Q06418 (TYRO3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tyrosine-protein kinase receptor TYRO3
EC=2.7.10.1

Alternative name(s):
Tyrosine-protein kinase BYK
Tyrosine-protein kinase DTK
Tyrosine-protein kinase RSE
Tyrosine-protein kinase SKY
Tyrosine-protein kinase TIF

Gene names

Name:	TYRO3
Synonyms:	BYK, DTK, RSE, SKY, TIF

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [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 › Homininae › Homo

Protein attributes

Sequence length	890 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 tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including TULP1 or GAS6. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of TYRO3 on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with PIK3R1 and thereby enhances PI3-kinase activity. Activates the AKT survival pathway, including nuclear translocation of NF-kappa-B and up-regulation of transcription of NF-kappa-B-regulated genes. TYRO3 signaling plays a role in various processes such as neuron protection from excitotoxic injury, platelet aggregation and cytoskeleton reorganization. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3. Ref.10 Ref.12
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subunit structure	Monomer and homodimer. Interacts (via N-terminus) with extracellular ligands TULP1 and GAS6 By similarity. Interacts with PIK3R1; this interaction increases PI3-kinase activity By similarity. Ref.8 Ref.13
Subcellular location	Cell membrane; Single-pass type I membrane protein.
Tissue specificity	Abundant in the brain and lower levels in other tissues.
Post-translational modification	Autophosphorylated. Ref.7
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. AXL/UFO subfamily. Contains 2 fibronectin type-III domains. Contains 2 Ig-like C2-type (immunoglobulin-like) domains. Contains 1 protein kinase domain.
Sequence caution	The sequence BAA21781.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	Cell adhesion
Cellular component	Cell membrane Membrane
Coding sequence diversity	Polymorphism
Domain	Immunoglobulin domain Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic cell clearance Inferred from sequence or structural similarity. Source: UniProtKB forebrain cell migration Inferred from sequence or structural similarity. Source: UniProtKB natural killer cell differentiation Inferred from electronic annotation. Source: Compara negative regulation of inflammatory response Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of innate immune response Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of lymphocyte activation Inferred from electronic annotation. Source: Compara negative regulation of neuron apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of toll-like receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB neuron homeostasis Inferred from sequence or structural similarity. Source: UniProtKB ovulation cycle Inferred from sequence or structural similarity. Source: UniProtKB phosphatidylinositol 3-kinase cascade Non-traceable author statement PubMed 10627473. Source: UniProtKB platelet aggregation Inferred from sequence or structural similarity. Source: UniProtKB protein autophosphorylation Inferred from direct assay Ref.1Ref.7. Source: UniProtKB protein kinase B signaling cascade Inferred from sequence or structural similarity. Source: UniProtKB secretion by cell Inferred from sequence or structural similarity. Source: UniProtKB spermatogenesis Inferred from sequence or structural similarity. Source: UniProtKB substrate adhesion-dependent cell spreading Inferred from sequence or structural similarity. Source: UniProtKB vagina development Inferred from electronic annotation. Source: Compara
Cellular_component	endoplasmic reticulum membrane Inferred from sequence or structural similarity. Source: UniProtKB integral to plasma membrane Non-traceable author statement Ref.1. Source: UniProtKB nuclear envelope Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW receptor signaling protein tyrosine kinase activity Non-traceable author statement Ref.1. Source: UniProtKB transmembrane receptor protein tyrosine kinase activity Non-traceable author statement Ref.1. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 40

40

Potential

Chain

41 – 890

850

Tyrosine-protein kinase receptor TYRO3

PRO_0000024478

Regions

Topological domain

41 – 429

389

Extracellular Potential

Transmembrane

430 – 450

21

Helical; Potential

Topological domain

451 – 890

440

Cytoplasmic Potential

Domain

41 – 128

88

Ig-like C2-type 1

Domain

139 – 220

82

Ig-like C2-type 2

Domain

225 – 317

93

Fibronectin type-III 1

Domain

322 – 413

92

Fibronectin type-III 2

Domain

518 – 790

273

Protein kinase

Nucleotide binding

524 – 532

9

ATP By similarity

Sites

Active site

655

1

Proton acceptor By similarity

Binding site

550

1

ATP By similarity

Amino acid modifications

Modified residue

681

1

Phosphotyrosine; by autocatalysis By similarity

Modified residue

685

1

Phosphotyrosine; by autocatalysis By similarity

Modified residue

686

1

Phosphotyrosine; by autocatalysis By similarity

Modified residue

804

1

Phosphotyrosine; by autocatalysis By similarity

Glycosylation

63

1

N-linked (GlcNAc...) Potential

Glycosylation

191

1

N-linked (GlcNAc...) Potential

Glycosylation

230

1

N-linked (GlcNAc...) Potential

Glycosylation

240

1

N-linked (GlcNAc...) Potential

Glycosylation

293

1

N-linked (GlcNAc...) Potential

Glycosylation

366

1

N-linked (GlcNAc...) Potential

Glycosylation

380

1

N-linked (GlcNAc...) Potential

Disulfide bond

64 ↔ 117

Ref.13

Disulfide bond

160 ↔ 203

Ref.13

Natural variations

Natural variant

21

1

P → L. Ref.5
Corresponds to variant rs17854578 [ dbSNP | Ensembl ].

