Cytoplasmic cyclin D1 regulates cell invasion and metastasis through the phosphorylation of paxillin

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.

This work was funded by Spanish Ministry of Education and Science (BFU2013-42895) (CSD2007-00015), grants BFU2015–71308 and BFU2013–50245-EXP from the Spanish Ministry of Economy and Competitivity, Catalan Government (SGR-559), and Fondo de Investigaciones Sanitarias (PI10/00604). N.P. Fusté was supported by a predoctoral fellowship of University of Lleida-Fundació Alicia Cuello de Merigó, R. Fernández-Hernández (FPI) and T. Cemeli (FPU) were supported by predoctoral fellowships from Spanish Ministry of Education and Science, and C. Mirantes was supported by a predoctoral fellowship of Fondo de Investigaciones Sanitarias