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CDK4 maintains cytoskeletal homeostasis by restraining actomyosin contractility

ABSTRACT: Cyclin-dependent kinase 4 (CDK4) is best known for its canonical role in cell-cycle control, yet how CDK4 activity intersects with cellular architecture remains poorly defined. Here, we uncover a non-canonical function of CDK4 in maintaining cytoskeletal mechanical homeostasis in triple-negative breast cancer (TNBC) cells. We show that CDK4 phosphorylates the RhoA-targeting RhoGAP Myo9b at serine 1935, enhancing its GAP activity and restraining RhoA–ROCK–pMLC-dependent actomyosin contractility. Loss or inhibition of CDK4 alters cell morphology, disrupts actin organization, and increases contractility. Elevated contractility in CDK4-deficient cells induces collapse of the intermediate filament network, characterized by Vimentin reorganization and mitochondrial redistribution, indicating a higher-order defect in cytoskeletal architecture. Furthermore, CDK4 expression negatively correlates with pMLC levels in both mouse TNBC tumors and human breast cancer samples, supporting the physiological relevance of this pathway. Together, these findings identify CDK4 as a regulator of cellular mechanical stability, integrating actin dynamics, intermediate filament integrity, and organelle positioning, and reveal an unexpected role for CDK4 beyond cell-cycle regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336354 | GEO | 2026/06/28

REPOSITORIES: GEO

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Cyclin Dependent Kinase 4 (CDK4) maintains cell cytoskeleton integrity and behavior in Triple Negative Breast Cancer (TNBC) cells

Project description:Cyclin-Dependent Kinase 4 (CDK4) is best known for its role in cell cycle progression, but its contribution to cellular architecture is less understood. Here, we identify CDK4 as a regulator of cytoskeletal homeostasis in triple-negative breast cancer (TNBC). CDK4 phosphorylates the RhoGAP Myo9b at serine 1935, enhancing its activity and suppressing RhoA–ROCK–mediated actomyosin contractility. Loss or inhibition of CDK4 disrupts cell morphology, destabilizes the actin cytoskeleton, and increases contractility, alongside collapse of the intermediate filament network, including vimentin disorganization and altered mitochondrial distribution. CDK4-deficient cells also show faster but less directed migration. In vivo, tumors derived from CDK4WT and CDK4KO MDA-MB-231 cells implanted in the mammary fat pad display elevated pMLC levels by IHC, consistent with increased contractility, while proteomic analysis reveals enrichment of cytoskeletal pathways. Transcriptomic analyses (SCAN-B, TCGA, I-SPY2) further show that low CDK4 activity correlates with enhanced EMT, migration, metastasis, and RhoA signaling programs in TNBC. Together, these findings establish CDK4 as an upstream regulator of cytoskeletal integrity, linking actin dynamics, intermediate filament organization, and cell behavior, and reveal a structural role beyond its canonical function in cell cycle control.

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