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

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

Cell death & disease (2022-07-20)
Md Al Nayem Chowdhury, Shih-Wei Wang, Ching-Shu Suen, Ming-Jing Hwang, Yi-An Hsueh, Sheau-Yann Shieh
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Chk2 Inhibitor II hydrate, ≥98% (HPLC)
Roche
cOmplete, EDTA-free Protease Inhibitor Cocktail, Tablets provided in EASYpacks
Sigma-Aldrich
Nocodazole, ≥99% (TLC), powder
Sigma-Aldrich
JAK2 Inhibitor IV, The JAK2 Inhibitor IV, also referenced under CAS 1110502-30-1, controls the biological activity of JAK2. This small molecule/inhibitor is primarily used for Phosphorylation & Dephosphorylation applications.