BioPAX pathway converted from "RAC1:GTP:FMNL1 binds profilin:G-actin" in the Reactome database. RAC1:GTP:FMNL1 binds profilin:G-actin RAC1:GTP:FMNL1 binds profilin:G-actin 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). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 203080 2 cytosol GO 0005829 Profilin:G-actin [cytosol] Profilin:G-actin PFN1,PFN2:G-actin Profilin:monomeric actin Converted from EntitySet in Reactome Reactome DB_ID: 203077 1 PFN [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome http://www.reactome.org Reactome DB_ID: 201857 1 G-actin [cytosol] G-actin actin:ATP Converted from EntitySet in Reactome Reactome DB_ID: 201859 1 actin [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ACTB(1-375) [cytosol] ACTG1 [cytosol] Homo sapiens NCBI Taxonomy 9606 UniProt P60709 UniProt P63261 Reactome DB_ID: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome Database ID Release 82 201857 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201857 Reactome R-HSA-201857 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201857.3 Reactome Database ID Release 82 203080 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203080 Reactome R-HSA-203080 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-203080.1 Reactome DB_ID: 5663231 1 plasma membrane GO 0005886 RAC1:GTP:FMNL1 [plasma membrane] RAC1:GTP:FMNL1 Reactome DB_ID: 442641 1 RAC1:GTP [plasma membrane] RAC1:GTP Reactome DB_ID: 29438 1 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI 37565 Reactome DB_ID: 351141 1 UniProt:P63000 RAC1 RAC1 TC25 RAC1 MIG5 FUNCTION Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate cellular responses such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization, neurons adhesion, migration and differentiation, and growth-factor induced formation of membrane ruffles (PubMed:1643658, PubMed:28886345). Rac1 p21/rho GDI heterodimer is the active component of the cytosolic factor sigma 1, which is involved in stimulation of the NADPH oxidase activity in macrophages. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. Stimulates PKN2 kinase activity (PubMed:9121475). In concert with RAB7A, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts (PubMed:1643658). In podocytes, promotes nuclear shuttling of NR3C2; this modulation is required for a proper kidney functioning. Required for atypical chemokine receptor ACKR2-induced LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In neurons, is involved in dendritic spine formation and synaptic plasticity (By similarity). In hippocampal neurons, involved in spine morphogenesis and synapse formation, through local activation at synapses by guanine nucleotide exchange factors (GEFs), such as ARHGEF6/ARHGEF7/PIX (PubMed:12695502). In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3. In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in PAK1 activation and eventually F-actin stabilization (By similarity).ACTIVITY REGULATION Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. GTP hydrolysis is stimulated by ARHGAP30.SUBUNIT Interacts with NISCH. Interacts with PIP5K1A. Interacts with the GTP-bound form of RAB7A. Interacts with SRGAP2. Interacts with CYFIP1/SRA-1. Interacts with PLXNB3. Interacts with ARHGDIA; the interaction is induced by SEMA5A, mediated through PLXNB3 and inactivates and stabilizes RAC1. Interacts (GTP-bound form preferentially) with PKN2 (via the REM repeats); the interaction stimulates autophosphorylation and phosphorylation of PKN2. Interacts with the GEF proteins PREX1, RASGRF2, FARP1, FARP2, DOCK1, DOCK2 and DOCK7, which promote the exchange between GDP and GTP, and therefore activate it. Interacts with PARD6A, PARD6B and PARD6G in a GTP-dependent manner. Part of a quaternary complex containing PARD3, some PARD6 protein (PARD6A, PARD6B or PARD6G) and some atypical PKC protein (PRKCI or PRKCZ), which plays a central role in epithelial cell polarization. Found in a trimeric complex composed of DOCK1 and ELMO1, which plays a central role in phagocytosis of apoptotic cells. Interacts with RALBP1 via its effector domain. Interacts with PLXNB1. Probably found in a ternary complex composed of DSCAM, PAK1 and RAC1. Interacts with DSCAM; the interaction requires PAK1. Part of a complex with MAP2K3, MAP3K3, CCM2 and DEF6. Interacts with BAIAP2, BAIAP2L1 and DEF6. Interacts with Y.pseudotuberculosis YPKA and PLCB2. Interacts with NOXA1. Interacts with ARHGEF2. Interacts with TBC1D2. Interacts with UNKL. Interacts with USP6. Interacts with SPATA13. Interacts with ARHGEF16; mediates activation of RAC1 by EPHA2. Interacts with ITGB4. Interacts with S100A8 and calprotectin (S100A8/9). Interacts with PACSIN2. Interacts with ITGB1BP1. Interacts (when active) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane. Interacts with RAPH1 (via Ras associating and PH domains) (PubMed:18499456). Interacts with MTSS2 (via IMD domain); this interaction may be important to potentiate PDGF-induced RAC1 activation (PubMed:20875796). Interacts with PAK2 (PubMed:20696164). Interacts (GTP-bound form) with SH3RF1 and SH3RF3 (PubMed:20696164). Found in a complex with SH3RF1, MAPK8IP1/JIP1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8/JNK1. Interacts (both active GTP- or inactive GDP-bound forms) with SH3RF2 (By similarity). Interacts (GTP-bound form preferentially) with CYRIB (PubMed:31285585, PubMed:30250061). Interacts with DOCK4 (via DOCKER domain); functions as a guanine nucleotide exchange factor (GEF) for RAC1 (PubMed:16464467). Interacts with GARRE1 (PubMed:31871319). Interacts with RAP1GDS1 (PubMed:20709748, PubMed:12551911).TISSUE SPECIFICITY Isoform B is predominantly identified in skin and epithelial tissues from the intestinal tract. Its expression is elevated in colorectal tumors at various stages of neoplastic progression, as compared to their respective adjacent tissues.DOMAIN The effector region mediates interaction with DEF6.PTM GTP-bound active form is ubiquitinated by HACE1, leading to its degradation by the proteasome.PTM (Microbial infection) AMPylation at Tyr-32 and Thr-35 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo.PTM (Microbial infection) Glycosylated at Tyr-32 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rac and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-35 by C.difficile toxins TcdA and TcdB in the colonic epithelium, and by P.sordellii toxin TcsL in the vascular endothelium (PubMed:7777059, PubMed:7775453, PubMed:8626575, PubMed:19744486, PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:7775453).PTM (Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-35 by C.novyi toxin TcdA (PubMed:8810274). O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:8810274).PTM (Microbial infection) Palmitoylated by the N-epsilon-fatty acyltransferase F2 chain of V.cholerae toxin RtxA (PubMed:29074776). Palmitoylation inhibits activation by guanine nucleotide exchange factors (GEFs), preventing Rho GTPase signaling (PubMed:29074776).SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt P63000 Chain Coordinates 1 EQUAL 189 EQUAL Reactome Database ID Release 82 442641 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442641 Reactome R-HSA-442641 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-442641.1 Reactome DB_ID: 5665949 1 FMNL1 [cytosol] FMNL1 FMNL1 dimer Reactome DB_ID: 5663224 2 UniProt:O95466 FMNL1 FMNL1 FRL1 FMNL1 FMNL C17orf1B C17orf1 FUNCTION May play a role in the control of cell motility and survival of macrophages (By similarity). Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the cortical actin filament dynamics and cell shape.SUBUNIT Interacts with RAC1, PFN1 and PFN2 (By similarity). Interacts (activated by RAC1) with SRGAP2 (via SH3 domain); regulates the actin filament severing activity of FMNL1.TISSUE SPECIFICITY Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.DOMAIN The DAD domain regulates activation via by an autoinhibitory interaction with the N-terminus. This autoinhibition is released upon competitive binding of an activated GTPase. The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments (By similarity).PTM Myristoylation mediates membrane localization and blebbing.SIMILARITY Belongs to the formin homology family. UniProt O95466 2 EQUAL 1100 EQUAL Reactome Database ID Release 82 5665949 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665949 Reactome R-HSA-5665949 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665949.1 Reactome Database ID Release 82 5663231 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5663231 Reactome R-HSA-5663231 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5663231.1 Reactome DB_ID: 5665660 1 RAC1:GTP:FMNL1:Profilin:G-actin [plasma membrane] RAC1:GTP:FMNL1:Profilin:G-actin Reactome DB_ID: 203080 2 Reactome DB_ID: 5663231 1 Reactome Database ID Release 82 5665660 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665660 Reactome R-HSA-5665660 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665660.1 Reactome Database ID Release 82 5665659 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665659 Reactome R-HSA-5665659 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665659.1 10958683 Pubmed 2000 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. 20:6872-81 15507212 Pubmed 2004 Formin is a processive motor that requires profilin to accelerate actin assembly and associated ATP hydrolysis Romero, Stéphane Le Clainche, Christophe Didry, Dominique Egile, Coumaran Pantaloni, Dominique Carlier, Marie-France Cell 119:419-29 16439214 Pubmed 2006 Control of the assembly of ATP- and ADP-actin by formins and profilin Kovar, David R Harris, Elizabeth S Mahaffy, Rachel Higgs, Henry N Pollard, Thomas D Cell 124:423-35 24914801 Pubmed 2014 Formins as effector proteins of Rho GTPases Kühn, Sonja Geyer, Matthias Small GTPases 5:e29513 21868368 Pubmed 2011 Dynamic remodeling of the actin cytoskeleton by FMNL1? is required for structural maintenance of the Golgi complex Colón-Franco, Jessica M Gomez, Timothy S Billadeau, Daniel D J. Cell. Sci. 124:3118-26