Reactome | RHO GTPases Activate Formins

RHO GTPases Activate Formins

Stable Identifier

R-HSA-5663220

Type

Pathway

Species

Homo sapiens

Compartment

cytosol, endosome membrane, nucleoplasm, plasma membrane

ReviewStatus

5/5

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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 Romero, S, Le Clainche, C, Didry, D, Egile, C, Pantaloni, D, Carlier, MF	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 Bione, S, Sala, C, Manzini, C, Arrigo, G, Zuffardi, O, Banfi, S, Borsani, G, Jonveaux, P, Philippe, C, Zuccotti, M, Ballabio, A, Toniolo, D	Am. J. Hum. Genet.	1998
21868368	Dynamic remodeling of the actin cytoskeleton by FMNL1? is required for structural maintenance of the Golgi complex Colón-Franco, JM, Gomez, TS, Billadeau, DD	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, Deward, AD, Resau, JH, Alberts, AS	Exp. Cell Res.	2007
15085137	Cdc42 and mDia3 regulate microtubule attachment to kinetochores Yasuda, S, Oceguera-Yanez, F, Kato, T, Okamoto, M, Yonemura, S, Terada, Y, Ishizaki, T, Narumiya, S	Nature	2004
12906795	The mouse Formin mDia1 is a potent actin nucleation factor regulated by autoinhibition Li, F, Higgs, HN	Curr. Biol.	2003
21576392	RhoA and RhoC have distinct roles in migration and invasion by acting through different targets Vega, FM, Fruhwirth, G, Ng, T, Ridley, AJ	J. Cell Biol.	2011
24914801	Formins as effector proteins of Rho GTPases Kühn, S, Geyer, M	Small GTPases	2014
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
16439214	Control of the assembly of ATP- and ADP-actin by formins and profilin Kovar, DR, Harris, ES, Mahaffy, R, Higgs, HN, Pollard, TD	Cell	2006
16292343	The regulation of mDia1 by autoinhibition and its release by Rho*GTP Lammers, M, Rose, R, Scrima, A, Wittinghofer, A	EMBO J.	2005
20233848	The small GTPase Rif is an alternative trigger for the formation of actin stress fibers in epithelial cells Fan, L, Pellegrin, S, Scott, A, Mellor, H	J. Cell. Sci.	2010
12577064	RhoD regulates endosome dynamics through Diaphanous-related Formin and Src tyrosine kinase Gasman, S, Kalaidzidis, Y, Zerial, M	Nat. Cell Biol.	2003
11779461	Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1 Habas, R, Kato, Y, He, X	Cell	2001
15944396	RhoB regulates endosome transport by promoting actin assembly on endosomal membranes through Dia1 Fernandez-Borja, M, Janssen, L, Verwoerd, D, Hordijk, P, Neefjes, J	J. Cell. Sci.	2005
21397845	Aurora B regulates formin mDia3 in achieving metaphase chromosome alignment Cheng, L, Zhang, J, Ahmad, S, Rozier, L, Yu, H, Deng, H, Mao, Y	Dev. Cell	2011
15006353	Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture Xu, Y, Moseley, JB, Sagot, I, Poy, F, Pellman, D, Goode, BL, Eck, MJ	Cell	2004
12732141	Actin dynamics control SRF activity by regulation of its coactivator MAL Miralles, F, Posern, G, Zaromytidou, AI, Treisman, R	Cell	2003
10678165	Diaphanous-related formins bridge Rho GTPase and Src tyrosine kinase signaling Tominaga, T, Sahai, E, Chardin, P, McCormick, F, Courtneidge, SA, Alberts, AS	Mol. Cell	2000
16943183	Autoinhibition regulates cellular localization and actin assembly activity of the diaphanous-related formins FRLalpha and mDia1 Seth, A, Otomo, C, Rosen, MK	J. Cell Biol.	2006
20101212	Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC Kitzing, TM, Wang, Y, Pertz, O, Copeland, JW, Grosse, R	Oncogene	2010