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).<p>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).
View original pathway at:Reactome.</div>
Li D, Sewer MB.; ''RhoA and DIAPH1 mediate adrenocorticotropin-stimulated cortisol biosynthesis by regulating mitochondrial trafficking.''; PubMedEurope PMCScholia
Gao GX, Dong HJ, Gu HT, Gao Y, Pan YZ, Yang Y, Chen XQ.; ''[PI3-kinase mediates activity of RhoA and interaction of RhoA with mDia1 in thrombin-induced platelet aggregation].''; PubMedEurope PMCScholia
Boudreau NJ, Jones PL.; ''Extracellular matrix and integrin signalling: the shape of things to come.''; PubMedEurope PMCScholia
Fernandez-Borja M, Janssen L, Verwoerd D, Hordijk P, Neefjes J.; ''RhoB regulates endosome transport by promoting actin assembly on endosomal membranes through Dia1.''; PubMedEurope PMCScholia
Wong GT, Gavin BJ, McMahon AP.; ''Differential transformation of mammary epithelial cells by Wnt genes.''; PubMedEurope PMCScholia
Block J, Breitsprecher D, Kühn S, Winterhoff M, Kage F, Geffers R, Duwe P, Rohn JL, Baum B, Brakebusch C, Geyer M, Stradal TE, Faix J, Rottner K.; ''FMNL2 drives actin-based protrusion and migration downstream of Cdc42.''; PubMedEurope PMCScholia
Romero S, Le Clainche C, Didry D, Egile C, Pantaloni D, Carlier MF.; ''Formin is a processive motor that requires profilin to accelerate actin assembly and associated ATP hydrolysis.''; PubMedEurope PMCScholia
Thompson ME, Heimsath EG, Gauvin TJ, Higgs HN, Kull FJ.; ''FMNL3 FH2-actin structure gives insight into formin-mediated actin nucleation and elongation.''; PubMedEurope PMCScholia
Saito-Diaz K, Chen TW, Wang X, Thorne CA, Wallace HA, Page-McCaw A, Lee E.; ''The way Wnt works: components and mechanism.''; PubMedEurope PMCScholia
Yasuda S, Oceguera-Yanez F, Kato T, Okamoto M, Yonemura S, Terada Y, Ishizaki T, Narumiya S.; ''Cdc42 and mDia3 regulate microtubule attachment to kinetochores.''; PubMedEurope PMCScholia
Bione S, Sala C, Manzini C, Arrigo G, Zuffardi O, Banfi S, Borsani G, Jonveaux P, Philippe C, Zuccotti M, Ballabio A, Toniolo D.; ''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.''; PubMedEurope PMCScholia
Lammers M, Rose R, Scrima A, Wittinghofer A.; ''The regulation of mDia1 by autoinhibition and its release by Rho*GTP.''; PubMedEurope PMCScholia
Colón-Franco JM, Gomez TS, Billadeau DD.; ''Dynamic remodeling of the actin cytoskeleton by FMNL1γ is required for structural maintenance of the Golgi complex.''; PubMedEurope PMCScholia
Brandt DT, Baarlink C, Kitzing TM, Kremmer E, Ivaska J, Nollau P, Grosse R.; ''SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of beta1-integrin.''; PubMedEurope PMCScholia
Cheeseman IM, Desai A.; ''Molecular architecture of the kinetochore-microtubule interface.''; PubMedEurope PMCScholia
Miralles F, Posern G, Zaromytidou AI, Treisman R.; ''Actin dynamics control SRF activity by regulation of its coactivator MAL.''; PubMedEurope PMCScholia
Faull RJ, Ginsberg MH.; ''Inside-out signaling through integrins.''; PubMedEurope PMCScholia
Nodelman IM, Bowman GD, Lindberg U, Schutt CE.; ''X-ray structure determination of human profilin II: A comparative structural analysis of human profilins.''; PubMedEurope PMCScholia
Kitzing TM, Wang Y, Pertz O, Copeland JW, Grosse R.; ''Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC.''; PubMedEurope PMCScholia
Vega FM, Fruhwirth G, Ng T, Ridley AJ.; ''RhoA and RhoC have distinct roles in migration and invasion by acting through different targets.''; PubMedEurope PMCScholia
Lal H, Verma SK, Foster DM, Golden HB, Reneau JC, Watson LE, Singh H, Dostal DE.; ''Integrins and proximal signaling mechanisms in cardiovascular disease.''; PubMedEurope PMCScholia
White DJ, Puranen S, Johnson MS, Heino J.; ''The collagen receptor subfamily of the integrins.''; PubMedEurope PMCScholia
