ID EPS8_PONAB Reviewed; 822 AA.
AC Q5R4H4; K7EUA3; Q5RDX8;
DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2013, sequence version 2.
DT 13-SEP-2023, entry version 104.
DE RecName: Full=Epidermal growth factor receptor kinase substrate 8;
GN Name=EPS8;
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex, and Kidney;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Wilson R.K., Mardis E.;
RT "A 6x draft sequence assembly of the Pongo pygmaeus abelii genome.";
RL Submitted (FEB-2008) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Signaling adapter that controls various cellular protrusions
CC by regulating actin cytoskeleton dynamics and architecture. Depending
CC on its association with other signal transducers, can regulate
CC different processes. Together with SOS1 and ABI1, forms a trimeric
CC complex that participates in transduction of signals from Ras to Rac by
CC activating the Rac-specific guanine nucleotide exchange factor (GEF)
CC activity. Acts as a direct regulator of actin dynamics by binding actin
CC filaments and has both barbed-end actin filament capping and actin
CC bundling activities depending on the context. Displays barbed-end actin
CC capping activity when associated with ABI1, thereby regulating actin-
CC based motility process: capping activity is auto-inhibited and
CC inhibition is relieved upon ABI1 interaction. Also shows actin bundling
CC activity when associated with BAIAP2, enhancing BAIAP2-dependent
CC membrane extensions and promoting filopodial protrusions. Involved in
CC the regulation of processes such as axonal filopodia growth,
CC stereocilia length, dendritic cell migration and cancer cell migration
CC and invasion. Acts as a regulator of axonal filopodia formation in
CC neurons: in the absence of neurotrophic factors, negatively regulates
CC axonal filopodia formation via actin-capping activity. In contrast, it
CC is phosphorylated in the presence of BDNF leading to inhibition of its
CC actin-capping activity and stimulation of filopodia formation.
CC Component of a complex with WHRN and MYO15A that localizes at
CC stereocilia tips and is required for elongation of the stereocilia
CC actin core. Indirectly involved in cell cycle progression; its
CC degradation following ubiquitination being required during G2 phase to
CC promote cell shape changes (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Homodimer. Part of a complex consisting of ABI1, EPS8 and
CC SOS1. Interacts with BAIAP2. Interacts with SHB and LANCL1. Interacts
CC with EGFR; mediates EPS8 phosphorylation. Interacts with MYO15A and
CC WHRN (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cell cortex {ECO:0000250}. Cell
CC projection, ruffle membrane {ECO:0000250}. Cell projection, growth cone
CC {ECO:0000250}. Cell projection, stereocilium {ECO:0000250,
CC ECO:0000250|UniProtKB:Q08509}. Synapse, synaptosome {ECO:0000250}.
CC Note=Localizes at the tips of the stereocilia of the inner and outer
CC hair cells (By similarity). Localizes to the midzone of dividing cells.
CC {ECO:0000250, ECO:0000250|UniProtKB:Q08509}.
CC -!- DOMAIN: The effector region is required for activating the Rac-specific
CC guanine nucleotide exchange factor (GEF) activity. It mediates both
CC barbed-end actin capping and actin bundling activities. The capping
CC activity is mediated by an amphipathic helix that binds within the
CC hydrophobic pocket at the barbed ends of actin blocking further
CC addition of actin monomers, while the bundling activity is mediated by
CC a compact 4 helix bundle, which contacts 3 actin subunits along the
CC filament (By similarity). {ECO:0000250}.
CC -!- DOMAIN: The SH3 domain mediates interaction with SHB. {ECO:0000250}.
CC -!- PTM: Ubiquitinated by the SCF(FBXW5) E3 ubiquitin-protein ligase
CC complex during G2 phase, leading to its transient degradation and
CC subsequent cell shape changes required to allow mitotic progression.
CC Reappears at the midzone of dividing cells (By similarity).
CC {ECO:0000250}.
CC -!- PTM: Phosphorylation at Ser-625 and Thr-629 by MAPK following BDNF
CC treatment promotes removal from actin and filopodia formation.
CC Phosphorylated by several receptor tyrosine kinases (By similarity).
