ARHG2_CANLF
ID ARHG2_CANLF Reviewed; 986 AA.
AC Q865S3; Q865S2;
DT 22-JUL-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2003, sequence version 1.
DT 25-MAY-2022, entry version 126.
DE RecName: Full=Rho guanine nucleotide exchange factor 2;
DE AltName: Full=Guanine nucleotide exchange factor H1;
DE Short=GEF-H1;
DE AltName: Full=Tight junction-associated guanine nucleotide exchange factor isoform A;
GN Name=ARHGEF2;
OS Canis lupus familiaris (Dog) (Canis familiaris).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX NCBI_TaxID=9615;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=12604587; DOI=10.1083/jcb.200211047;
RA Benais-Pont G., Punn A., Flores-Maldonado C., Eckert J., Raposo G.,
RA Fleming T.P., Cereijido M., Balda M.S., Matter K.;
RT "Identification of a tight junction-associated guanine nucleotide exchange
RT factor that activates Rho and regulates paracellular permeability.";
RL J. Cell Biol. 160:729-740(2003).
RN [2]
RP REVIEW ON FUNCTION.
RX PubMed=18394899; DOI=10.1016/j.tcb.2008.02.006;
RA Birkenfeld J., Nalbant P., Yoon S.-H., Bokoch G.M.;
RT "Cellular functions of GEF-H1, a microtubule-regulated Rho-GEF: is altered
RT GEF-H1 activity a crucial determinant of disease pathogenesis?";
RL Trends Cell Biol. 18:210-219(2008).
RN [3]
RP INTERACTION WITH DYNLT1, AND MUTAGENESIS OF ARG-138; ARG-139; GLY-140;
RP VAL-150 AND SER-151.
RX PubMed=27502274; DOI=10.1074/jbc.m116.736884;
RA Merino-Gracia J., Zamora-Carreras H., Bruix M., Rodriguez-Crespo I.;
RT "Molecular basis for the protein recognition specificity of the dynein
RT light chain DYNLT1/Tctex1: characterization of the interaction with activin
RT receptor IIB.";
RL J. Biol. Chem. 291:20962-20975(2016).
CC -!- FUNCTION: Activates Rho-GTPases by promoting the exchange of GDP for
CC GTP. May be involved in epithelial barrier permeability, cell motility
CC and polarization, dendritic spine morphology, antigen presentation,
CC leukemic cell differentiation, cell cycle regulation, innate immune
CC response, and cancer. Binds Rac-GTPases, but does not seem to promote
CC nucleotide exchange activity toward Rac-GTPases. May stimulate instead
CC the cortical activity of Rac. Inactive toward CDC42, TC10, or Ras-
CC GTPases. Forms an intracellular sensing system along with NOD1 for the
CC detection of microbial effectors during cell invasion by pathogens.
CC Involved in innate immune signaling transduction pathway promoting
CC cytokine IL6/interleukin-6 and TNF-alpha secretion in macrophage upon
CC stimulation by bacterial peptidoglycans; acts as a signaling
CC intermediate between NOD2 receptor and RIPK2 kinase. Contributes to the
CC tyrosine phosphorylation of RIPK2 through Src tyrosine kinase leading
CC to NF-kappaB activation by NOD2. Involved in neuronal progenitor cell
CC division and differentiation. Involved in the migration of
CC precerebellar neurons (By similarity). Overexpression activates Rho-,
CC but not Rac-GTPases, and increases paracellular permeability
CC (PubMed:12604587). {ECO:0000250, ECO:0000250|UniProtKB:Q60875,
CC ECO:0000269|PubMed:12604587}.