Seth A, Otomo C, Rosen MK.; ''Autoinhibition regulates cellular localization and actin assembly activity of the diaphanous-related formins FRLalpha and mDia1.''; PubMedEurope PMCScholia
Tominaga T, Sahai E, Chardin P, McCormick F, Courtneidge SA, Alberts AS.; ''Diaphanous-related formins bridge Rho GTPase and Src tyrosine kinase signaling.''; PubMedEurope PMCScholia
Rose R, Weyand M, Lammers M, Ishizaki T, Ahmadian MR, Wittinghofer A.; ''Structural and mechanistic insights into the interaction between Rho and mammalian Dia.''; PubMedEurope PMCScholia
Watanabe N, Higashida C.; ''Formins: processive cappers of growing actin filaments.''; PubMedEurope PMCScholia
Korenbaum E, Nordberg P, Björkegren-Sjögren C, Schutt CE, Lindberg U, Karlsson R.; ''The role of profilin in actin polymerization and nucleotide exchange.''; PubMedEurope PMCScholia
Mason FM, Heimsath EG, Higgs HN, Soderling SH.; ''Bi-modal regulation of a formin by srGAP2.''; PubMedEurope PMCScholia
Nezami AG, Poy F, Eck MJ.; ''Structure of the autoinhibitory switch in formin mDia1.''; PubMedEurope PMCScholia
Sagot I, Rodal AA, Moseley J, Goode BL, Pellman D.; ''An actin nucleation mechanism mediated by Bni1 and profilin.''; PubMedEurope PMCScholia
Otomo T, Otomo C, Tomchick DR, Machius M, Rosen MK.; ''Structural basis of Rho GTPase-mediated activation of the formin mDia1.''; PubMedEurope PMCScholia
Cheng L, Zhang J, Ahmad S, Rozier L, Yu H, Deng H, Mao Y.; ''Aurora B regulates formin mDia3 in achieving metaphase chromosome alignment.''; PubMedEurope PMCScholia
Li F, Higgs HN.; ''The mouse Formin mDia1 is a potent actin nucleation factor regulated by autoinhibition.''; PubMedEurope PMCScholia
Xu Y, Moseley JB, Sagot I, Poy F, Pellman D, Goode BL, Eck MJ.; ''Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture.''; PubMedEurope PMCScholia
Heimsath EG, Higgs HN.; ''The C terminus of formin FMNL3 accelerates actin polymerization and contains a WH2 domain-like sequence that binds both monomers and filament barbed ends.''; PubMedEurope PMCScholia
Grosse R, Copeland JW, Newsome TP, Way M, Treisman R.; ''A role for VASP in RhoA-Diaphanous signalling to actin dynamics and SRF activity.''; PubMedEurope PMCScholia
Habas R, Kato Y, He X.; ''Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1.''; PubMedEurope PMCScholia
Kursula P, Kursula I, Massimi M, Song YH, Downer J, Stanley WA, Witke W, Wilmanns M.; ''High-resolution structural analysis of mammalian profilin 2a complex formation with two physiological ligands: the formin homology 1 domain of mDia1 and the proline-rich domain of VASP.''; PubMedEurope PMCScholia
Arnaout MA, Goodman SL, Xiong JP.; ''Coming to grips with integrin binding to ligands.''; PubMedEurope PMCScholia
Hetheridge C, Scott AN, Swain RK, Copeland JW, Higgs HN, Bicknell R, Mellor H.; ''The formin FMNL3 is a cytoskeletal regulator of angiogenesis.''; PubMedEurope PMCScholia
Copeland JW, Treisman R.; ''The diaphanous-related formin mDia1 controls serum response factor activity through its effects on actin polymerization.''; PubMedEurope PMCScholia
Favaro P, Traina F, Machado-Neto JA, Lazarini M, Lopes MR, Pereira JK, Costa FF, Infante E, Ridley AJ, Saad ST.; ''FMNL1 promotes proliferation and migration of leukemia cells.''; PubMedEurope PMCScholia
Otomo T, Tomchick DR, Otomo C, Machius M, Rosen MK.; ''Crystal structure of the Formin mDia1 in autoinhibited conformation.''; PubMedEurope PMCScholia
Yayoshi-Yamamoto S, Taniuchi I, Watanabe T.; ''FRL, a novel formin-related protein, binds to Rac and regulates cell motility and survival of macrophages.''; PubMedEurope PMCScholia
Liu ST, Rattner JB, Jablonski SA, Yen TJ.; ''Mapping the assembly pathways that specify formation of the trilaminar kinetochore plates in human cells.''; PubMedEurope PMCScholia
