BioPAX pathway converted from "SRGAP2 stimulates RAC1 GTP-ase activity and ends FMNL1-mediated elongation of actin filaments" in the Reactome database.
3.6.5.4
3.6.5.3
3.6.5.2
3.6.5.1
SRGAP2 stimulates RAC1 GTP-ase activity and ends FMNL1-mediated elongation of actin filaments
SRGAP2 stimulates RAC1 GTP-ase activity and ends FMNL1-mediated elongation of actin filaments
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).
Authored: Orlic-Milacic, Marija, 2014-10-24
Authored: Rivero Crespo, Francisco, 2014-12-26
Edited: Orlic-Milacic, Marija, 2015-02-02
Reactome DB_ID: 29356
1
cytosol
GO
0005829
water [ChEBI:15377]
water
Reactome
http://www.reactome.org
ChEBI
15377
Reactome DB_ID: 5665803
1
plasma membrane
GO
0005886
SRGAP2:RAC1:GTP:FMNL1:Profilin:G-actin [plasma membrane]
SRGAP2:RAC1:GTP:FMNL1:Profilin:G-actin
Reactome DB_ID: 195131
1
UniProt:O75044 SRGAP2
SRGAP2
FNBP2
KIAA0456
SRGAP2
ARHGAP34
SRGAP2A
FUNCTION Postsynaptic RAC1 GTPase activating protein (GAP) that plays a key role in neuronal morphogenesis and migration mainly during development of the cerebral cortex (PubMed:20810653, PubMed:27373832, PubMed:28333212). Regulates excitatory and inhibitory synapse maturation and density in cortical pyramidal neurons (PubMed:22559944, PubMed:27373832). SRGAP2/SRGAP2A limits excitatory and inhibitory synapse density through its RAC1-specific GTPase activating activity, while it promotes maturation of both excitatory and inhibitory synapses through its ability to bind to the postsynaptic scaffolding protein HOMER1 at excitatory synapses, and the postsynaptic protein GPHN at inhibitory synapses (By similarity). Mechanistically, acts by binding and deforming membranes, thereby regulating actin dynamics to regulate cell migration and differentiation (PubMed:27373832). Promotes cell repulsion and contact inhibition of locomotion: localizes to protrusions with curved edges and controls the duration of RAC1 activity in contact protrusions (By similarity). In non-neuronal cells, may also play a role in cell migration by regulating the formation of lamellipodia and filopodia (PubMed:20810653, PubMed:21148482).ACTIVITY REGULATION Activity is strongly inhibited by SRGAP2C, which heterodimerize with SRGAP2/SRGAP2A, thereby reducing SRGAP2/SRGAP2A levels through proteasome-dependent degradation.SUBUNIT Homodimer (PubMed:20810653, PubMed:26365803, PubMed:28333212). Heterodimer; forms a heterodimer with SRGAP2C, altering SRGAP2 function (PubMed:22559944, PubMed:27373832, PubMed:28333212). Forms a heterooligomer with SRGAP1 and SRGAP3 through its F-BAR domain (PubMed:22467852). Interacts (via SH3 domain) with GPHN (By similarity). Interacts (via SH3 domain) with FMNL1 (activated by RAC1); regulates the actin filament severing activity of FMNL1 and actin dynamics (PubMed:21148482). Interacts (via SH3 domain) with FMNL3 (PubMed:21148482). Interacts with RAC1; specifically stimulates RAC1 GTPase activity (PubMed:21148482). Interacts (via F-BAR domain) with HOMER1 (By similarity). Interacts with ROBO1 and ROBO2 (PubMed:11672528, PubMed:21148482, PubMed:26365803). Interacts with FASLG (PubMed:19807924). Interacts with PRMT5 (PubMed:20810653).DOMAIN The F-BAR domain mediates oligomerization, binds membranes, and induces plasma membrane protrusions.PTM Methylation at Arg-927 is required for the stimulation of cell migration, dimerization and localization at the plasma membrane protrusions.DISEASE A chromosomal aberration disrupting SRGAP2 has been found in a patient with early infantile epileptic encephalopathy. Balanced translocation t(1;9)(q32;q13) (PubMed:22106086).MISCELLANEOUS There are 3 duplications of SRGAP2 in the human genome as a result of segmental gene duplications. SRGAP2C is the only one to be fixed at a diploid state in the human genome. Moreover, SRGAP2C is functional, interacts with and inhibits SRGAP2 and is human-specific. The appearance of SRGAP2C in the human genome is estimated to 2,4 million years ago, which corresponds to the beginning of neocortex expansion in human evolution and it may have played an important role in this process through its interaction with SRGAP2 function.
Homo sapiens
NCBI Taxonomy
9606
UniProt
O75044
Chain Coordinates
1
EQUAL
1071
EQUAL
Reactome DB_ID: 5665660
1
RAC1:GTP:FMNL1:Profilin:G-actin [plasma membrane]
RAC1:GTP:FMNL1:Profilin:G-actin
Reactome DB_ID: 203080
2
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 DB_ID: 201857
1
G-actin [cytosol]
G-actin
actin:ATP
Reactome DB_ID: 113592
1
ATP(4-) [ChEBI:30616]
ATP(4-)
Adenosine 5'-triphosphate
atp
ATP
ChEBI
30616
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
ACTG1 [cytosol]
ACTB(1-375) [cytosol]
UniProt
P63261
UniProt
P60709
Reactome Database ID Release 83
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 83
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
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. 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.CAUTION The interaction between DSCAM, PAK1 and RAC1 has been described. This article has been withdrawn by the authors.
UniProt
P63000
1
EQUAL
189
EQUAL
Reactome Database ID Release 83
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 83
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 83
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 Database ID Release 83
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 83
5665803
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=5665803
Reactome
R-HSA-5665803
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-5665803.1
Reactome DB_ID: 195131
1
1
EQUAL
1071
EQUAL
Reactome DB_ID: 445010
1
RAC1:GDP [cytosol]
RAC1:GDP
Reactome DB_ID: 442615
1
1
EQUAL
189
EQUAL
Reactome DB_ID: 29420
1
GDP(3-) [ChEBI:58189]
GDP(3-)
guanosine 5'-diphosphate(3-)
5'-O-[(phosphonatooxy)phosphinato]guanosine
guanosine 5'-diphosphate trianion
GDP
GDP trianion
guanosine 5'-diphosphate
ChEBI
58189
Reactome Database ID Release 83
445010
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=445010
Reactome
R-HSA-445010
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-445010.1
Reactome DB_ID: 5665949
1
Reactome DB_ID: 29372
1
hydrogenphosphate [ChEBI:43474]
hydrogenphosphate
[PO3(OH)](2-)
HYDROGENPHOSPHATE ION
hydrogen phosphate
[P(OH)O3](2-)
HPO4(2-)
phosphate
INORGANIC PHOSPHATE GROUP
ChEBI
43474
Reactome DB_ID: 203080
2
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 5665803
GO
0003924
GO molecular function
Reactome Database ID Release 83
5665807
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=5665807
Reactome Database ID Release 83
5665809
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=5665809
Reactome
R-HSA-5665809
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-5665809.1
21148482
Pubmed
2011
Bi-modal regulation of a formin by srGAP2
Mason, Frank M
Heimsath, Ernest G
Higgs, Henry N
Soderling, Scott H
J. Biol. Chem. 286:6577-86