PXD056821-1

PXD056821 is an original dataset announced via ProteomeXchange.

Title	JAK2-CHK2 signaling safeguards the integrity of the mitotic spindle assembly checkpoint and genome stability
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.
HostingRepository	PRIDE
AnnounceDate	2024-10-16
AnnouncementXML	Submission_2024-10-15_23:29:35.083.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD056821
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Fu-An Li
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-15 09:53:43	ID requested
⏵ 1	2024-10-15 23:29:44	announced

10.6019/PXD056821;

10.1038/S41419-022-05077-0;

Chowdhury MAN, Wang SW, Suen CS, Hwang MJ, Hsueh YA, Shieh SY, JAK2-CHK2 signaling safeguards the integrity of the mitotic spindle assembly checkpoint and genome stability. Cell Death Dis, 13(7):619(2022) [pubmed]

10.1038/s41419-022-05077-0;

submitter keyword: Phosphorylation, CHK2, LC-MS/MS

Sheau-Yann Shieh
contact affiliation	Institute of Biomedical Sciences, Academia Sinica
contact email	sy88@ibms.sinica.edu.tw
lab head
Fu-An Li
contact affiliation	Institute of Biomedical Sciences, Academia Sinica
contact email	falee@ibms.sinica.edu.tw
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD056821
     1. Label: PRIDE project
     2. Name: JAK2-CHK2 signaling safeguards the integrity of the mitotic spindle assembly checkpoint and genome stability