CC -!- SUBUNIT: Interacts with YWHAZ/14-3-3 zeta; when phosphorylated at Ser-
CC 886. Interacts with the kinases PAK4, AURKA and MAPK1. Interacts with
CC RHOA and RAC1. Interacts with NOD1. Interacts (via the N- terminal zinc
CC finger) with CAPN6 (via domain II). Found in a complex composed at
CC least of ARHGEF2, NOD2 and RIPK2. Interacts with RIPK2; the interaction
CC mediates tyrosine phosphorylation of RIPK2 by Src kinase CSK. Interacts
CC with RIPK1 and RIPK3 (By similarity). Interacts with DYNLT1.
CC {ECO:0000250, ECO:0000269|PubMed:27502274}.
CC -!- INTERACTION:
CC Q865S3; Q9N1Q2: ZONAB; NbExp=5; IntAct=EBI-7207989, EBI-7207962;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
CC {ECO:0000269|PubMed:12604587}. Cytoplasm {ECO:0000269|PubMed:12604587}.
CC Cell junction, tight junction {ECO:0000269|PubMed:12604587}. Golgi
CC apparatus {ECO:0000250|UniProtKB:Q92974}. Cytoplasm, cytoskeleton,
CC spindle {ECO:0000269|PubMed:12604587}. Cytoplasmic vesicle
CC {ECO:0000250|UniProtKB:Q92974}. Note=Colocalized with NOD2 and RIPK2 in
CC vesicles and with the cytoskeleton (By similarity). Localizes to the
CC mitotic spindle in mitotic cells, and to tight junctions in interphase
CC cells (PubMed:12604587). {ECO:0000250|UniProtKB:Q92974,
CC ECO:0000269|PubMed:12604587}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q865S3-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q865S3-2; Sequence=VSP_034959;
CC -!- DOMAIN: The DH (DBL-homology) domain promotes tyrosine phosphorylation
CC of RIPK2 (By similarity). The DH (DBL-homology) domain interacts with
CC and promotes loading of GTP on RhoA. {ECO:0000250}.
CC -!- DOMAIN: The PH domain has no affinity for phosphoinositides suggesting
CC that it does not interact directly with membranes.
CC {ECO:0000250|UniProtKB:Q92974}.
CC -!- DOMAIN: The phorbol-ester/DAG-type zinc-finger and the C-terminal
CC coiled-coil domains (606-986) are both important for association with
CC microtubules. {ECO:0000250|UniProtKB:Q92974}.
CC -!- PTM: Phosphorylation of Ser-886 by PAK1 induces binding to protein
CC YWHAZ, promoting its relocation to microtubules and the inhibition of
CC its activity. Phosphorylated by AURKA and CDK1 during mitosis, which
CC negatively regulates its activity. Phosphorylation by MAPK1 or MAPK3
CC increases nucleotide exchange activity. Phosphorylation by PAK4
CC releases GEF-H1 from the microtubules. Phosphorylated on serine,
CC threonine and tyrosine residues in a RIPK2-dependent manner (By
CC similarity). {ECO:0000250}.
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DR EMBL; AF494096; AAO91667.1; -; mRNA.
DR EMBL; AF494097; AAO91668.1; -; mRNA.
DR RefSeq; NP_001002995.1; NM_001002995.1. [Q865S3-1]
DR RefSeq; NP_001006123.1; NM_001006123.1.
DR AlphaFoldDB; Q865S3; -.
DR SMR; Q865S3; -.
DR IntAct; Q865S3; 3.
DR MINT; Q865S3; -.
DR STRING; 9615.ENSCAFP00000057462; -.
DR PaxDb; Q865S3; -.
DR GeneID; 403498; -.
DR KEGG; cfa:403498; -.
DR CTD; 9181; -.
DR eggNOG; KOG3520; Eukaryota.
DR InParanoid; Q865S3; -.
DR OrthoDB; 69816at2759; -.
DR Proteomes; UP000002254; Unplaced.
DR GO; GO:0005923; C:bicellular tight junction; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:UniProtKB-KW.
DR GO; GO:0005856; C:cytoskeleton; ISS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0005874; C:microtubule; ISS:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; ISS:UniProtKB.
DR GO; GO:0032587; C:ruffle membrane; ISS:UniProtKB.