VAR_045886

Natural variant

346

1

I → N.
Corresponds to variant rs12148316 [ dbSNP | Ensembl ].

VAR_045887

Natural variant

542

1

G → S. Ref.5
Corresponds to variant rs17857363 [ dbSNP | Ensembl ].

VAR_045888

Natural variant

815

1

A → V. Ref.3
Corresponds to variant rs1042057 [ dbSNP | Ensembl ].

VAR_045889

Natural variant

819

1

L → M. Ref.5
Corresponds to variant rs17854579 [ dbSNP | Ensembl ].

VAR_045890

Natural variant

824

1

R → G. Ref.5
Corresponds to variant rs17857364 [ dbSNP | Ensembl ].

VAR_045891

Natural variant

831

1

A → T. Ref.14

VAR_041876

Experimental info

Mutagenesis

99

1

I → R: Abolishes dimerization. Ref.13

Sequence conflict

29 – 36

8

Missing in AAC50070. Ref.3

Sequence conflict

285

1

L → F in BAA21781. Ref.4

Sequence conflict

293

1

N → I in BAA21781. Ref.4

Sequence conflict

341

1

E → V in BAA21781. Ref.4

Sequence conflict

812

1

E → D in BAA21781. Ref.4

Secondary structure

1

.

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890

Helix Strand Turn

Details...

Beta strand

50 – 55

6

Beta strand

60 – 68

9

Beta strand

74 – 78

5

Beta strand

85 – 94

10

Beta strand

97 – 106

10

Helix

109 – 111

3

Beta strand

113 – 121

9

Beta strand

131 – 136

6

Beta strand

140 – 143

4

Beta strand

148 – 150

3

Beta strand

156 – 163

8

Beta strand

165 – 167

3

Beta strand

170 – 175

6

Beta strand

183 – 192

10

Beta strand

199 – 207

9

Beta strand

210 – 213

4

Beta strand

217 – 221

5

Sequences

	Sequence		Length	Mass (Da)
	Q06418 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: F9EC675077C4E8F1	FASTA	890	96,905
	10 20 30 40 50 60 MALRRSMGRP GLPPLPLPPP PRLGLLLAAL ASLLLPESAA AGLKLMGAPV KLTVSQGQPV 70 80 90 100 110 120 KLNCSVEGME EPDIQWVKDG AVVQNLDQLY IPVSEQHWIG FLSLKSVERS DAGRYWCQVE 130 140 150 160 170 180 DGGETEISQP VWLTVEGVPF FTVEPKDLAV PPNAPFQLSC EAVGPPEPVT IVWWRGTTKI 190 200 210 220 230 240 GGPAPSPSVL NVTGVTQSTM FSCEAHNLKG LASSRTATVH LQALPAAPFN ITVTKLSSSN 250 260 270 280 290 300 ASVAWMPGAD GRALLQSCTV QVTQAPGGWE VLAVVVPVPP FTCLLRDLVP ATNYSLRVRC 310 320 330 340 350 360 ANALGPSPYA DWVPFQTKGL APASAPQNLH AIRTDSGLIL EWEEVIPEAP LEGPLGPYKL 370 380 390 400 410 420 SWVQDNGTQD ELTVEGTRAN LTGWDPQKDL IVRVCVSNAV GCGPWSQPLV VSSHDRAGQQ 430 440 450 460 470 480 GPPHSRTSWV PVVLGVLTAL VTAAALALIL LRKRRKETRF GQAFDSVMAR GEPAVHFRAA 490 500 510 520 530 540 RSFNRERPER IEATLDSLGI SDELKEKLED VLIPEQQFTL GRMLGKGEFG SVREAQLKQE 550 560 570 580 590 600 DGSFVKVAVK MLKADIIASS DIEEFLREAA CMKEFDHPHV AKLVGVSLRS RAKGRLPIPM 610 620 630 640 650 660 VILPFMKHGD LHAFLLASRI GENPFNLPLQ TLIRFMVDIA CGMEYLSSRN FIHRDLAARN 670 680 690 700 710 720 CMLAEDMTVC VADFGLSRKI YSGDYYRQGC ASKLPVKWLA LESLADNLYT VQSDVWAFGV 730 740 750 760 770 780 TMWEIMTRGQ TPYAGIENAE IYNYLIGGNR LKQPPECMED VYDLMYQCWS ADPKQRPSFT 790 800 810 820 830 840 CLRMELENIL GQLSVLSASQ DPLYINIERA EEPTAGGSLE LPGRDQPYSG AGDGSGMGAV 850 860 870 880 890 GGTPSDCRYI LTPGGLAEQP GQAEHQPESP LNETQRLLLL QQGLLPHSSC

