RPGF2_BOVIN
ID RPGF2_BOVIN Reviewed; 1486 AA.
AC F1MSG6;
DT 16-OCT-2013, integrated into UniProtKB/Swiss-Prot.
DT 16-NOV-2011, sequence version 2.
DT 03-AUG-2022, entry version 74.
DE RecName: Full=Rap guanine nucleotide exchange factor 2;
DE AltName: Full=Cyclic nucleotide ras GEF;
DE Short=CNrasGEF;
DE AltName: Full=Neural RAP guanine nucleotide exchange protein;
DE Short=nRap GEP;
DE AltName: Full=PDZ domain-containing guanine nucleotide exchange factor 1;
DE Short=PDZ-GEF1;
DE AltName: Full=RA-GEF-1;
DE AltName: Full=Ras/Rap1-associating GEF-1;
GN Name=RAPGEF2; Synonyms=NRAPGEP, PDZGEF1;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Hereford;
RX PubMed=19393038; DOI=10.1186/gb-2009-10-4-r42;
RA Zimin A.V., Delcher A.L., Florea L., Kelley D.R., Schatz M.C., Puiu D.,
RA Hanrahan F., Pertea G., Van Tassell C.P., Sonstegard T.S., Marcais G.,
RA Roberts M., Subramanian P., Yorke J.A., Salzberg S.L.;
RT "A whole-genome assembly of the domestic cow, Bos taurus.";
RL Genome Biol. 10:R42.01-R42.10(2009).
RN [2]
RP INTERACTION WITH CTNNB1, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=10873669; DOI=10.1006/bbrc.2000.3002;
RA Kawajiri A., Itoh N., Fukata M., Nakagawa M., Yamaga M., Iwamatsu A.,
RA Kaibuchi K.;
RT "Identification of a novel beta-catenin-interacting protein.";
RL Biochem. Biophys. Res. Commun. 273:712-717(2000).
RN [3]
RP FUNCTION.
RX PubMed=23800469; DOI=10.1126/scisignal.2003993;
RA Emery A.C., Eiden M.V., Mustafa T., Eiden L.E.;
RT "Rapgef2 Connects GPCR-Mediated cAMP Signals to ERK Activation in Neuronal
RT and Endocrine Cells.";
RL Sci. Signal. 6:RA51-RA51(2013).
CC -!- FUNCTION: Functions as a guanine nucleotide exchange factor (GEF),
CC which activates Rap and Ras family of small GTPases by exchanging bound
CC GDP for free GTP in a cAMP-dependent manner. Serves as a link between
CC cell surface receptors and Rap/Ras GTPases in intracellular signaling
CC cascades. Acts also as an effector for Rap1 by direct association with
CC Rap1-GTP thereby leading to the amplification of Rap1-mediated
CC signaling. Shows weak activity on HRAS. It is controversial whether
CC RAPGEF2 binds cAMP and cGMP or not. Its binding to ligand-activated
CC beta-1 adrenergic receptor ADRB1 leads to the Ras activation through
CC the G(s)-alpha signaling pathway. Involved in the cAMP-induced Ras and
CC Erk1/2 signaling pathway that leads to sustained inhibition of long
CC term melanogenesis by reducing dendrite extension and melanin
CC synthesis. Provides also inhibitory signals for cell proliferation of
CC melanoma cells and promotes their apoptosis in a cAMP-independent
CC nanner. Regulates cAMP-induced neuritogenesis by mediating the Rap1/B-
CC Raf/ERK signaling through a pathway that is independent on both PKA and
CC RAPGEF3/RAPGEF4. Involved in neuron migration and in the formation of
CC the major forebrain fiber connections forming the corpus callosum, the
CC anterior commissure and the hippocampal commissure during brain
CC development. Involved in neuronal growth factor (NGF)-induced sustained
CC activation of Rap1 at late endosomes and in brain-derived neurotrophic
CC factor (BDNF)-induced axon outgrowth of hippocampal neurons. Plays a
CC role in the regulation of embryonic blood vessel formation and in the
CC establishment of basal junction integrity and endothelial barrier
CC function. May be involved in the regulation of the vascular endothelial
CC growth factor receptor KDR and cadherin CDH5 expression at allantois
CC endothelial cell-cell junctions (By similarity). Binds to cAMP.
CC {ECO:0000250, ECO:0000269|PubMed:23800469}.
CC -!- SUBUNIT: Found in a complex, at least composed of KIDINS220, MAGI2,
CC NTRK1 and RAPGEF2; the complex is mainly formed at late endosomes in a
CC neuronal growth factor (NGF)-dependent manner. Interacts (via C-
CC terminal domain) with NEDD4 (via WW domains); this interaction leads to
CC ubiquitination and degradation via the proteasome pathway in a cAMP-
CC independent manner. Interacts with MAGI1 (via PDZ domain). Interacts
CC with ADRB1 (via C-terminal PDZ motif); the interaction is direct.
