CHK2-NOC.raw	Raw
	160118-1-2-CHK2.raw	Raw
	160118-1-3-KD-NOC.raw	Raw
	160118-1-4-KD.raw	Raw
	F005970.mgf	Mgf