PLK1

PLK1 phosphorylates and activates the transcription factor FOXM1 which stimulates the expression of a number of genes needed for G2/M transition, including PLK1, thereby creating a positive feedback loop (Laoukili et al. 2005, Fu et al. 2008, Sadasivam et al. 2012, Chen et al. 2013)

DRFs activated by RHO GTPases contain a GTPase binding domain (GBD) at their N-terminus, followed by formin homology domains 3, 1, and 2 (FH3, FH1, FH2) and a diaphanous autoregulatory domain (DAD) at the C-terminus. Most DRFs contain a dimerization domain (DD) and a coiled-coil region (CC) in between FH3 and FH1 domains (reviewed by Kuhn and Geyer 2014). RHO GTPase-activated DRFs are autoinhibited through the interaction between FH3 and DAD which is disrupted upon binding to an active RHO GTPase (Li and Higgs 2003, Lammers et al. 2005, Nezami et al. 2006). Since formins dimerize, it is not clear whether the FH3-DAD interaction is intra- or intermolecular. FH2 domain is responsible for binding to the F-actin and contributes to the formation of head-to-tail formin dimers (Xu et al. 2004). The proline-rich FH1 domain interacts with the actin-binding proteins profilins, thereby facilitating actin recruitment to formins and accelerating actin polymerization (Romero et al. 2004, Kovar et al. 2006).

Different formins are activated by different RHO GTPases in different cell contexts. FMNL1 (formin-like protein 1) is activated by binding to the RAC1:GTP and is involved in the formation of lamellipodia in macrophages (Yayoshi-Yamamoto et al. 2000) and is involved in the regulation of the Golgi complex structure (Colon-Franco et al. 2011). Activation of FMNL1 by CDC42:GTP contributes to the formation of the phagocytic cup (Seth et al. 2006). Activation of FMNL2 (formin-like protein 2) and FMNL3 (formin-like protein 3) by RHOC:GTP is involved in cancer cell motility and invasiveness (Kitzing et al. 2010, Vega et al. 2011). DIAPH1, activated by RHOA:GTP, promotes elongation of actin filaments and activation of SRF-mediated transcription which is inhibited by unpolymerized actin (Miralles et al. 2003). RHOF-mediated activation of DIAPH1 is implicated in formation of stress fibers (Fan et al. 2010). Activation of DIAPH1 and DIAPH3 by RHOB:GTP leads to actin coat formation around endosomes and regulates endosome motility and trafficking (Fernandez-Borja et al. 2005, Wallar et al. 2007). Endosome trafficking is also regulated by DIAPH2 transcription isoform 3 (DIAPH2-3) which, upon activation by RHOD:GTP, recruits SRC kinase to endosomes (Tominaga et al. 2000, Gasman et al. 2003). DIAPH2 transcription isoform 2 (DIAPH2-2) is involved in mitosis where, upon being activated by CDC42:GTP, it facilitates the capture of astral microtubules by kinetochores (Yasuda et al. 2004, Cheng et al. 2011). DIAPH2 is implicated in ovarian maintenance and premature ovarian failure (Bione et al. 1998). DAAM1, activated by RHOA:GTP, is involved in linking WNT signaling to cytoskeleton reorganization (Habas et al. 2001)

In G1 cells, GTSE1 is found at the microtubule lattice, likely due to direct binding to tubulin. An evolutionarily conserved interaction between GTSE1 and MAPRE1 (EB1), a microtubule plus end protein, promotes GTSE1 localization to the growing tip of the microtubules, which contributes to cell migration and is likely involved in cancer cell invasiveness. Highly invasive breast cancer cell lines exhibit high GTSE1 levels in G1, while GTSE1 levels in G1 are normally low. At the beginning of mitotic prometaphase, GTSE1 is phosphorylated by mitotic kinase(s), possibly CDK1, in proximity to the MAPRE1-binding region, causing GTSE1 dissociation from the plus end microtubule ends (Scolz et al. 2012).

During G2 checkpoint recovery (cell cycle re-entry after DNA damage induced G2 arrest), GTSE1 relocates to the nucleus where it binds TP53 and, in an MDM2-dependent manner, promotes TP53 cytoplasmic translocation and proteasome mediated degradation (Monte et al. 2003, Monte et al. 2004). Relocation of GTSE1 to the nucleus in G2 phase depends on PLK1-mediated phosphorylation of GTSE1 (Liu et al. 2010).

GTSE1-facilitated down-regulation of TP53 in G2 allows cells to avoid TP53 mediated apoptosis upon DNA damage and to re-enter cell cycle (Monte et al. 2003). While TP53 down-regulation mediated by GTSE1 in G2 correlates with decreased expression of TP53 target genes involved in apoptosis and cell cycle arrest, GTSE1 can also increase the half-life of the TP53 target p21 (CDKN1A). GTSE1-mediated stabilization of CDKN1A involves interaction of GTSE1 with CDKN1A and its chaperone complex, consisting of HSP90 and FKBPL (WISp39), and may be involved in resistance to paclitaxel treatment (Bublik et al. 2010)