biostudies-literatureTian JChina Postdoctoral Science FoundationScience and Technology Department of Henan Province (Henan Provincial Department of Science and Technology)National Natural Science Foundation of China (National Science Foundation of China)3625-3639https://www.ebi.ac.uk/biostudies/studies/S-EPMC12436196biostudies-literatureUnknown44(38)Centrosome amplification, a hallmark of diverse malignancies, enables cancer cell survival through centrosome clustering during mitosis, presenting a promising therapeutic target for selective elimination of cancer cells with supernumerary centrosomes. While the regulatory mechanisms underlying centrosome clustering remain poorly understood, our study identifies LIM kinase 2 (LIMK2) as a critical regulator of this process, demonstrating cancer correlation with tumor progression. Mechanistically, LIMK2 phosphorylates mammalian sterile-20-like kinase 4 (MST4) at threonine 178 (T178), activating its kinase function. Activated MST4 subsequently binds and phosphorylates nucleophosmin 1 (NPM1) at T95, a modification essential for centrosome clustering and tumor cell proliferation. Genetic depletOncogeneLIMK2 promotes centrosome clustering and cancer progression by activating MST4-mediated phosphorylation of NPM1.PMC124361962421023112182023M733222820711215382073075Tian JLiu KSong MZhang YDong ZJia HYang RGe MLiu SNie WfalseLIMK2 promotes centrosome clustering and cancer progression by activating MST4-mediated phosphorylation of NPM1.Centrosome amplification, a hallmark of diverse malignancies, enables cancer cell survival through centrosome clustering during mitosis, presenting a promising therapeutic target for selective elimination of cancer cells with supernumerary centrosomes. While the regulatory mechanisms underlying centrosome clustering remain poorly understood, our study identifies LIM kinase 2 (LIMK2) as a critical regulator of this process, demonstrating cancer correlation with tumor progression. Mechanistically, LIMK2 phosphorylates mammalian sterile-20-like kinase 4 (MST4) at threonine 178 (T178), activating its kinase function. Activated MST4 subsequently binds and phosphorylates nucleophosmin 1 (NPM1) at T95, a modification essential for centrosome clustering and tumor cell proliferation. Genetic deplet2025-01-01T00:00:00Z2025 Oct2026-06-03T03:02:26.092Z2026-04-23T03:13:56.628ZS-EPMC124361964077539710.1038/s41388-025-03518-6