Fan L, Pellegrin S, Scott A, Mellor H.; ''The small GTPase Rif is an alternative trigger for the formation of actin stress fibers in epithelial cells.''; PubMedEurope PMCScholia
Cheeseman IM, Chappie JS, Wilson-Kubalek EM, Desai A.; ''The conserved KMN network constitutes the core microtubule-binding site of the kinetochore.''; PubMedEurope PMCScholia
Gasman S, Kalaidzidis Y, Zerial M.; ''RhoD regulates endosome dynamics through Diaphanous-related Formin and Src tyrosine kinase.''; PubMedEurope PMCScholia
Kovar DR, Harris ES, Mahaffy R, Higgs HN, Pollard TD.; ''Control of the assembly of ATP- and ADP-actin by formins and profilin.''; PubMedEurope PMCScholia
Foltz DR, Jansen LE, Black BE, Bailey AO, Yates JR, Cleveland DW.; ''The human CENP-A centromeric nucleosome-associated complex.''; PubMedEurope PMCScholia
Du SJ, Purcell SM, Christian JL, McGrew LL, Moon RT.; ''Identification of distinct classes and functional domains of Wnts through expression of wild-type and chimeric proteins in Xenopus embryos.''; PubMedEurope PMCScholia
Pring M, Weber A, Bubb MR.; ''Profilin-actin complexes directly elongate actin filaments at the barbed end.''; PubMedEurope PMCScholia
Amano M, Nakayama M, Kaibuchi K.; ''Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity.''; PubMedEurope PMCScholia
Liu W, Sato A, Khadka D, Bharti R, Diaz H, Runnels LW, Habas R.; ''Mechanism of activation of the Formin protein Daam1.''; PubMedEurope PMCScholia
Han Y, Eppinger E, Schuster IG, Weigand LU, Liang X, Kremmer E, Peschel C, Krackhardt AM.; ''Formin-like 1 (FMNL1) is regulated by N-terminal myristoylation and induces polarized membrane blebbing.''; PubMedEurope PMCScholia
Lai SL, Chien AJ, Moon RT.; ''Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis.''; PubMedEurope PMCScholia
Wallar BJ, Deward AD, Resau JH, Alberts AS.; ''RhoB and the mammalian Diaphanous-related formin mDia2 in endosome trafficking.''; PubMedEurope PMCScholia
Moriya K, Yamamoto T, Takamitsu E, Matsunaga Y, Kimoto M, Fukushige D, Kimoto C, Suzuki T, Utsumi T.; ''Protein N-myristoylation is required for cellular morphological changes induced by two formin family proteins, FMNL2 and FMNL3.''; PubMedEurope PMCScholia
Okada M, Cheeseman IM, Hori T, Okawa K, McLeod IX, Yates JR, Desai A, Fukagawa T.; ''The CENP-H-I complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres.''; PubMedEurope PMCScholia
Tanegashima K, Zhao H, Dawid IB.; ''WGEF activates Rho in the Wnt-PCP pathway and controls convergent extension in Xenopus gastrulation.''; PubMedEurope PMCScholia
Humans and mice have 19 identified WNT proteins that were originally classified as either 'canonical' or 'non-canonical' depending upon whether they were able to transform the mouse mammary epithelial cell line C57MG and to induce secondary axis formation in Xenopus (Wong et al, 1994; Du et al, 1995). So-called canonical WNTs, including Wnt1, 3, 3a and 7, initiate signaling pathways that destabilize the destruction complex and allow beta-catenin to accumulate and translocate to the nucleus where it promotes transcription (reviewed in Saito-Diaz et al, 2013). Non-canonical WNTs, including Wnt 2, 4, 5a, 5b, 6, 7b, and Wnt11 activate beta-catenin-independent responses that regulate many aspects of morphogenesis and development, often by impinging on the cytoskeleton (reviewed in van Amerongen, 2012). Two of the main beta-catenin-independent pathways are the Planar Cell Polarity (PCP) pathway, which controls the establishment of polarity in the plane of a field of cells, and the WNT/Ca2+ pathway, which promotes the release of intracellular calcium and regulates numerous downstream effectors (reviewed in Gao, 2012; De, 2011).