DR GO; GO:0005819; C:spindle; IEA:UniProtKB-SubCell.
DR GO; GO:0031982; C:vesicle; ISS:UniProtKB.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008017; F:microtubule binding; ISS:UniProtKB.
DR GO; GO:0031267; F:small GTPase binding; ISS:UniProtKB.
DR GO; GO:0007015; P:actin filament organization; ISS:UniProtKB.
DR GO; GO:0055059; P:asymmetric neuroblast division; ISS:UniProtKB.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0000902; P:cell morphogenesis; ISS:UniProtKB.
DR GO; GO:0071474; P:cellular hyperosmotic response; IMP:BHF-UCL.
DR GO; GO:0071225; P:cellular response to muramyl dipeptide; ISS:UniProtKB.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IMP:BHF-UCL.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; IMP:BHF-UCL.
DR GO; GO:1902219; P:negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress; IMP:BHF-UCL.
DR GO; GO:0007026; P:negative regulation of microtubule depolymerization; ISS:UniProtKB.
DR GO; GO:0060546; P:negative regulation of necroptotic process; IMP:BHF-UCL.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISS:UniProtKB.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; ISS:UniProtKB.
DR GO; GO:2001224; P:positive regulation of neuron migration; ISS:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:UniProtKB.
DR GO; GO:0035023; P:regulation of Rho protein signal transduction; IBA:GO_Central.
DR CDD; cd00029; C1; 1.
DR CDD; cd13393; PH_ARHGEF2; 1.
DR CDD; cd00160; RhoGEF; 1.
DR Gene3D; 1.20.900.10; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR037806; ARHGEF2_PH.
DR InterPro; IPR046349; C1-like_sf.
DR InterPro; IPR035899; DBL_dom_sf.
DR InterPro; IPR000219; DH-domain.
DR InterPro; IPR002219; PE/DAG-bd.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR041020; PH_16.
DR InterPro; IPR001849; PH_domain.
DR Pfam; PF17838; PH_16; 1.
DR Pfam; PF00621; RhoGEF; 1.
DR SMART; SM00109; C1; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00325; RhoGEF; 1.
DR SUPFAM; SSF48065; SSF48065; 1.
DR SUPFAM; SSF57889; SSF57889; 1.
DR PROSITE; PS50010; DH_2; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS00479; ZF_DAG_PE_1; 1.
DR PROSITE; PS50081; ZF_DAG_PE_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Cell cycle; Cell division;
KW Cell junction; Coiled coil; Cytoplasm; Cytoplasmic vesicle; Cytoskeleton;
KW Developmental protein; Differentiation; Golgi apparatus;
KW Guanine-nucleotide releasing factor; Immunity; Innate immunity;
KW Metal-binding; Microtubule; Mitosis; Neurogenesis; Phosphoprotein;
KW Proto-oncogene; Reference proteome; Tight junction; Zinc; Zinc-finger.
FT CHAIN 1..986
FT /note="Rho guanine nucleotide exchange factor 2"
FT /id="PRO_0000345622"
FT DOMAIN 236..433
FT /note="DH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00062"
FT DOMAIN 473..572
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT ZN_FING 39..86
FT /note="Phorbol-ester/DAG-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00226"
FT REGION 1..30
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 131..161
FT /note="Interaction with DYNLT1"
FT /evidence="ECO:0000269|PubMed:27502274"
FT REGION 687..707
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 862..887
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 893..912
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 920..986
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 591..612
FT /evidence="ECO:0000255"
FT COILED 798..867
FT /evidence="ECO:0000255"
FT COMPBIAS 693..707
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 920..949
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 965..986
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 109
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 122
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 129
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 133
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 137
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 143
FT /note="Phosphoserine; by PAK4"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 151
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 163
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 172
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 174
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 177
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 354
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 645
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 679
FT /note="Phosphothreonine; by MAPK1 or MAPK3"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 691
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 696
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 711
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 782
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q60875"
FT MOD_RES 886
FT /note="Phosphoserine; by PAK1 and AURKA"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 894
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 896
FT /note="Phosphoserine; by PAK4"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 932
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 940
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 941
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 945
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 947
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 956
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT MOD_RES 960
FT /note="Phosphoserine; by CDK1"
FT /evidence="ECO:0000250|UniProtKB:Q92974"
FT VAR_SEQ 902..923
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:12604587"
FT /id="VSP_034959"
FT MUTAGEN 138
FT /note="R->A: Decreases interaction with DYNLT1; when
FT associated with A-139."
