Life sciences · 2026
MAPK1 phosphorylates CCNB1 at Ser128 to drive mitotic progression and cell proliferation in triple-negative breast cancer.
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Han Beinan, Zhu Xiangping, Han Zhiren, Zhang Jijun, Zhong Jiaxin, Zhao Yiming, Wang Pei, Weng Haiyan, Zhou Ziwei, Wu Jie, Li Hongde
Аннотация
AIMS: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking effective targeted therapies. The MAPK pathway is frequently activated in TNBC, but clinical responses to MAPK inhibitors remain limited, largely due to adverse effects and adaptive resistance. MAPK1 (ERK2) is well known to promote tumor progression primarily by phosphorylating transcription factors that regulate gene expression, yet its downstream substrates beyond transcription factors remains poorly defined. Identifying these noncanonical substrates is crucial for uncovering alternative MAPK1-driven oncogenic mechanisms and may reveal therapeutic vulnerabilities to overcome the limitations of MAPK pathway inhibition.
MATERIALS AND METHODS: TurboID-based proximity labeling coupled with mass spectrometry was performed in TNBC cells to identify MAPK1-interacting proteins. Biochemical assays, including co-immunoprecipitation and in vitro kinase assays, were performed to confirm MAPK1-substrate interactions. Generation of CCNB1-Ser128 mutants, nuclear-cytoplasmic fractionation, immunofluorescence, cell cycle analysis, and in vivo xenograft experiments were conducted to determine functional consequences.
KEY FINDINGS: Cyclin B1 (CCNB1), a key regulator of early mitotic entry, was identified as a MAPK1-associated protein. MAPK1 phosphorylates CCNB1 at serine 128, and this modification facilitates CCNB1 nuclear translocation and the G2-to-prophase transition. Pharmacological inhibition or genetic depletion of MAPK1 reduced CCNB1 Ser128 phosphorylation and impaired mitotic progression. The phospho-mimetic CCNB1-S128D mutant partially rescued proliferation defects induced by MAPK1 knockdown.
SIGNIFICANCE: These findings expand the functional scope of MAPK1 beyond transcriptional regulation and identify CCNB1 Ser128 phosphorylation as a key effector mechanism linking MAPK signaling to mitotic control in TNBC. The MAPK1-CCNB1 axis may represent a mechanistically informed therapeutic target for TNBC.
MATERIALS AND METHODS: TurboID-based proximity labeling coupled with mass spectrometry was performed in TNBC cells to identify MAPK1-interacting proteins. Biochemical assays, including co-immunoprecipitation and in vitro kinase assays, were performed to confirm MAPK1-substrate interactions. Generation of CCNB1-Ser128 mutants, nuclear-cytoplasmic fractionation, immunofluorescence, cell cycle analysis, and in vivo xenograft experiments were conducted to determine functional consequences.
KEY FINDINGS: Cyclin B1 (CCNB1), a key regulator of early mitotic entry, was identified as a MAPK1-associated protein. MAPK1 phosphorylates CCNB1 at serine 128, and this modification facilitates CCNB1 nuclear translocation and the G2-to-prophase transition. Pharmacological inhibition or genetic depletion of MAPK1 reduced CCNB1 Ser128 phosphorylation and impaired mitotic progression. The phospho-mimetic CCNB1-S128D mutant partially rescued proliferation defects induced by MAPK1 knockdown.
SIGNIFICANCE: These findings expand the functional scope of MAPK1 beyond transcriptional regulation and identify CCNB1 Ser128 phosphorylation as a key effector mechanism linking MAPK signaling to mitotic control in TNBC. The MAPK1-CCNB1 axis may represent a mechanistically informed therapeutic target for TNBC.