The extracellular matrix (ECM) is a network of macro-molecules that underlies all epithelia and endothelia and that surrounds all connective tissue cells. This matrix provides the mechanical strength and also influences the behavior and differentiation state of cells in contact with it. The ECM are diverse in composition, but they generally comprise a mixture of fibrillar proteins, polysaccharides synthesized, secreted and organized by neighboring cells. Collagens, fibronectin, and laminins are the principal components involved in cell matrix interactions; other components, such as vitronectin, thrombospondin, and osteopontin, although less abundant, are also important adhesive molecules. Integrins are the receptors that mediate cell adhesion to ECM. Integrins consists of one alpha and one beta subunit forming a noncovalently bound heterodimer. 18 alpha and 8 beta subunits have been identified in humans that combine to form 24 different receptors. The integrin dimers can be broadly divided into three families consisting of the beta1, beta2/beta7, and beta3/alphaV integrins. beta1 associates with 12 alpha-subunits and can be further divided into RGD-, collagen-, or laminin binding and the related alpha4/alpha9 integrins that recognise both matrix and vascular ligands. beta2/beta7 integrins are restricted to leukocytes and mediate cell-cell rather than cell-matrix interactions, although some recognize fibrinogen. The beta3/alphaV family members are all RGD receptors and comprise aIIbb3, an important receptor on platelets, and the remaining b-subunits, which all associate with alphaV. It is the collagen receptors and leukocyte-specific integrins that contain alpha A-domains.
Profilins PFN1 and PFN2 bind to monomeric actin (G-actin), forming a 1:1 complex and subsequently regulate actin filament barbed end assembly downstream of various signaling pathways (Pring et al. 1992, Korenbaum et al. 1998, Nodelman et al. 1999)
DAAM1 (Dishevelled-associated activator of morphogenesis) is a formin-homology protein that was identified in a yeast two-hybrid screen for interactors with the DVL PDZ domain (Habas et al, 2001). FH proteins play a well-characterized role in regulating cytoskeletal reorganization (reviewed in Aspenstrom, 2010). DAAM1 contains an N-terminal GTPase binding domain (GBD), two central proline-rich FH domains and a C-terminal diaphanous autoinhibitory domain (DAD). In the absence of a WNT signal, DAAM1 exists in an autoinhibited conformation mediated by an intramolecular interaction between the DBD and DAD regions (Habas et al, 2001; Liu et al, 2007). Upon WNT signaling, a direct interaction between the DAD of DAAM1 and the PDZ domain of DVL relieves the autoinhibition. In the activated conformation, DAAM1 may undergo FH-dependent oligomerization and had been shown to recruit RHOA in a GBD-dependent manner (Habas et al, 2001; Liu et al, 2007).
Activated DAAM1 recruits RHOA to the DVL complex in a WNT-dependent manner. Activated DAAM1 is able to bind to RHOA in both the GDP and GTP bound form in vitro, but displays higher affinity for GTP-bound RHOA (Habas et al, 2001; Liu et al, 2007). Studies in Xenopus have identified a DVL-associated weak guanine exchange factor (WGEF) that promotes the exchange of GDP for GTP on RHOA and is required for WNT-PCP signaling (Tanegashima et al, 2008). Evidence suggests that a similar GEF activity is associated with the DVL-DAAM1-RHOA complex in human cells, but the protein has not been definitively identified (Habas et al, 2001; Liu et al, 2007). GTP-bound RHOA relieves the auto-inhibition of RHO-associated kinases, allowing them to dimerize and effect changes to cytoskeletal organization (reviewed in Amano et al, 2010; Lai et al, 2009). DAAM1 may also play a more direct role in regulating the cytoskeleton in response to WNT signaling, since FH domains have been shown to bind actin directly to nucleate linear actin cables (Sagot et al, 2002; Watanabe and Higashida, 2004).
