DUSP12 promotes cell cycle progression and protects cells from cell death by regulating ZPR9

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Protein phosphatases, particularly dual specificity phosphatases (DUSPs), are key regulators of cellular processes.
• Dysregulation of DUSPs is linked to cancer development and resistance to therapy.
• DUSP12 is an atypical DUSP with roles in stress response and cell cycle, but its substrates and functions remain largely unknown.

Purpose of the Study:

• To identify novel interactors and functions of DUSP12.
• To elucidate the role of DUSP12 in cell cycle regulation and apoptosis.
• To investigate the molecular mechanism by which DUSP12 influences cell fate.

Main Methods:

• Affinity and proximity-based biochemical purification coupled with mass spectrometry.
• In-cell and in-vitro immunoprecipitation (IP) assays for interaction validation.
• Analysis of phosphorylation, mitotic defects, and apoptosis upon DUSP12 and ZPR9 manipulation.

Main Results:

• ZPR9 was identified as a novel DUSP12 interactor, binding to its unique zinc-binding domain.
• DUSP12 overexpression de-phosphorylated ZPR9 at Ser143.
• ZPR9 overexpression caused mitotic defects, while DUSP12 knockdown also induced mitotic abnormalities.
• DUSP12 knockdown enhanced stress-induced apoptosis, whereas ZPR9 knockdown suppressed it.

Conclusions:

• DUSP12 interacts with ZPR9 and regulates its phosphorylation status.
• DUSP12 protects cells from stress-induced apoptosis, partly through the de-phosphorylation of ZPR9.
• This DUSP12-ZPR9 axis plays a significant role in maintaining cell cycle integrity and promoting cell survival under stress.