CC Interacts (via Ras-associating domain) with RAP1A (via GTP-bound active
CC form). Interacts weakly with HRAS (via GDP- and GTP-bound forms).
CC Interacts (via C-terminal domain) with MAGI2 (via PDZ and WW domains).
CC Interacts with CDH1 and TJP1 (By similarity). Interacts with CTNNB1.
CC {ECO:0000250, ECO:0000269|PubMed:10873669}.
CC -!- INTERACTION:
CC F1MSG6; Q02248: Ctnnb1; Xeno; NbExp=2; IntAct=EBI-6927068, EBI-397872;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Cytoplasm, perinuclear
CC region {ECO:0000250}. Cell membrane {ECO:0000250}. Late endosome
CC {ECO:0000250}. Cell junction {ECO:0000250}. Note=Associated with the
CC synaptic plasma membrane. Localized diffusely in the cytoplasm before
CC neuronal growth factor (NGF) stimulation. Recruited to late endosomes
CC after NGF stimulation. Colocalized with the high affinity nerve growth
CC factor receptor NTRK1 at late endosomes. Translocated to the
CC perinuclear region in a RAP1A-dependent manner. Translocated to the
CC cell membrane. Colocalized with CTNNB1 at cell-cell contacts (By
CC similarity). {ECO:0000250}.
CC -!- DOMAIN: The Ras-associating domain is necessary for the Rap guanine
CC nucleotide exchange activity. The N-terminal regionis necessary for
CC cAMP-binding. The PDZ domain is necessary for its targeting to the cell
CC membrane (By similarity). {ECO:0000250}.
CC -!- PTM: Ubiquitinated by NEDD4, leading to proteasomal degradation.
CC {ECO:0000250}.
CC -!- PTM: Phosphorylation by PLK2 promotes its activity. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the RAPGEF2 family. {ECO:0000305}.
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DR EMBL; DAAA02044847; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; NP_001178255.1; NM_001191326.1.
DR AlphaFoldDB; F1MSG6; -.
DR IntAct; F1MSG6; 2.
DR STRING; 9913.ENSBTAP00000029739; -.
DR PaxDb; F1MSG6; -.
DR PRIDE; F1MSG6; -.
DR Ensembl; ENSBTAT00000029742; ENSBTAP00000029739; ENSBTAG00000012450.
DR GeneID; 100139484; -.
DR KEGG; bta:100139484; -.
DR CTD; 9693; -.
DR VEuPathDB; HostDB:ENSBTAG00000012450; -.
DR VGNC; VGNC:33723; RAPGEF2.
DR eggNOG; KOG3542; Eukaryota.
DR GeneTree; ENSGT00940000156418; -.
DR HOGENOM; CLU_002782_0_1_1; -.
DR InParanoid; F1MSG6; -.
DR OrthoDB; 31139at2759; -.
DR TreeFam; TF313184; -.
DR Proteomes; UP000009136; Chromosome 17.
DR Bgee; ENSBTAG00000012450; Expressed in cardiac ventricle and 107 other tissues.
DR ExpressionAtlas; F1MSG6; baseline and differential.
DR GO; GO:0016324; C:apical plasma membrane; IBA:GO_Central.
DR GO; GO:0005911; C:cell-cell junction; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0030139; C:endocytic vesicle; IBA:GO_Central.
DR GO; GO:0005770; C:late endosome; ISS:UniProtKB.
DR GO; GO:0043005; C:neuron projection; ISS:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; ISS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; ISS:UniProtKB.
DR GO; GO:0045202; C:synapse; ISS:UniProtKB.
DR GO; GO:0031697; F:beta-1 adrenergic receptor binding; ISS:UniProtKB.
DR GO; GO:0030552; F:cAMP binding; IDA:UniProtKB.
DR GO; GO:0005096; F:GTPase activator activity; IEA:UniProtKB-KW.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; ISS:UniProtKB.
DR GO; GO:0030165; F:PDZ domain binding; ISS:UniProtKB.
DR GO; GO:0050699; F:WW domain binding; ISS:UniProtKB.
DR GO; GO:0071880; P:adenylate cyclase-activating adrenergic receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0001568; P:blood vessel development; ISS:UniProtKB.
DR GO; GO:0031547; P:brain-derived neurotrophic factor receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0019933; P:cAMP-mediated signaling; ISS:UniProtKB.
DR GO; GO:0071320; P:cellular response to cAMP; ISS:UniProtKB.
DR GO; GO:0071321; P:cellular response to cGMP; ISS:UniProtKB.
DR GO; GO:1990090; P:cellular response to nerve growth factor stimulus; ISS:UniProtKB.
DR GO; GO:0061028; P:establishment of endothelial barrier; ISS:UniProtKB.