FMNL1 (formin-like protein 1) binds the active, GTP-bound, form of RAC1 (Yayoshi-Yamamoto et al. 2000). Based on the sequence similarity with mouse formin Dia1, binding of RAC1:GTP relieves the autoinhibition of FMNL1 by displacing the C-terminal autoregulatory DAD domain of FMNL1 from the N-terminal FH3 domain (Rose et al. 2005, Lammers et al. 2005). As formins dimerize through their FH2 domains, it is not clear whether the autoinhibitory interaction between FH3 and DAD domains is intramolecular or intermolecular (Xu et al. 2004, Kuhn and Geyer 2014). Endogenous human FMNL1 interacts with endogenous human RAC1 in some leukemia-derived cell lines and promotes their migration (Favaro et al. 2013). FMNL1 gamma, a transcriptional isoform of FMNL1 with a DAD domain that significantly differs in sequence from DAD domains of FMNL1 transcription isoforms alpha and beta, localizes to the membrane and is active in the absence of RHO GTPase signaling. The membrane localization of FMNL1 gamma is regulated by the myristoylation of the N-terminal glycine which is triggered by an unknown mechanism (Han et al. 2009).
FMNL1, activated by binding to GTP-bound RAC1, binds actin-associated profilins PFN1 and PFN2 through the proline-rich FH1 domain of FMNL1 (Yayoshi-Yamamoto et al. 2000). The interaction with actin is achieved through the FH2 domain of FMNL1 (Romero et al. 2004, Kovar et al. 2006, Kuhn and Geyer 2014). FMNL1 and profilin-mediated reorganization of actin cytoskeleton is involved in the formation of lamellipodia, which regulates the motility of macrophages (Yayoshi-Yamamoto et al. 2000). FMNL1 was shown to regulate the structure of the Golgi complex, where different transcriptional isoforms of FMNL1 may play different roles (Colon-Franco et al. 2011).
FMNL1 binds activated CDC42 and this interaction is implicated in the phagocytic cup formation, but the precise mechanism has not been elucidated (Seth et al. 2006).
FMNL2 binds activated (GTP-bound) CDC42. FMNL2 can be myristoylated on its N-terminal glycine. Although myristoylation is not necessary for the interaction with CDC42, it contributes to FMNL2 activation. Based on the sequence similarity with mouse formin Dia1, binding of CDC42:GTP relieves the autoinhibition of FMNL2 by displacing the C-terminal autoregulatory DAD domain of FMNL2 from the N-terminal FH3 domain (Rose et al. 2005, Lammers et al. 2005). Since formins function as dimers, it is unclear whether the autoinhibitory interaction between FH3 and DAD domain is intramolecular or intermolecular (Xu et al. 2004, Kuhn and Geyer 2014). FMNL2 can also interact with RAC1 in vitro, but it seems that this interaction is not physiologically relevant (Block et al. 2012).
FMNL2 specifically interacts with the GTP-bound RHOC, which relieves FMNL2 autoinhibition and contributes to RHOC-mediated ameboid cell motility involved in cancer cell invasion (Kitzing et al. 2010). Myristoylation of the N-terminal glycine may be required for the full activation of FMNL2 (Moriya et al. 2012).
Once activated by binding to GTP-bound CDC42, FMNL2 interacts with actin bound profilin(s) and drives elongation but not nucleation of actin filaments (Block et al. 2012). The interaction between formins and profilins is achieved through the proline-rich FH1 domain of formins, while the interaction with actin is achieved through the FH2 domain of formins (Romero et al. 2004, Kovar et al. 2006, Kuhn and Geyer 2014).
FMNL3 binds activated (GTP-bound) RHOC. RHOC-mediated activation of FMNL3 promotes polarized cell migration which may be involved in cancer cell invasion (Vega et al. 2011). Myristoylation of the N-terminal glycine may be required for the full activation of FMNL3 (Moriya et al. 2012).