CC {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the EPS8 family. {ECO:0000305}.
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DR EMBL; CR857764; CAH90029.1; -; mRNA.
DR EMBL; CR861274; CAH93342.1; -; mRNA.
DR EMBL; ABGA01225282; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225283; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225284; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225285; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225286; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225287; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225288; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225289; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225290; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225291; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225292; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225293; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225294; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225295; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225296; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225297; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225298; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225299; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ABGA01225300; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; NP_001127655.1; NM_001134183.1.
DR RefSeq; XP_009245788.1; XM_009247513.1.
DR AlphaFoldDB; Q5R4H4; -.
DR SMR; Q5R4H4; -.
DR STRING; 9601.ENSPPYP00000004948; -.
DR GeneID; 100174737; -.
DR KEGG; pon:100174737; -.
DR CTD; 2059; -.
DR eggNOG; KOG3557; Eukaryota.
DR HOGENOM; CLU_014510_0_0_1; -.
DR InParanoid; Q5R4H4; -.
DR OrthoDB; 2997036at2759; -.
DR Proteomes; UP000001595; Chromosome 12.
DR GO; GO:0005938; C:cell cortex; ISS:UniProtKB.
DR GO; GO:0030426; C:growth cone; IEA:UniProtKB-SubCell.
DR GO; GO:0032587; C:ruffle membrane; ISS:UniProtKB.
DR GO; GO:0032420; C:stereocilium; ISS:UniProtKB.
DR GO; GO:0045202; C:synapse; IEA:UniProtKB-SubCell.
DR GO; GO:0003779; F:actin binding; ISS:UniProtKB.
DR GO; GO:0031267; F:small GTPase binding; ISS:UniProtKB.
DR GO; GO:0051764; P:actin crosslink formation; ISS:UniProtKB.
DR GO; GO:0051017; P:actin filament bundle assembly; ISS:UniProtKB.
DR GO; GO:0070358; P:actin polymerization-dependent cell motility; ISS:UniProtKB.
DR GO; GO:0051016; P:barbed-end actin filament capping; ISS:UniProtKB.
DR GO; GO:0036336; P:dendritic cell migration; ISS:UniProtKB.
DR GO; GO:0010458; P:exit from mitosis; ISS:UniProtKB.
DR GO; GO:0016601; P:Rac protein signal transduction; ISS:UniProtKB.
DR GO; GO:0030832; P:regulation of actin filament length; ISS:UniProtKB.
DR GO; GO:0008360; P:regulation of cell shape; ISS:UniProtKB.
DR CDD; cd01210; PTB_EPS8; 1.
DR CDD; cd09540; SAM_EPS8-like; 1.
DR CDD; cd11764; SH3_Eps8; 1.
DR Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 1.
DR Gene3D; 2.30.30.40; SH3 Domains; 1.
DR Gene3D; 1.10.150.50; Transcription Factor, Ets-1; 1.
DR InterPro; IPR039801; EPS8-like.
DR InterPro; IPR033928; EPS8_PTB.
DR InterPro; IPR035462; Eps8_SH3.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR013625; PTB.
DR InterPro; IPR006020; PTB/PI_dom.
DR InterPro; IPR013761; SAM/pointed_sf.
DR InterPro; IPR041418; SAM_3.
DR InterPro; IPR036028; SH3-like_dom_sf.
DR InterPro; IPR001452; SH3_domain.
DR PANTHER; PTHR12287:SF21; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE SUBSTRATE 8; 1.
DR PANTHER; PTHR12287; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE SUBSTRATE EPS8-RELATED PROTEIN; 1.
DR Pfam; PF08416; PTB; 1.
DR Pfam; PF18016; SAM_3; 1.
DR Pfam; PF00018; SH3_1; 1.
DR SMART; SM00462; PTB; 1.
DR SMART; SM00326; SH3; 1.
DR SUPFAM; SSF50729; PH domain-like; 1.
DR SUPFAM; SSF50044; SH3-domain; 1.
DR PROSITE; PS50002; SH3; 1.
PE 2: Evidence at transcript level;
KW Actin-binding; Cell membrane; Cell projection; Cytoplasm; Membrane;
KW Phosphoprotein; Reference proteome; SH3 domain; Synapse; Synaptosome;
KW Ubl conjugation.
