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<p>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 depletion of NPM1 disrupts centrosome clustering and suppresses malignant growth. In vivo studies revealed that LIMK2 knockout significantly attenuates 4-nitroquinoline-1-oxide (4NQO) induced esophageal tumorigenesis in murine models. Therapeutic targeting of LIMK2 through shRNA-mediated knock down or pharmacological inhibition (CRT0105950) suppresses centrosome clustering by preventing “pseudo-bipolar” spindle formation, inducing mitosis arrest. This centrosome de-clustering promotes multipolar spindle assembly, ultimately triggering apoptotic cell death. Notably, CRT0105950 treatment effectively suppressed cell-derived xenograft tumor growth. Our findings elucidate the pivotal role of the LIMK2/MST4/NPM1 pathway in cancer progression and establish a novel therapeutic paradigm for broad-spectrum anticancer intervention.</p>

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LIMK2 promotes centrosome clustering and cancer progression by activating MST4-mediated phosphorylation of NPM1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月7日

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  • Jie Tian,
  • Shihui Liu,
  • Yunqing Zhang,
  • Huajie Jia,
  • Wenna Nie,
  • Ran Yang,
  • Mengmeng Ge,
  • Kangdong Liu,
  • Mengqiu Song,
  • Zigang Dong

摘要

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 depletion of NPM1 disrupts centrosome clustering and suppresses malignant growth. In vivo studies revealed that LIMK2 knockout significantly attenuates 4-nitroquinoline-1-oxide (4NQO) induced esophageal tumorigenesis in murine models. Therapeutic targeting of LIMK2 through shRNA-mediated knock down or pharmacological inhibition (CRT0105950) suppresses centrosome clustering by preventing “pseudo-bipolar” spindle formation, inducing mitosis arrest. This centrosome de-clustering promotes multipolar spindle assembly, ultimately triggering apoptotic cell death. Notably, CRT0105950 treatment effectively suppressed cell-derived xenograft tumor growth. Our findings elucidate the pivotal role of the LIMK2/MST4/NPM1 pathway in cancer progression and establish a novel therapeutic paradigm for broad-spectrum anticancer intervention.