RHO GTPases Activate Formins

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Homo sapiens
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Formins are a family of proteins with 15 members in mammals, organized into 8 subfamilies. Formins are involved in the regulation of actin cytoskeleton. Many but not all formin family members are activated by RHO GTPases. Formins that serve as effectors of RHO GTPases belong to different formin subfamilies but they all share a structural similarity to Drosophila protein diaphanous and are hence named diaphanous-related formins (DRFs).

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).

Literature References
PubMed ID Title Journal Year
15507212 Formin is a processive motor that requires profilin to accelerate actin assembly and associated ATP hydrolysis

Carlier, MF, Egile, C, Didry, D, Romero, S, Pantaloni, D, Le Clainche, C

Cell 2004
9497258 A human homologue of the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure: evidence for conserved function in oogenesis and implications for human sterility

Banfi, S, Philippe, C, Arrigo, G, Borsani, G, Ballabio, A, Manzini, C, Toniolo, D, Jonveaux, P, Zuffardi, O, Sala, C, Bione, S, Zuccotti, M

Am. J. Hum. Genet. 1998
21868368 Dynamic remodeling of the actin cytoskeleton by FMNL1? is required for structural maintenance of the Golgi complex

Gomez, TS, Billadeau, DD, Colón-Franco, JM

J. Cell. Sci. 2011
16472745 Structure of the autoinhibitory switch in formin mDia1

Nezami, AG, Poy, F, Eck, MJ

Structure 2006
17198702 RhoB and the mammalian Diaphanous-related formin mDia2 in endosome trafficking

Wallar, BJ, Alberts, AS, Deward, AD, Resau, JH

Exp. Cell Res. 2007
15085137 Cdc42 and mDia3 regulate microtubule attachment to kinetochores

Narumiya, S, Ishizaki, T, Kato, T, Okamoto, M, Yasuda, S, Oceguera-Yanez, F, Yonemura, S, Terada, Y

Nature 2004
12906795 The mouse Formin mDia1 is a potent actin nucleation factor regulated by autoinhibition

Higgs, HN, Li, F

Curr. Biol. 2003
21576392 RhoA and RhoC have distinct roles in migration and invasion by acting through different targets

Ridley, AJ, Vega, FM, Fruhwirth, G, Ng, T

J. Cell Biol. 2011
24914801 Formins as effector proteins of Rho GTPases

Kühn, S, Geyer, M

Small GTPases 2014
12732141 Actin dynamics control SRF activity by regulation of its coactivator MAL

Posern, G, Treisman, R, Miralles, F, Zaromytidou, AI

Cell 2003
10678165 Diaphanous-related formins bridge Rho GTPase and Src tyrosine kinase signaling

McCormick, F, Chardin, P, Courtneidge, SA, Alberts, AS, Tominaga, T, Sahai, E

Mol. Cell 2000
16943183 Autoinhibition regulates cellular localization and actin assembly activity of the diaphanous-related formins FRLalpha and mDia1

Rosen, MK, Otomo, C, Seth, A

J. Cell Biol. 2006
20101212 Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC

Grosse, R, Copeland, JW, Kitzing, TM, Pertz, O, Wang, Y

Oncogene 2010
15006353 Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture

Sagot, I, Moseley, JB, Poy, F, Eck, MJ, Goode, BL, Pellman, D, Xu, Y

Cell 2004
21397845 Aurora B regulates formin mDia3 in achieving metaphase chromosome alignment

Rozier, L, Deng, H, Cheng, L, Mao, Y, Ahmad, S, Yu, H, Zhang, J

Dev. Cell 2011
15944396 RhoB regulates endosome transport by promoting actin assembly on endosomal membranes through Dia1

Janssen, L, Fernandez-Borja, M, Neefjes, J, Hordijk, P, Verwoerd, D

J. Cell. Sci. 2005
11779461 Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1

Kato, Y, He, X, Habas, R

Cell 2001
12577064 RhoD regulates endosome dynamics through Diaphanous-related Formin and Src tyrosine kinase

Kalaidzidis, Y, Gasman, S, Zerial, M

Nat. Cell Biol. 2003
20233848 The small GTPase Rif is an alternative trigger for the formation of actin stress fibers in epithelial cells

Scott, A, Mellor, H, Fan, L, Pellegrin, S

J. Cell. Sci. 2010
16292343 The regulation of mDia1 by autoinhibition and its release by Rho*GTP

Lammers, M, Wittinghofer, A, Scrima, A, Rose, R

EMBO J. 2005
16439214 Control of the assembly of ATP- and ADP-actin by formins and profilin

Pollard, TD, Higgs, HN, Harris, ES, Mahaffy, R, Kovar, DR

Cell 2006
10958683 FRL, a novel formin-related protein, binds to Rac and regulates cell motility and survival of macrophages

Yayoshi-Yamamoto, S, Taniuchi, I, Watanabe, T

Mol. Cell. Biol. 2000
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