Abstract
Cyclin D1 (Ccnd1) together with its binding partner Cdk4 act as a transcriptional regulator to control cell proliferation and migration, and abnormal Ccnd1·Cdk4 expression promotes tumour growth and metastasis. While different nuclear Ccnd1·Cdk4 targets participating in cell proliferation and tissue development have been identified, little is known about how Ccnd1·Cdk4 controls cell adherence and invasion. Here, we show that the focal adhesion component paxillin is a cytoplasmic substrate of Ccnd1·Cdk4. This complex phosphorylates a fraction of paxillin specifically associated to the cell membrane, and promotes Rac1 activation, thereby triggering membrane ruffling and cell invasion in both normal fibroblasts and tumour cells. Our results demonstrate that localization of Ccnd1·Cdk4 to the cytoplasm does not simply act to restrain cell proliferation, but constitutes a functionally relevant mechanism operating under normal and pathological conditions to control cell adhesion, migration and metastasis through activation of a Ccnd1·Cdk4-paxillin-Rac1 axis.
Highlights
Cyclin D1 (Ccnd1) together with its binding partner Cdk[4] act as a transcriptional regulator to control cell proliferation and migration, and abnormal Ccnd[1] Á Cdk[4] expression promotes tumour growth and metastasis
We show that the Ccnd[1] Á Cdk[4] complex phosphorylates a subpopulation of Pxn present in membrane ruffles but not in focal adhesions (FAs), which is functionally relevant in the control of cell spreading and invasion in both normal fibroblasts and tumour cells
It is widely accepted that the accumulation of Ccnd[1] in the cytoplasm operates only as a sequestration mechanism to prevent cell proliferation[27,28], our results demonstrate that cytoplasmic Ccnd[1] has an active role in the induction of cell migration and invasion
Summary
Cyclin D1 (Ccnd1) together with its binding partner Cdk[4] act as a transcriptional regulator to control cell proliferation and migration, and abnormal Ccnd[1] Á Cdk[4] expression promotes tumour growth and metastasis. We show that the focal adhesion component paxillin is a cytoplasmic substrate of Ccnd[1] Á Cdk[4] This complex phosphorylates a fraction of paxillin associated to the cell membrane, and promotes Rac[1] activation, thereby triggering membrane ruffling and cell invasion in both normal fibroblasts and tumour cells. We show that the Ccnd[1] Á Cdk[4] complex phosphorylates a subpopulation of Pxn present in membrane ruffles but not in FAs, which is functionally relevant in the control of cell spreading and invasion in both normal fibroblasts and tumour cells. Our results indicate that there is a specific and direct interaction between Pxn and Ccnd[1] Á Cdk[4] at endogenous levels in unperturbed cells
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