Reviewed, UniProtKB/Swiss-Prot P00533 (EGFR_HUMAN)

Names and origin

Protein names

Recommended name:
    Epidermal growth factor receptor
    EC=2.7.10.1
Alternative name(s):
    Receptor tyrosine-protein kinase ErbB-1

Gene names

Name:	EGFR
Synonyms:	ERBB1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1210 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Receptor for EGF, but also for other members of the EGF family, as TGF-alpha, amphiregulin, betacellulin, heparin-binding EGF-like growth factor, GP30 and vaccinia virus growth factor. Is involved in the control of cell growth and differentiation. Phosphorylates MUC1 in breast cancer cells and increases the interaction of MUC1 with C-SRC and CTNNB1/beta-catenin. Isoform 2/truncated isoform may act as an antagonist.
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subunit structure	Binds RIPK1. CBL interacts with the autophosphorylated C-terminal tail of the EGF receptor. Part of a complex with ERBB2 and either PIK3C2A or PIK3C2B. The autophosphorylated form interacts with PIK3C2B, maybe indirectly. Interacts with PELP1. Binds MUC1.
Subcellular location	Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted.
Tissue specificity	Ubiquitously expressed. Isoform 2 is also expressed in ovarian cancers.
Post-translational modification	Phosphorylation of Ser-695 is partial and occurs only if Thr-693 is phosphorylated. Monoubiquitinated and polyubiquitinated upon EGF stimulation; which does not affect tyrosine kinase activity or signaling capacity but may play a role in lysosomal targeting. Polyubiquitin linkage is mainly through 'Lys-63', but linkage through 'Lys-48', 'Lys-11' and 'Lys-29' also occur.
Involvement in disease	Defects in EGFR are associated with lung cancer [MIM:211980].
Miscellaneous	Binding of EGF to the receptor leads to dimerization, internalization of the EGF-receptor complex, induction of the tyrosine kinase activity, stimulation of cell DNA synthesis, and cell proliferation.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Cell membrane Membrane Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Repeat Signal Transmembrane
Ligand	ATP-binding Nucleotide-binding
Molecular function	Anti-oncogene Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Glycoprotein Phosphoprotein Ubl conjugation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	activation of phospholipase C activity Traceable author statement. Source: UniProtKB calcium-dependent phospholipase A2 activation Traceable author statement. Source: UniProtKB cell-cell adhesion Inferred from mutant phenotype. Source: UniProtKB epidermal growth factor receptor signaling pathway Inferred from direct assay. Source: UniProtKB negative regulation of cell cycle Inferred from electronic annotation. Source: UniProtKB-KW ossification Non-traceable author statement. Source: UniProtKB positive regulation of MAP kinase activity Inferred from direct assay. Source: UniProtKB positive regulation of cell migration Inferred from mutant phenotype. Source: UniProtKB positive regulation of epithelial cell proliferation Inferred from direct assay. Source: UniProtKB positive regulation of nitric oxide biosynthetic process Inferred from direct assay. Source: UniProtKB positive regulation of phosphorylation Inferred from direct assay. Source: UniProtKB protein insertion into membrane Traceable author statement. Source: UniProtKB regulation of nitric-oxide synthase activity Inferred from direct assay. Source: UniProtKB regulation of peptidyl-tyrosine phosphorylation Inferred from mutant phenotype. Source: UniProtKB response to stress Non-traceable author statement. Source: UniProtKB
Cellular component	basolateral plasma membrane Inferred from direct assay. Source: UniProtKB endoplasmic reticulum Inferred from direct assay. Source: HPA endosome Inferred from direct assay. Source: UniProtKB extracellular space Ref.4 Non-traceable author statement. Source: UniProtKB integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW nucleus Inferred from direct assay. Source: UniProtKB
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro MAP/ERK kinase kinase activity Non-traceable author statement. Source: UniProtKB actin filament binding Inferred from direct assay. Source: UniProtKB double-stranded DNA binding Ref.21 Non-traceable author statement. Source: UniProtKB epidermal growth factor receptor activity Ref.21 Ref.23 Inferred from direct assay. Source: UniProtKB identical protein binding Inferred from physical interaction. Source: IntAct protein heterodimerization activity Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		1	EBI-297353,EBI-297353
	Q29376	1	EBI-297353,EBI-1256881	From a different organism.
CALM	P62157	1	EBI-297353,EBI-397403	From a different organism.
CALM1	P62158	1	EBI-297353,EBI-397435
Calm1	P62161	2	EBI-297353,EBI-397530	From a different organism.
Calm1	P62204	1	EBI-297353,EBI-397460	From a different organism.
CBL	P22681	1	EBI-297353,EBI-518228
Cbl	P22682	1	EBI-297353,EBI-640919	From a different organism.
CD59	P13987	1	EBI-297353,EBI-297972
EGF	P01133	2	EBI-297353,EBI-640857
ERBB2	P04626	2	EBI-297353,EBI-641062
ERBB3	P21860	2	EBI-297353,EBI-720706
ERBB4	Q15303	2	EBI-297353,EBI-80371
GRB2	P62993	2	EBI-297353,EBI-401755
PIK3C2B	O00750	4	EBI-297353,EBI-641107
RABGEF1	Q9UJ41	2	EBI-297353,EBI-913954
Shc1	P98083	1	EBI-297353,EBI-300201	From a different organism.
SLC5A1	P13866	3	EBI-297353,EBI-1772443
YWHAZ	P63104	1	EBI-297353,EBI-347088

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P00533-1)

Also known as: p170;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P00533-2)

Also known as: p60; Truncated; TEGFR;

The sequence of this isoform differs from the canonical sequence as follows:
     404-405: FL → LS
     406-1210: Missing.