Activated FMNL3 (presumably associated with RHOC:GTP) has the ability to directly bind G-actin through knob and coiled-coil subdomains of the FMNL3 FH2 domain. The proline-rich FH1 domain which precedes the FH2 domain presumably interacts with profilins bound to G-actin (Romero et al. 2004, Kovar et al. 2006, Kuhn and Geyer 2014). FMNL3 contributes to the elongation of actin filaments (Heimsath and Higgs 2012, Thompson et al. 2013). Activated FMNL3 may also trigger microtubule alignment during angiogenesis (Hetheridge et al. 2012).
SRGAP2 binds FMNL1 activated by RAC1:GTP by simultaneously interacting with RAC1 and FMNL1. SRGAP2 co-localizes with RAC1, FMNL1, profilin and actin at the plasma membrane after RAC1-mediated activation of FMNL1 (Mason et al. 2011).
SRGAP2 is a GTPase activating protein that stimulates the GTPase activity of RAC1 bound to FMNL1. GTP hydrolysis produces inactive GDP-bound RAC1 which is unable to bind and activate FMNL1. SRGAP2 thereby limits the duration of FMNL1-mediated elongation of actin filaments downstream of RAC1:GTP (Mason et al. 2011).
Once activated by binding to RHOA:GTP, DIAPH1 binds profilin:G-actin complexes together with EVL (VASP) homotetramers and promotes elongation of actin filaments (Copeland and Treisman 2002, Grosse et al. 2003, Kursula et al. 2008, Breitsprecher et al. 2008). Binding of nonpolymerized actin (G-actin) to DIAPH1 and EVL releases MKL1 (MAL) transcription co-factor which is inhibited when bound to G-actin (Miralles et al. 2003).
DIAPH1 is activated by binding of the DIAPH1 dimer to GTP-bound (active) RHOA. Binding to RHOA releaves the autoinhibitory interaction of DIAPH1 FH3 and DAD domains (Otomo et al. 2005). Phosphorylation of RHOA at serine residue S188 may be required for RHOA binding to DIAPH1 (Li and Sewer 2010). The interaction between RHOA and DIAPH1 may also be positively regulated by PI3K signaling (Gao et al. 2009).
The release of MKL1 (MAL) from nonpolymerized actin (G-actin), after profilin:G-actin complexes bind DIAPH1 and EVL (VASP) downstream of activated RHOA, enables MKL1 to translocate from the cytosol to the nucleus (Miralles et al. 2003).
SCAI forms a ternary complex with MKL1 and SRF, inhibiting the transcriptional activity of the SRF:MKL1 complex. SCAI negatively regulates cancer cell invasion facilitated by the SRF:MKL1-mediated transcription downstream of RHOA and DIAPH1, and therefore acts as a tumor suppressor (Brandt et al. 2009).
SRF:MKL1 binding to the promoter region of the integrin beta-1 gene stimulates ITGB1 expression downstream of RHOA:GTP:DIAPH1-induced actin cytoskeleton changes. Binding of SCAI to SRF:MKL1 inhibits RHOA:GTP:DIAPH1-induced ITGB1 transcription (Brandt et al. 2009).
Activated RHOB (RHOB:GTP) recruits DIAPH1 or DIAPH3 to endosomes where they regulate actin coat formation around endosomes and endosome motility/trafficking (Fernandez-Borja et al. 2005, Wallar et al. 2007).
Activated RHOD (RHOD:GTP) binds DIAPH2 transcription isoform DIAPH2-3 (DIAPH2C) and recruits it to endosomes. RHOD and DIAPH2 regulate endosome motility through SRC-dependent regulation of actin dynamics (Gasman et al. 2003).
RHOD:GTP:DIAPH2-3 complex recruits SRC to endosomes. SRC recruitment is necessary for RHOD:GTP:DIAPH2-3-mediated regulation of endosome-associated actin cytoskeleton and endosome motility (Gasman et al. 2003). SRC directly binds to DIAPH2 (Tominaga et al. 2000).
Activated CDC42 (CDC42:GTP) can localize to kinetochores of metaphase cells and recruit DIAPH2 transcriptional isoform DIAPH2-2 (DIA-12C, mDia3) to kinetochores. The CDC42:GTP:DIAPH2-2 complex regulates the attachment of microtubules to kinetochores (Yasuda et al. 2004).