DR GO; GO:0021884; P:forebrain neuron development; ISS:UniProtKB.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:0050774; P:negative regulation of dendrite morphogenesis; ISS:UniProtKB.
DR GO; GO:0048022; P:negative regulation of melanin biosynthetic process; ISS:UniProtKB.
DR GO; GO:0038180; P:nerve growth factor signaling pathway; ISS:UniProtKB.
DR GO; GO:0001764; P:neuron migration; ISS:UniProtKB.
DR GO; GO:0031175; P:neuron projection development; ISS:UniProtKB.
DR GO; GO:0007218; P:neuropeptide signaling pathway; ISS:UniProtKB.
DR GO; GO:2000481; P:positive regulation of cAMP-dependent protein kinase activity; ISS:UniProtKB.
DR GO; GO:0043950; P:positive regulation of cAMP-mediated signaling; ISS:UniProtKB.
DR GO; GO:2000670; P:positive regulation of dendritic cell apoptotic process; ISS:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0043547; P:positive regulation of GTPase activity; ISS:UniProtKB.
DR GO; GO:2001224; P:positive regulation of neuron migration; ISS:UniProtKB.
DR GO; GO:0010976; P:positive regulation of neuron projection development; ISS:UniProtKB.
DR GO; GO:0032092; P:positive regulation of protein binding; ISS:UniProtKB.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; ISS:UniProtKB.
DR GO; GO:2001214; P:positive regulation of vasculogenesis; ISS:UniProtKB.
DR GO; GO:0032486; P:Rap protein signal transduction; ISS:UniProtKB.
DR GO; GO:0007265; P:Ras protein signal transduction; IBA:GO_Central.
DR GO; GO:1901888; P:regulation of cell junction assembly; ISS:UniProtKB.
DR GO; GO:0021591; P:ventricular system development; ISS:UniProtKB.
DR CDD; cd00038; CAP_ED; 1.
DR CDD; cd00155; RasGEF; 1.
DR CDD; cd06224; REM; 1.
DR Gene3D; 1.10.840.10; -; 1.
DR Gene3D; 2.30.42.10; -; 1.
DR Gene3D; 2.60.120.10; -; 1.
DR InterPro; IPR018490; cNMP-bd-like.
DR InterPro; IPR000595; cNMP-bd_dom.
DR InterPro; IPR001478; PDZ.
DR InterPro; IPR036034; PDZ_sf.
DR InterPro; IPR000159; RA_dom.
DR InterPro; IPR030739; RapGEF2.
DR InterPro; IPR008937; Ras-like_GEF.
DR InterPro; IPR000651; Ras-like_Gua-exchang_fac_N.
DR InterPro; IPR023578; Ras_GEF_dom_sf.
DR InterPro; IPR001895; RASGEF_cat_dom.
DR InterPro; IPR036964; RASGEF_cat_dom_sf.
DR InterPro; IPR014710; RmlC-like_jellyroll.
DR InterPro; IPR029071; Ubiquitin-like_domsf.
DR PANTHER; PTHR23113; PTHR23113; 1.
DR PANTHER; PTHR23113:SF217; PTHR23113:SF217; 1.
DR Pfam; PF00595; PDZ; 1.
DR Pfam; PF00788; RA; 1.
DR Pfam; PF00617; RasGEF; 1.
DR Pfam; PF00618; RasGEF_N; 1.
DR SMART; SM00100; cNMP; 1.
DR SMART; SM00228; PDZ; 1.
DR SMART; SM00314; RA; 1.
DR SMART; SM00147; RasGEF; 1.
DR SMART; SM00229; RasGEFN; 1.
DR SUPFAM; SSF48366; SSF48366; 1.
DR SUPFAM; SSF50156; SSF50156; 1.
DR SUPFAM; SSF51206; SSF51206; 1.
DR SUPFAM; SSF54236; SSF54236; 1.
DR PROSITE; PS50042; CNMP_BINDING_3; 1.
DR PROSITE; PS50106; PDZ; 1.
DR PROSITE; PS50200; RA; 1.
DR PROSITE; PS50009; RASGEF_CAT; 1.
DR PROSITE; PS50212; RASGEF_NTER; 1.
PE 1: Evidence at protein level;
KW Cell junction; Cell membrane; Cytoplasm; Developmental protein;
KW Differentiation; Endosome; GTPase activation;
KW Guanine-nucleotide releasing factor; Membrane; Neurogenesis;
KW Phosphoprotein; Reference proteome; Ubl conjugation.
