ERBB4_HUMAN » Receptor tyrosine-protein kinase erbB-4

ERBB4_HUMAN » Receptor tyrosine-protein kinase erbB-4
Magnify ERBB4_HUMAN » Receptor tyrosine-protein kinase erbB-4Enlarged view of image
3D view in GLMol or JMol

gray dot

Download Coordinates

gray dot

Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
ERBB4_HUMAN » Receptor tyrosine-protein kinase erbB-4 » Proto-oncogene-like protein c-ErbB-4;Tyrosine kinase-type cell surface receptor HER4;p180erbB4;
Hydrophobic Thickness 30.4 ± 1.0 Å
Tilt Angle 5 ± 4°
ΔGtransfer -47.4 kcal/mol
ΔGfold -20.3 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 651-675 (651-678)
Pathways

Calcium signaling pathway (KEGG)

Endocytosis (KEGG)

ErbB signaling pathway (KEGG)

Immune System (Reactome)

Proteoglycans in cancer (KEGG)

Signal Transduction (Reactome)

PDB 3u2p (26-522), 2r4b (690-999), 3bbt (702-1029), 3bbw (702-1029), 3bce (702-1029), 3u7u (A/B...=26-640), 2ahx (A/B=26-641), 2l2t (A/B=642-685), 2lcx (A/B=642-685), 3u9u (E/F=26-650)
OPM 2l2t
Complexes

NRG1:ERBB4_HUMAN

ERBB4:ERBB4_HUMAN

Interactions

ADA17, Complex: ERBB4:ADA17, PubMed

BTC, Complex: ERBB4:BTC, PubMed

CD44, Complex: ERBB4:CD44, PubMed

EGFR, Complex: EGFR:ERBB4, PubMed

ERBB2, Complex: ERBB4:ERBB2, PubMed

ERBB3, Complex: ERBB3:ERBB4, PubMed

ERBB4, Complex: Transmembrane homodimer of ERBB4, PDBID: 2L2T

EREG, Complex: ERBB4:EREG, PubMed

HBEGF, Complex: ERBB4:HBEGF, PubMed

LRIG1, Complex: LRIG1:ERBB4, PubMed

MUC1, Complex: MUC1:ERBB4, PubMed

NRG1, Complex: NRG1:ERBB4, PDBID: 3u7u, PubMed

NRG2, Complex: NRG2:ERBB4, PubMed

NRG3, Complex: ERBB4:NRG3, PubMed

NRG4, Complex: NRG4:ERBB4, PubMed

TGFA, Complex: TGFA:ERBB4, PubMed

Domains

AA: 55-167, PDBID: 2AHX, Subunit A, Seq Identity:100%, Receptor L domain

AA: 176-335, PDBID: 2AHX, Subunit A, Seq Identity:100%, Furin-like cysteine rich region

AA: 358-478, PDBID: 2AHX, Subunit A, Seq Identity:100%, Receptor L domain

AA: 502-634, PDBID: 2AHX, Subunit A, Seq Identity:100%, Growth factor receptor domain IV

AA: 718-974, PDBID: 2R4B, Subunit B, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for ERBB4_HUMAN » Receptor tyrosine-protein kinase erbB-4
FUNCTION: Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis.

CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

ENZYME REGULATION: Binding of a cognate ligand leads to dimerization and activation by autophosphorylation on tyrosine residues. In vitro kinase activity is increased by Mg(2+). Inhibited by PD153035, lapatinib, gefitinib (iressa, ZD1839), AG1478 and BIBX1382BS.

SUBUNIT: Monomer in the absence of bound ligand. Homodimer or heterodimer with another ERBB family member upon ligand binding, thus forming heterotetramers. Interacts with EGFR and ERBB2. Interacts with CBFA2T3 (By similarity). Interacts with DLG2 (via its PDZ domain), DLG3 (via its PDZ domain), DLG4 (via its PDZ domain) and SNTB2 (via its PDZ domain). Interacts with MUC1. Interacts (via its PPxy motifs) with WWOX. Interacts (via the PPxY motif 3 of isoform JM-A CYT-2) with YAP1 (via the WW domain 1 of isoform 1). Interacts (isoform JM-A CYT-1 and isoform JM-B CYT-1) with WWP1. Interacts (via its intracellular domain) with TRIM28. Interacts (via the intracellular domains of both CYT-1 and CYT-2 isoforms) with KAP1; the interaction does not phosphorylate KAP1 but represses ERBB4-mediated transcriptional activity. Interacts with PRPU, DDX23, MATR3, RBM15, ILF3, KAP1, U5S1, U2SURP, ITCH, HNRPU, AP2A1, NULC, LEO1, WWP2, IGHG1, HXK1, GRB7 AND ARS2. Interacts (phosphorylated isoform JM-A CYT-1 and isoform JM-B CYT- 1) with PIK3R1. Interacts with SHC1. Interacts with GRB2. Interacts (soluble intracellular domain) with STAT5A. Interacts (soluble intracellular domain) with BCL2. Interacts (phosphorylated) with STAT1.