Aurora kinase B (AURKB), which is part of the kinetochore, phosphorylates DIAPH2-2 (DIA-12C, mDia3) on serine residue S196 in the FH3 (DID) domain and probably on several other residues in the FH3 and FH2 domains. AURKB-mediated phosphorylation of DIAPH2-2 is necessary for the regulation of microtubule binding to kinetochores by the CDC42:GTP:DIAPH2-2 complex (Cheng et al. 2011).
The recruitment of DIAPH2-2 (DIA-12C, mDia3) to kinetochores by activated CDC42 (CDC42:GTP) and DIAPH2-2 phosphorylation by AURKB positively regulates the attachment of microtubules to kinetochores (Yasuda et al. 2004, Cheng et al. 2011).
The human kinetochore, is a complex proteinaceous structure that assembles on centromeric DNA and mediates the association of mitotic chromosomes with spindle microtubules in prometaphase. The molecular composition of the human kinetochore is reviewed in detail in Cheeseman et al., 2008. This complex structure is composed of numerous protein complexes and networks including: the constitutive centromere-associated network (CCAN) containing several sub-networks such as (CENP-H, I, K), (CENP-50/U, O, P, Q, R), the KMN network (containing KNL1, the Mis12 complex, and the Ndc80 complex), the chromosomal passenger complex, the mitotic checkpoint complex, the nucleoporin 107-160 complex and the RZZ complex. At prometaphase, following breakdown of the nuclear envelope, the kinetochores of condensed chromosomes begin to interact with spindle microtubules. In humans, 15-20 microtubules are bound to each kinetochore (McEwen et al., 2001), and the attachment of 15 microtubules to the kinetochore is shown in this reaction. Recently, it was found that the core kinetochore-microtubule attachment site is within the KMN network and is likely to be formed by two closely apposed low-affinity microtubule-binding sites, one in the Ndc80 complex and a second in KNL1 (Cheeseman et al., 2006).
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independent WNT
signalingsurface
interactionsIntegrins are the receptors that mediate cell adhesion to ECM. Integrins consists of one alpha and one beta subunit forming a noncovalently bound heterodimer. 18 alpha and 8 beta subunits have been identified in humans that combine to form 24 different receptors.
The integrin dimers can be broadly divided into three families consisting of the beta1, beta2/beta7, and beta3/alphaV integrins. beta1 associates with 12 alpha-subunits and can be further divided into RGD-, collagen-, or laminin binding and the related alpha4/alpha9 integrins that recognise both matrix and vascular ligands. beta2/beta7 integrins are restricted to leukocytes and mediate cell-cell rather than cell-matrix interactions, although some recognize fibrinogen. The beta3/alphaV family members are all RGD receptors and comprise aIIbb3, an important receptor on platelets, and the remaining b-subunits, which all associate with alphaV. It is the collagen receptors and leukocyte-specific integrins that contain alpha A-domains.
Annotated Interactions
The human kinetochore, is a complex proteinaceous structure that assembles on centromeric DNA and mediates the association of mitotic chromosomes with spindle microtubules in prometaphase. The molecular composition of the human kinetochore is reviewed in detail in Cheeseman et al., 2008. This complex structure is composed of numerous protein complexes and networks including: the constitutive centromere-associated network (CCAN) containing several sub-networks such as (CENP-H, I, K), (CENP-50/U, O, P, Q, R), the KMN network (containing KNL1, the Mis12 complex, and the Ndc80 complex), the chromosomal passenger complex, the mitotic checkpoint complex, the nucleoporin 107-160 complex and the RZZ complex.
At prometaphase, following breakdown of the nuclear envelope, the kinetochores of condensed chromosomes begin to interact with spindle microtubules. In humans, 15-20 microtubules are bound to each kinetochore (McEwen et al., 2001), and the attachment of 15 microtubules to the kinetochore is shown in this reaction. Recently, it was found that the core kinetochore-microtubule attachment site is within the KMN network and is likely to be formed by two closely apposed low-affinity microtubule-binding sites, one in the Ndc80 complex and a second in KNL1 (Cheeseman et al., 2006).