Cyclin D1/D2–CDK4 Drives Cell Migration by Orchestrating Cytoskeletal Dynamics Through a TGFβ–FAK–Rac1 Axis
Issued Date
2026-02-01
Resource Type
ISSN
16616596
eISSN
14220067
Scopus ID
2-s2.0-105030113404
Journal Title
International Journal of Molecular Sciences
Volume
27
Issue
3
Rights Holder(s)
SCOPUS
Bibliographic Citation
International Journal of Molecular Sciences Vol.27 No.3 (2026)
Suggested Citation
Guo R., Wang Y., Zhang A., Jirawatnotai S., Chu C., Liu L. Cyclin D1/D2–CDK4 Drives Cell Migration by Orchestrating Cytoskeletal Dynamics Through a TGFβ–FAK–Rac1 Axis. International Journal of Molecular Sciences Vol.27 No.3 (2026). doi:10.3390/ijms27031228 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/115204
Title
Cyclin D1/D2–CDK4 Drives Cell Migration by Orchestrating Cytoskeletal Dynamics Through a TGFβ–FAK–Rac1 Axis
Corresponding Author(s)
Other Contributor(s)
Abstract
Beyond their canonical role in promoting G1/S progression, the complexes formed by cyclin D and cyclin-dependent kinase (CDK) 4/6 have emerged as contributors to enhanced cell migration. However, a direct link between this complex and cytoskeletal remodeling during cell motility has remained poorly understood. Here, we show that CDK4/6 inhibition in HeLa cells disrupts lamellipodia formation and subsequent focal adhesion assembly, leading to a reduction in cell migration and invasion. Notably, CDK4, but not CDK6, in complex with cyclin D1/D2, localizes to membrane ruffles to facilitate cytoskeletal reorganization. Mechanistically, proteomic and phosphoproteomic analyses revealed that CDK4 inhibition attenuates the transforming growth factor β (TGFβ) pathway via reduced Smad3 phosphorylation at Thr8, downregulating integrin subunits (α5, α6, and β1). Furthermore, CDK4 inhibition significantly decreased focal adhesion kinase (FAK) phosphorylation at Tyr397 and Rac1-GTP levels. Importantly, the resulting migration defect was largely restored by activation of either Rac1 or FAK. Thus, our data support a model in which cyclin D1/D2–CDK4 promotes phosphorylation of Smad3, leading to upregulation of integrin subunits, activation of FAK and Rac1, and consequent lamellipodia formation and cell migration. These findings provide direct evidence that CDK4 regulates actin cytoskeletal reorganization during cell migration and suggest that CDK4/6 inhibitors may dampen cytoskeleton-dependent tumor invasion, in addition to their antiproliferative effects.