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.

Cyclin D1 promotes tumor cell invasion and metastasis by cytoplasmic mechanisms

“…As mentioned above, Ccnd1 induces invasion through the phosphorylation of paxillin in the cell membrane. 5 In agreement with this, we have observed that a phosphomimetic allele of paxillin rescues the metastatic potential of Ccnd1-deficient cells without affecting their proliferative state. This also agrees with the reported requirement for phospho-Pxn for the induction of metastases in different tumor models.…”

“…For instance, Ccnd1 has been shown to interact with filamin A (FLNA) and to co-localize with this protein in membrane ruffles. 8 Our recent contribution confirms that a subpopulation of the Ccnd1 protein is localized in the membrane, 5 together with paxillin and active Rac1, and strongly suggests that this localization is functionally relevant in the regulation of cell adhesion and invasion. Hence, we provide new and compelling evidence that cytoplasmic Ccnd1 has an important role in regulating different pathways to induce migration and invasion.…”

“…In a recent study we identified another member of this repertoire, the GTPase RAC1, and showed that Ccnd1 regulates cell adhesion and migration via activation of this small GTPase. 5 The Ccnd1-Cdk4 complex reduces cell adhesion and increases cell migration/invasion through the phosphorylation of paxillin (PXN) at serines 83 and 178. Although paxillin is a scaffold protein that is mainly localized at focal adhesions we have shown that a subpopulation of paxillin and Ccnd1 exclusively co-localizes at the cell membrane, and that Ccnd1-Cdk4 triggers the accumulation of Rac1-GTP in a manner that depends on its ability to phosphorylate paxillin.…”

The role of Sox6 and Netrin-1 in ovarian cancer cell growth, invasiveness, and angiogenesis

“…Recent studies have demonstrated that cyclinD1 has been associated with tumor invasion and metastasis in clinical studies and in vivo experiments, and cyclin D1 regulates invasion and metastasis through the phosphorylation of paxillin. [24][25][26] In addition to the suppression of cell growth by SOX6 in the ovarian cancer cells, inhibitory effect of SOX6 on ovarian cancer cell invasion was also observed in this study, suggesting that SOX6 may prevent metastasis of ovarian tumors. The SOX family of transcription factors has emerged as modulators of canonical Wnt/β-catenin signaling in diverse development and disease contexts.…”

Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction

“…Furthermore, cyclin D1 was highly immune reactive in the cytoplasm of Bmpr2 fl/+ MPCs and in the nuclei of βOE MPCs. Cytoplasmic cyclin D1 can regulate invasion as well as survival (37), while nuclear localization is typically associated with proliferation and survival (38).…”