Isoform 3 (identifier: P00533-3)

Also known as: p110;

The sequence of this isoform differs from the canonical sequence as follows:
     628-705: CTGPGLEGCP...GEAPNQALLR → PGNESLKAML...SVIITASSCH
     706-1210: Missing.

Isoform 4 (identifier: P00533-4)

The sequence of this isoform differs from the canonical sequence as follows:
     628-628: C → S
     629-1210: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 24	24
	Chain	25 – 1210	1186	Epidermal growth factor receptor		PRO_0000016665
Regions
	Topological domain	25 – 645	621	Extracellular Potential
	Transmembrane	646 – 668	23	Potential
	Topological domain	669 – 1210	542	Cytoplasmic Potential
	Repeat	75 – 300	226	Approximate
	Repeat	390 – 600	211	Approximate
	Domain	712 – 979	268	Protein kinase
	Nucleotide binding	718 – 726	9	ATP By similarity
	Compositional bias	1025 – 1071	47	Ser-rich
Sites
	Active site	837	1	Proton acceptor By similarity
	Binding site	745	1	ATP By similarity
	Site	1016	1	Important for interaction with PIK3C2B
Amino acid modifications
	Modified residue	678	1	Phosphothreonine; by PKC
	Modified residue	693	1	Phosphothreonine
	Modified residue	695	1	Phosphoserine
	Modified residue	869	1	Phosphotyrosine
	Modified residue	978	1	Phosphotyrosine
	Modified residue	991	1	Phosphoserine
	Modified residue	995	1	Phosphoserine
	Modified residue	998	1	Phosphotyrosine
	Modified residue	1026	1	Phosphoserine
	Modified residue	1064	1	Phosphoserine
	Modified residue	1069	1	Phosphotyrosine
	Modified residue	1070	1	Phosphoserine
	Modified residue	1071	1	Phosphoserine
	Modified residue	1092	1	Phosphotyrosine; by autocatalysis
	Modified residue	1110	1	Phosphotyrosine; by autocatalysis
	Modified residue	1138	1	Phosphotyrosine
	Modified residue	1166	1	Phosphoserine
	Modified residue	1172	1	Phosphotyrosine; by autocatalysis
	Modified residue	1197	1	Phosphotyrosine; by autocatalysis
	Glycosylation	56	1	N-linked (GlcNAc...) (complex); atypical; partial		CAR_000227
	Glycosylation	128	1	N-linked (GlcNAc...)
	Glycosylation	175	1	N-linked (GlcNAc...)
	Glycosylation	196	1	N-linked (GlcNAc...)
	Glycosylation	352	1	N-linked (GlcNAc...)
	Glycosylation	361	1	N-linked (GlcNAc...)
	Glycosylation	413	1	N-linked (GlcNAc...)
	Glycosylation	444	1	N-linked (GlcNAc...)
	Glycosylation	528	1	N-linked (GlcNAc...)
	Glycosylation	568	1	N-linked (GlcNAc...); partial
	Glycosylation	603	1	N-linked (GlcNAc...); partial
	Disulfide bond	31 ↔ 58
	Disulfide bond	157 ↔ 187
	Disulfide bond	190 ↔ 199
	Disulfide bond	194 ↔ 207
	Disulfide bond	215 ↔ 223
	Disulfide bond	219 ↔ 231
	Disulfide bond	232 ↔ 240
	Disulfide bond	236 ↔ 248
	Disulfide bond	251 ↔ 260
	Disulfide bond	264 ↔ 291
	Disulfide bond	295 ↔ 307
	Disulfide bond	311 ↔ 326
	Disulfide bond	329 ↔ 333
	Disulfide bond	337 ↔ 362
	Disulfide bond	470 ↔ 499
	Disulfide bond	506 ↔ 515
	Disulfide bond	510 ↔ 523
	Disulfide bond	526 ↔ 535
	Disulfide bond	539 ↔ 555
	Disulfide bond	558 ↔ 571
	Disulfide bond	562 ↔ 579
	Disulfide bond	582 ↔ 591
	Disulfide bond	595 ↔ 617
	Disulfide bond	620 ↔ 628
	Disulfide bond	624 ↔ 636
	Cross-link	716		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
	Cross-link	737		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
	Cross-link	754		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
	Cross-link	867		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
	Cross-link	929		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
	Cross-link	970		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Natural variations
	Alternative sequence	404 – 405	2	FL → LS in isoform 2.		VSP_002887
	Alternative sequence	406 – 1210	805	Missing in isoform 2.		VSP_002888
	Alternative sequence	628 – 705	78	CTGPG…QALLR → PGNESLKAMLFCLFKLSSCN QSNDGSVSHQSGSPAAQESC LGWIPSLLPSEFQLGWGGCS HLHAWPSASVIITASSCH in isoform 3.		VSP_002889
	Alternative sequence	628	1	C → S in isoform 4.		VSP_002891
	Alternative sequence	629 – 1210	582	Missing in isoform 4.		VSP_002892
	Alternative sequence	706 – 1210	505	Missing in isoform 3.		VSP_002890
	Natural variant	98	1	R → Q: dbSNP rs17289589.		VAR_019293
	Natural variant	266	1