FT CHAIN 1..822
FT /note="Epidermal growth factor receptor kinase substrate 8"
FT /id="PRO_0000086996"
FT DOMAIN 64..194
FT /note="PTB"
FT /evidence="ECO:0000255"
FT DOMAIN 531..590
FT /note="SH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT REGION 1..39
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 201..225
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 298..320
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 612..689
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 649..822
FT /note="Effector region"
FT /evidence="ECO:0000250"
FT REGION 680..698
FT /note="Amphipathic helix"
FT /evidence="ECO:0000250"
FT REGION 718..738
FT /note="Helix bundle 1"
FT /evidence="ECO:0000250"
FT REGION 752..757
FT /note="Helix bundle 2"
FT /evidence="ECO:0000250"
FT REGION 762..767
FT /note="Helix bundle 3"
FT /evidence="ECO:0000250"
FT REGION 766..785
FT /note="Helix bundle 4"
FT /evidence="ECO:0000250"
FT REGION 787..822
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..34
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 206..220
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 617..646
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 651..668
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 674..689
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 58
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:F1M3L7"
FT MOD_RES 223
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q12929"
FT MOD_RES 317
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q08509"
FT MOD_RES 476
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12929"
FT MOD_RES 625
FT /note="Phosphoserine; by MAPK"
FT /evidence="ECO:0000250|UniProtKB:Q08509"
FT MOD_RES 629
FT /note="Phosphothreonine; by MAPK"
FT /evidence="ECO:0000250|UniProtKB:Q08509"
FT MOD_RES 659
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q08509"
FT MOD_RES 662
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q08509"
FT MOD_RES 685
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q08509"
FT MOD_RES 811
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q08509"
FT MOD_RES 815
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q08509"
FT CONFLICT 41
FT /note="A -> V (in Ref. 1; CAH90029)"
FT /evidence="ECO:0000305"
FT CONFLICT 270
FT /note="V -> A (in Ref. 1; CAH90029)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 822 AA; 91972 MW; 32ABBCDE17505774 CRC64;
MNGHISNHPS SFEMYPSQMN GYGSSPTFSQ MDREHGSKTS AKALYEQRKN YARDSVSSVS
DISQYRVEHL TTFVLDRKDA MITVDDGIRK LKLLDAKGKV WTQDMILQVD DRAVSLIDLE
SKNELENFPL NTIQHCQAVM HSCSYDSVLA LVCKEPTQNK PDLHLFQCDE VKANLISEDI
ESAISDSKGG KQKRRPDALR MISNADPGIP PPPRAPAPAP PGTVTQVDVR SRVAAWSAWA
ADQGDFEKPR QYHEQEETPE MMAARIDRDV QILNHILDDI EFFITKLQKA AEAFSELSKR
KKNKKGKRKG PGEGVLTLRA KPPPPDEFLD CFQKFKHGFN LLAKLKSHIQ NPSAADLVHF
LFTPLNMVVQ ATGGPELASS VLSPLLNKDT IDFLNYTVNG DERQLWMSLG GTWTKARAEW
PKEQFIPPYV PRFRNGWEPP MLNFMGATME QDLYQLAESV ANVAEHQRKQ EIKRLSTEHS
SVSEYHPADG YAFSSNIYTR GSHLDQGEAA VAFKPTSNRH IDRNYEPLKT QPKKYAKSKY
DFVARNNSEL SVLKDDILEI LDDRKQWWKV RNASGDSGFV PNNILDIVRP PESGLGRADP
PYTHTIQKQR MEYGPRPADT PPAPSPPPTP APVPVPLPPS TPAPVPVSKF PANITRQNSS
SSDSGGSIVR DSQRHKQLPV DRRKSQMEEV QDELIHRLTI GRSAAQKKFH VPRQNVPVIN
ITYDSTPEDV KTWLQSKGFN PVTVNSLGVL NGAQLFSLNK DELRTVCPEG ARVYSQITVQ
KAALEDSSGS SELQEIMRRR QEKISAAASD SGVESFDEGS SH
//