FT /evidence="ECO:0000269|PubMed:27502274"
FT MUTAGEN 139
FT /note="R->A: Decreases interaction with DYNLT1; when
FT associated with A-138."
FT /evidence="ECO:0000269|PubMed:27502274"
FT MUTAGEN 140
FT /note="G->A: Decreases interaction with DYNLT1."
FT /evidence="ECO:0000269|PubMed:27502274"
FT MUTAGEN 150
FT /note="V->A: Disrupts interaction with DYNLT1; when
FT associated with A-151."
FT /evidence="ECO:0000269|PubMed:27502274"
FT MUTAGEN 151
FT /note="S->A: Disrupts interaction with DYNLT1; when
FT associated with A-150."
FT /evidence="ECO:0000269|PubMed:27502274"
FT CONFLICT 978
FT /note="D -> E (in Ref. 1; AAO91668)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 986 AA; 111516 MW; 2D72FFB44F108290 CRC64;
MSRIESLTRA RTERSRELAS KNREKEKMKE AKDARYTNGH LFTTISVSGM TMCYACNKSI
TAKEALICPT CNVTIHNRCK DTLANCTKVK QKQQKAALLK NSTALQSVSL RSKTTPRERP
SSAIYPSDSF RQSLLGSRRG RSSLSLAKSV STTNIAGHFS DESPLGLRRI LSQSTDSLNM
RNRALSVESL IDEGAEVIYS ELMSDFETDE RDFAADSWSL AVDSSFLQQQ KKEVMKQQDV
IYELIQTELH HVRTLKIMTR LFRTGMLEEL QLEPGVVQGL FPCVDELSDI HTRFLSQLLE
RRRQALCPGS TRNFVIHRLA DLLISQFSGP SAERMRKAYS EFCSRHTKAL KLYKELYARD
KRFQQFIRKV TRSAVLKRHG VQECILLVTQ RITKYPVLIN RILQHSHGTD EERQDLTTAL
GLVKELLSNV DQDVHELEKG ARLQEIYHRM DPRAQAPVPS KGPFGREELL RRKLIHDGCL
LWKTATGRFK DVLMLLMTDV LVFLQEKDQK YIFPALDKPS VVSLQNLIVR DIANQEKGMF
LISAAPPEMY EVHTASRDDR STWVRVIQQS VRVCPSREDF PLIETEDEAY LRRIKMELQQ
KDKALVELLR EKVGLFAEMT HFQVEEDSGG VALPALPRGL FRSESLECPR GERLLQDAIR
EVEGLKDLLV GPGVELLLTP RDPALLVDPD SGGSTSPGVT ANGEARNFNG SIELCRTDSD
SSQKDRNGNQ LRAPQEEALQ RLVNLYGLLH GLQAAVAQQD TLMEARFPEG PERREKLARA
NSRDGEAGRV GPAPVAPDKQ ATELALLQRQ HALLQEELRR CRRLGEERAT EAGNLEARLR
ESEQARALLE REAEEARRQL AILGQSEPPP AEAPWARRPL DPRRRSLPAG DALYLSFTPP
QPSRGHDRLD LSVTIRSVHR PFEDRERQEL GSPEERLQDS SDPDTGSEEE GGGRLSPPHS
PRDFTRMQDI PEETESRDGE PMVSES
