Q5R4H4 (EPS8_PONAB) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Epidermal growth factor receptor kinase substrate 8

Gene names

Name:

EPS8

Organism

Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii) [Reference proteome]

Taxonomic identifier

9601 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Ponginae › Pongo

Protein attributes

Sequence length	822 AA.
Sequence status	Complete.
Protein existence	Evidence at transcript level

General annotation (Comments)

Function	Signaling adapter that controls various cellular protrusions by regulating actin cytoskeleton dynamics and architecture. Depending on its association with other signal transducers, can regulate different processes. Together with SOS1 and ABI1, forms a trimeric complex that participates in transduction of signals from Ras to Rac by activating the Rac-specific guanine nucleotide exchange factor (GEF) activity. Acts as a direct regulator of actin dynamics by binding actin filaments and has both barbed-end actin filament capping and actin bundling activities depending on the context. Displays barbed-end actin capping activity when associated with ABI1, thereby regulating actin-based motility process: capping activity is auto-inhibited and inhibition is relieved upon ABI1 interaction. Also shows actin bundling activity when associated with BAIAP2, enhancing BAIAP2-dependent membrane extensions and promoting filopodial protrusions. Involved in the regulation of processes such as axonal filopodia growth, stereocilia length, dendritic cell migration and cancer cell migration and invasion. Acts as a regulator of axonal filopodia formation in neurons: in the absence of neurotrophic factors, negatively regulates axonal filopodia formation via actin-capping activity. In contrast, it is phosphorylated in the presence of BDNF leading to inhibition of its actin-capping activity and stimulation of filopodia formation. Component of a complex with DFNB31 and MYO15A that localizes at stereocilia tips and is required for elongation of the stereocilia actin core. Indirectly involved in cell cycle progression; its degradation following ubiquitination being required during G2 phase to promote cell shape changes By similarity.
Subunit structure	Homodimer. Part of a complex consisting of ABI1, EPS8 and SOS1. Interacts with BAIAP2. Interacts with SHB and LANCL1. Interacts with EGFR; mediates EPS8 phosphorylation. Interacts with MYO15A and DFNB31 By similarity.
Subcellular location	Cytoplasm › cell cortex By similarity. Cell projection › ruffle membrane By similarity. Cell projection › growth cone By similarity. Cell projection › stereocilium By similarity. Note: Localizes to the midzone of dividing cells By similarity.
Domain	The effector region is required for activating the Rac-specific guanine nucleotide exchange factor (GEF) activity. It mediates both barbed-end actin capping and actin bundling activities. The capping activity is mediated by an amphipathic helix that binds within the hydrophobic pocket at the barbed ends of actin blocking further addition of actin monomers, while the bundling activity is mediated by a compact 4 helix bundle, which contacts 3 actin subunits along the filament By similarity. The SH3 domain mediates interaction with SHB By similarity.
Post-translational modification	Ubiquitinated by the SCF(FBXW5) E3 ubiquitin-protein ligase complex during G2 phase, leading to its transient degradation and subsequent cell shape changes required to allow mitotic progression. Reappears at the midzone of dividing cells By similarity. Phosphorylation at Ser-625 and Thr-629 by MAPK following BDNF treatment promotes removal from actin and filopodia formation. Phosphorylated by several receptor tyrosine kinases By similarity.
Sequence similarities	Belongs to the EPS8 family. Contains 1 PH domain. Contains 1 SH3 domain.

