Age-related guanine nucleotide exchange factor, mouse Zizimin2, induces filopodia in bone marrow-derived dendritic cells

In this study, we show that the protein expression of Zizimin2, which is also restricted to lymphoid tissues and lymphocytes, is reduced in aged mice. Over-expression of full-length Zizimin2 induced filopodial formation in 293T cells, whereas expression of CZH2 domain inhibited it. Stimulation of Fcγ receptor and Toll-like receptor 4 triggered Zizimin2 up-regulation and Cdc42 activation in bone marrow-derived dendritic cells.These data suggest that Zizimin2 is an immune-related and age-regulated guanine nucleotide exchange factor, which facilitates filopodial formation through activation of Cdc42, which results in activation of cell migration.Zizimin2, also called Dock11 (dedicator of cytokinesis 11), has been reported as one of the human Dock180 super-family proteins [1]. We recently identified Zizimin2 as a 238-kDa protein that is highly expressed in germinal center B lymphocytes after T-cell-dependent antigen immunization [2]. The expression of this gene is regulated in lymphocytes and organs, such as spleen, thymus, and lymph nodes [2,3]. It has been shown that Zizimin2 binds and activates nucleotide-free Cdc42 via its CZH2 [CDM(ced5/DOCK180/myoblast city)-Zizimin homology 2] domain [4] and mediates positive feedback on the active form, GTP-bound Cdc42 [5]. Cdc42, one of the well-known Rho family members, regulates signaling pathways that control diverse cellular functions including morphology, migration, endocytosis, and cell cycle progression [6-8]. These reports suggest that Zizimin2 has a role in regulating the pathway downstream of Cdc42, leading to cellular functions.Cdc42 affects the formation of highly dynamic finger-like actin-rich protrusions known as filopodia. Filopodia contain parallel bundles of filamentous F-actin, and are thought to be important for sensing the environment, for example, guidance toward chemoattractants [9,10]. Cdc42 induces filopodia and lamellipodia in activated B cells [11]. Microinjection of constitutively active Cdc42 stimula