Methylation Signals Outside the Nucleus

Abstract

Ezh2 is a member of the polycomb group of proteins and functions in the control of development by catalyzing methylation of lysine residues on histone proteins, thereby causing changes in gene expression. However, Ezh2 exists in the cytoplasm as well as in the nucleus, so Su et al. explored whether the enzyme might have functions independent of its known role in modification of chromatin in the nucleus. Ezh2 has been reported to associate with the guanine nucleotide exchange factor Vav1, which is an important component of T cell signaling, particularly changes in actin polymerization in response to stimulation of the T cell receptor (TCR). Studies of mouse peripheral T cells confirmed interaction of Ezh2 with Vav. Furthermore, T cells lacking Ezh-2 had defective TCR-induced actin polymerization and an impaired proliferative response. Similarly, mouse embryo fibroblasts lacking Ezh2 showed decreased actin polymerization in response to fibroblast growth factor and failed to form surface ruffles normally seen in platelet-derived growth factor (PDGF)-treated cells. These effects could be rescued by expression of a modified form of Ezh2 that was not localized to the nucleus, supporting a role for the cytoplasmic protein independent of its nuclear effects. Proliferation in response to PDGF was also reduced in cells lacking Ezh2. The presumed cytoplasmic methylation target of Ezh2 remains unknown but appears to act at a point between TCR activation and activation of the guanosine triphosphatase (GTPase) Cdc42. Vav1, though, appears not to be modified by Ezh2. Together, the findings indicate that posttranslational modification by methylation has key regulatory roles outside the nucleus, with implications for immune responses to the TCR and cancer biology, where increased expression of Ezh2 in cancer cells is associated with increased metastatic capacity. I-h. Su, M.-W. Dobenecker, E. Dickinson, M. Oser, A. Basavaraj, R. Marqueron, A. Viale, D. Reinberg, C. Wulfing, A. Tarakhovsky, Polycomb group protein Ezh2 controls actin polymerization and cell signaling. Cell 121 , 425-436. [Online Journal]