Ontologies

Keywords
Cellular component	Cell membrane Cell projection Cytoplasm Membrane
Domain	SH3 domain
Ligand	Actin-binding
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Rac protein signal transduction Inferred from sequence or structural similarity. Source: UniProtKB actin crosslink formation Inferred from sequence or structural similarity. Source: UniProtKB actin filament bundle assembly Inferred from sequence or structural similarity. Source: UniProtKB actin polymerization-dependent cell motility Inferred from sequence or structural similarity. Source: UniProtKB barbed-end actin filament capping Inferred from sequence or structural similarity. Source: UniProtKB dendritic cell migration Inferred from sequence or structural similarity. Source: UniProtKB exit from mitosis Inferred from sequence or structural similarity. Source: UniProtKB regulation of cell shape Inferred from sequence or structural similarity. Source: UniProtKB regulation of mitotic prometaphase Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	cell cortex Inferred from sequence or structural similarity. Source: UniProtKB growth cone Inferred from electronic annotation. Source: UniProtKB-SubCell ruffle membrane Inferred from sequence or structural similarity. Source: UniProtKB stereocilium Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	Rac GTPase binding Inferred from sequence or structural similarity. Source: UniProtKB actin binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 822	822	Epidermal growth factor receptor kinase substrate 8		PRO_0000086996
Regions
	Domain	69 – 129	61	PH; first part
	Domain	381 – 414	34	PH; second part
	Domain	531 – 590	60	SH3
	Region	649 – 822	174	Effector region By similarity
	Region	680 – 698	19	Amphipathic helix By similarity
	Region	718 – 738	21	Helix bundle 1 By similarity
	Region	752 – 757	6	Helix bundle 2 By similarity
	Region	762 – 767	6	Helix bundle 3 By similarity
	Region	766 – 785	20	Helix bundle 4 By similarity
	Compositional bias	615 – 651	37	Pro-rich
Amino acid modifications
	Modified residue	476	1	Phosphoserine By similarity
	Modified residue	625	1	Phosphoserine; by MAPK By similarity
	Modified residue	629	1	Phosphothreonine; by MAPK By similarity
Experimental info
	Sequence conflict	41	1	A → V in CAH90029. Ref.1
	Sequence conflict	270	1	V → A in CAH90029. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q5R4H4 [UniParc]. Last modified April 3, 2013. Version 2. Checksum: 32ABBCDE17505774	FASTA	822	91,972
	10 20 30 40 50 60 MNGHISNHPS SFEMYPSQMN GYGSSPTFSQ MDREHGSKTS AKALYEQRKN YARDSVSSVS 70 80 90 100 110 120 DISQYRVEHL TTFVLDRKDA MITVDDGIRK LKLLDAKGKV WTQDMILQVD DRAVSLIDLE 130 140 150 160 170 180 SKNELENFPL NTIQHCQAVM HSCSYDSVLA LVCKEPTQNK PDLHLFQCDE VKANLISEDI 190 200 210 220 230 240 ESAISDSKGG KQKRRPDALR MISNADPGIP PPPRAPAPAP PGTVTQVDVR SRVAAWSAWA 250 260 270 280 290 300 ADQGDFEKPR QYHEQEETPE MMAARIDRDV QILNHILDDI EFFITKLQKA AEAFSELSKR 310 320 330 340 350 360 KKNKKGKRKG PGEGVLTLRA KPPPPDEFLD CFQKFKHGFN LLAKLKSHIQ NPSAADLVHF 370 380 390 400 410 420 LFTPLNMVVQ ATGGPELASS VLSPLLNKDT IDFLNYTVNG DERQLWMSLG GTWTKARAEW 430 440 450 460 470 480 PKEQFIPPYV PRFRNGWEPP MLNFMGATME QDLYQLAESV ANVAEHQRKQ EIKRLSTEHS 490 500 510 520 530 540 SVSEYHPADG YAFSSNIYTR GSHLDQGEAA VAFKPTSNRH IDRNYEPLKT QPKKYAKSKY 550 560 570 580 590 600 DFVARNNSEL SVLKDDILEI LDDRKQWWKV RNASGDSGFV PNNILDIVRP PESGLGRADP 610 620 630 640 650 660 PYTHTIQKQR MEYGPRPADT PPAPSPPPTP APVPVPLPPS TPAPVPVSKF PANITRQNSS 670 680 690 700 710 720 SSDSGGSIVR DSQRHKQLPV DRRKSQMEEV QDELIHRLTI GRSAAQKKFH VPRQNVPVIN 730 740 750 760 770 780 ITYDSTPEDV KTWLQSKGFN PVTVNSLGVL NGAQLFSLNK DELRTVCPEG ARVYSQITVQ 790 800 810 820 KAALEDSSGS SELQEIMRRR QEKISAAASD SGVESFDEGS SH

References

[1]	The German cDNA consortium Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain cortex and Kidney.
[2]	"A 6x draft sequence assembly of the Pongo pygmaeus abelii genome." Wilson R.K., Mardis E. Submitted (FEB-2008) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].

Cross-references

Sequence databases
EMBL GenBank DDBJ	CR857764 mRNA. Translation: CAH90029.1. CR861274 mRNA. Translation: CAH93342.1. ABGA01225282 Genomic DNA. No translation available. ABGA01225283 Genomic DNA. No translation available. ABGA01225284 Genomic DNA. No translation available. ABGA01225285 Genomic DNA. No translation available. ABGA01225286 Genomic DNA. No translation available. ABGA01225287 Genomic DNA. No translation available. ABGA01225288 Genomic DNA. No translation available. ABGA01225289 Genomic DNA. No translation available. ABGA01225290 Genomic DNA. No translation available. ABGA01225291 Genomic DNA. No translation available. ABGA01225292 Genomic DNA. No translation available. ABGA01225293 Genomic DNA. No translation available. ABGA01225294 Genomic DNA. No translation available. ABGA01225295 Genomic DNA. No translation available. ABGA01225296 Genomic DNA. No translation available. ABGA01225297 Genomic DNA. No translation available. ABGA01225298 Genomic DNA. No translation available. ABGA01225299 Genomic DNA. No translation available. ABGA01225300 Genomic DNA. No translation available.
RefSeq	NP_001127655.1. NM_001134183.1.
UniGene	Pab.1694.
3D structure databases
ProteinModelPortal	Q5R4H4.
ModBase	Search...
Proteomic databases
PRIDE	Q5R4H4.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	100174737.
KEGG	pon:100174737.
Organism-specific databases
CTD	2059.
Phylogenomic databases
GeneTree	ENSGT00390000003646.
HOVERGEN	HBG003090.
InParanoid	Q5R4H4.
Family and domain databases
Gene3D	2.30.29.30. 1 hit.
InterPro	IPR011993. PH_like_dom. IPR013625. PTB. IPR006020. PTyr_interaction_dom. IPR001452. SH3_domain. [Graphical view]
Pfam	PF08416. PTB. 1 hit. PF00018. SH3_1. 1 hit. [Graphical view]
SMART	SM00462. PTB. 1 hit. SM00326. SH3. 1 hit. [Graphical view]
SUPFAM	SSF50044. SH3. 1 hit.
PROSITE	PS50003. PH_DOMAIN. False negative. PS50002. SH3. 1 hit. [Graphical view]
ProtoNet	Search...

Entry information

Entry name

EPS8_PONAB

Accession

Primary (citable) accession number: Q5R4H4
Secondary accession number(s): K7EUA3, Q5RDX8

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 30, 2005
Last sequence update:	April 3, 2013
Last modified:	May 1, 2013
This is version 52 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program