TISSUE SPECIFICITY: Expressed at highest levels in brain, heart, kidney, in addition to skeletal muscle, parathyroid, cerebellum, pituitary, spleen, testis and breast. Lower levels in thymus, lung, salivary gland, and pancreas. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are expressed in cerebellum, but only the isoform JM-B is expressed in the heart.

DISEASE: Amyotrophic lateral sclerosis 19 (ALS19) OMIM: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. is caused by mutations affecting the gene represented in this entry.

UniProt features for ERBB4_HUMAN » Receptor tyrosine-protein kinase erbB-4
SIGNAL 1 25 Potential.
CHAIN 26 1308 Receptor tyrosine-protein kinase erbB-4.
CHAIN 676 1308 ERBB4 intracellular domain (By similarity).
DOMAIN 718 985 Protein kinase.
MOTIF 676 684 Nuclear localization signal.
MOTIF 1032 1035 PPxY motif 1.
MOTIF 1053 1056 PPxY motif 2.
MOTIF 1298 1301 PPxY motif 3.
MOTIF 1306 1308 PDZ-binding.
ACT_SITE 843 843 Proton acceptor (By similarity).
DISULFID 29 56
DISULFID 156 186
DISULFID 189 197
DISULFID 193 205
DISULFID 213 221
DISULFID 217 229
DISULFID 230 238
DISULFID 234 246
DISULFID 249 258
DISULFID 262 289
DISULFID 293 304
DISULFID 308 323
DISULFID 326 330
DISULFID 503 512
DISULFID 507 520
DISULFID 523 532
DISULFID 536 552
DISULFID 555 569
DISULFID 559 577
DISULFID 580 589
DISULFID 593 614
DISULFID 617 625
DISULFID 621 633
Amino Acid Sequence for ERBB4_HUMAN » Receptor tyrosine-protein kinase erbB-4
MKPATGLWVW VSLLVAAGTV QPSDSQSVCA GTENKLSSLS DLEQQYRALR KYYENCEVVM GNLEITSIEH NRDLSFLRSV REVTGYVLVA LNQFRYLPLE NLRIIRGTKL YEDRYALAIF LNYRKDGNFG LQELGLKNLT EILNGGVYVD QNKFLCYADT IHWQDIVRNP WPSNLTLVST NGSSGCGRCH KSCTGRCWGP TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG PKDTDCFACM NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS SNIDKFINCT KINGNLIFLV TGIHGDPYNA IEAIDPEKLN VFRTVREITG FLNIQSWPPN MTDFSVFSNL VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST INQRIVIRDN RKAENCTAEG MVCNHLCSSD GCWGPGPDQC LSCRRFSRGR ICIESCNLYD GEFREFENGS ICVECDPQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA NSFIFKYADP DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART PLIAAGVIGG LFILVIVGLT FAVYVRRKSI KKKRALRRFL ETELVEPLTP SGTAPNQAQL RILKETELKR VKVLGSGAFG TVYKGIWVPE GETVKIPVAI KILNETTGPK ANVEFMDEAL IMASMDHPHL VRLLGVCLSP TIQLVTQLMP HGCLLEYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV HRDLAARNVL VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY MVMVKCWMID ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND SKFFQNLLDE EDLEDMMDAE EYLVPQAFNI PPPIYTSRAR IDSNRSEIGH SPPPAYTPMS GNQFVYRDGG FAAEQGVSVP YRAPTSTIPE APVAQGATAE IFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERS PRGELDEEGY MTPMRDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHN ASNGPPKAED EYVNEPLYLN TFANTLGKAE YLKNNILSMP EKAKKAFDNP DYWNHSLPPR STLQHPDYLQ EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTVLPPPP YRHRNTVV