FT CHAIN 1..1486
FT /note="Rap guanine nucleotide exchange factor 2"
FT /id="PRO_0000423853"
FT DOMAIN 267..380
FT /note="N-terminal Ras-GEF"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00135"
FT DOMAIN 385..468
FT /note="PDZ"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143"
FT DOMAIN 606..692
FT /note="Ras-associating"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00166"
FT DOMAIN 717..944
FT /note="Ras-GEF"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00168"
FT REGION 40..59
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 68..101
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1002..1049
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1090..1176
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1221..1254
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1303..1357
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1391..1486
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 81..96
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1033..1047
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1103..1161
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1303..1333
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1336..1350
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 135..252
FT /ligand="a nucleoside 3',5'-cyclic phosphate"
FT /ligand_id="ChEBI:CHEBI:58464"
FT MOD_RES 501
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:F1M386"
FT MOD_RES 644
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:F1M386"
FT MOD_RES 806
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:F1M386"
FT MOD_RES 930
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:F1M386"
FT MOD_RES 933
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:F1M386"
FT MOD_RES 1022
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8CHG7"
FT MOD_RES 1077
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4G8"
FT MOD_RES 1086
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4G8"
FT MOD_RES 1092
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4G8"
FT MOD_RES 1113
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8CHG7"
FT MOD_RES 1117
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8CHG7"
FT MOD_RES 1156
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4G8"
FT MOD_RES 1173
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:F1M386"
SQ SEQUENCE 1486 AA; 165144 MW; 74F841446BDEC76F CRC64;
MKPLAIPANH GVMGQQEKHS LPADFTKLHL TDSLHPQVTH VSSSHSGCSI TSDSGSSSLS
DIYQATESEA GDMDLSGLPE TAVDSEDDDD EEDIERASDP LMSRDIVRDC LEKDPIDRTD
DDIEQLLEFM HQLPAFANMT MSVRRELCAV MVFAVVERAG TIVLNDGEEL DSWSVILNGS
VEVTYPDGKA EILCMGNSFG VSPTMDKEYM KGVMRTKVDD CQFVCIAQQD YCRILNQVEK
NMQKVEEEGE IVMVKEHREL DRTGTRKGHI VIKGTSERLT MHLVEEHSVV DPTFIEDFLL
TYRTFLCSPM EVGKKLLEWF NDPSLRDKVT RVVLLWVNNH FNDFEGDPAM TRFLEEFENN
LEREKMGGHL RLLNIACAAK AKRRLMTLTK PAREAPLPFI LLGGSEKGFG IFVDSVDSAS
KATEAGLKRG DQILEVNGQN FENIQLSKAM EILRNNTHLS ITVKTNLFVF KELLTRLSEE
KRNGAPHLPK IGDIKKASRY SIPDLAVDVE QVIGLEKVNK KSKANTVGGR NKLKKILDKT
RISILPQKPY NDIGIGQSQD DSIVGLRQTK HIPTALPVSG TLSSSNPDLL QSHHRILDFS
ATPDLPDQVL RVFKADQQSR YIMISKDTTA KEVVVQAIRE FAVTATPDQY SLCEVSVTPE
GVIKQRRLPD QLSKLADRIQ LSGRYYLKNN METETLCSDE DAQELLRESQ ISLLQLSTVE
VATQLSMRNF ELFRNIEPTE YIDDLFKLKS KTSCANLKTF EEVINQETFW VASEILRETN
QLKRMKIIKH FIKIALHCRE CKNFNSMFAI ISGLNLAPVA RLRTTWEKLP NKYEKLFQDL
QDLFDPSRNM AKYRNVLNSQ NLQPPIIPLF PVIKKDLTFL HEGNDSKVDG LVNFEKLRMI
AKEIRHVGRM ASVNMDPALM FRTRKKKWRS LGSLSQGSTN ATVLDVAQTG GHKKRVRRSS
FLNAKKLYED AQMARKVKQY LSNLELEMDE ESLQTLSLQC EPATNTLPKN PTDKKPVKSE
TSPVAPRAGL QPKAQPQPQP PQPPHKLNQG LQVPAVSLYP SRKKVPVKDL PPFGINSPQA
LKKILSLSEE GSLERHRRPA EDTISNTSSQ LSSPPTSPQS SPRKGYTLAP SGTVDNFSDS
GHSEISSRSS IVSNSSFDSL PVSLPDERRQ RPSVSIVETS LASGRLERRP AVEPDQYSLG
SCAPLSESRG LYAAATVISS PSTEELSQDQ GDRASLDAAD SGRGSWTSCS SGSHDNIQTI
QHQRSWETLP FGHTHFDYPG DAAGLWASSS HMDQIMFPDH SAKYSRQSQS RESLDQAQSR
ASWASSTGYW GEDSEGDTGT IKRRGGKDVS LDADSSSMTA VTAEEAKPAA MAAHIAVTPS
AAKGLIARKE GRYREPPPTP PGYVGIPITD FPEAHPHPAR KPPDYTVALQ RSRMLARPAE
PPAPGSARPA PRPQWHRPGD GDPRAGPCAP PGLTAEEDED EQVSAV