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"RSE, a novel receptor-type tyrosine kinase with homology to Axl/Ufo, is expressed at high levels in the brain." Mark M.R., Scadden D.T., Wang Z., Gu Q., Goddard A., Godowski P.J. J. Biol. Chem. 269:10720-10728(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Cloning of the cDNA for a novel receptor tyrosine kinase, Sky, predominantly expressed in brain." Ohashi K., Mizuno K., Kuma K., Miyata T., Nakamura T. Oncogene 9:699-705(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Isolation and characterization of the human DTK receptor tyrosine kinase." Crosier K.E., Hall L.R., Lewis P.M., Morris C.M., Wood C.R., Morris J.C., Crosier P.S. Growth Factors 11:137-144(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT VAL-815. Tissue: Brain.
[4]	"A tyrosine kinase-like molecule is localized in the nuclear membrane of neurons: hippocampal behavior under stress." Kajii Y., Ninomiya D., Kato M., Mizuguchi M., Saji M., Katsumoto T., Ohno K., Takashima S., Onodera K. Biol. Cell 88:45-54(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANTS LEU-21; SER-542; MET-819 AND GLY-824. Tissue: Skin and Testis.
[6]	"The human TYRO3 gene and pseudogene are located in chromosome 15q14-q25." Polvi A., Armstrong E., Lai C., Lemke G., Huebner K., Spritz R.A., Giuda L.C., Nicholls R.D., Alitalo K. Gene 134:289-293(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 519-720.
[7]	"Autophosphorylation activity and association with Src family kinase of Sky receptor tyrosine kinase." Toshima J., Ohashi K., Iwashita S., Mizuno K. Biochem. Biophys. Res. Commun. 209:656-663(1995) [PubMed] [Europe PMC] [Abstract] Cited for: AUTOPHOSPHORYLATION.
[8]	"Reevaluation of the roles of protein S and Gas6 as ligands for the receptor tyrosine kinase Rse/Tyro 3." Godowski P.J., Mark M.R., Chen J., Sadick M.D., Raab H., Hammonds R.G. Cell 82:355-358(1995) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH GAS6.
[9]	"Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases." Hafizi S., Dahlback B. Cytokine Growth Factor Rev. 17:295-304(2006) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[10]	"Tyro3 family-mediated cell entry of Ebola and Marburg viruses." Shimojima M., Takada A., Ebihara H., Neumann G., Fujioka K., Irimura T., Jones S., Feldmann H., Kawaoka Y. J. Virol. 80:10109-10116(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS CELL ENTRY FACTOR IN FILOVIRUS INFECTION.
[11]	"Immunobiology of the TAM receptors." Lemke G., Rothlin C.V. Nat. Rev. Immunol. 8:327-336(2008) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[12]	"Potentiating role of Gas6 and Tyro3, Axl and Mer (TAM) receptors in human and murine platelet activation and thrombus stabilization." Cosemans J.M., Van Kruchten R., Olieslagers S., Schurgers L.J., Verheyen F.K., Munnix I.C., Waltenberger J., Angelillo-Scherrer A., Hoylaerts M.F., Carmeliet P., Heemskerk J.W. J. Thromb. Haemost. 8:1797-1808(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PLATELET ACTIVATION.
[13]	"Ligand recognition and homophilic interactions in Tyro3: structural insights into the Axl/Tyro3 receptor tyrosine kinase family." Heiring C., Dahlbaeck B., Muller Y.A. J. Biol. Chem. 279:6952-6958(2004) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.96 ANGSTROMS) OF 41-222, SUBUNIT, INTERACTION WITH GAS6, MUTAGENESIS OF ILE-99, DISULFIDE BONDS.
[14]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] THR-831.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U05682 mRNA. Translation: AAA19236.1.
D17517 mRNA. Translation: BAA04467.1.
U18934 mRNA. Translation: AAC50070.1.
D50479 mRNA. Translation: BAA21781.1. Different initiation.
BC049368 mRNA. Translation: AAH49368.1.
BC051756 mRNA. Translation: AAH51756.1.
X72886 mRNA. Translation: CAA51396.1.

IPI

IPI00030887.

PIR

A53743.
I38912.

RefSeq

NP_006284.2. NM_006293.3.

UniGene

Hs.381282.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1RHF	X-ray	1.96	A/B	41-222	[»]

ProteinModelPortal

Q06418.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q06418. 2 interactions.

STRING

9606.ENSP00000263798.

PTM databases

PhosphoSite

Q06418.

Polymorphism databases

DMDM

1717829.

Proteomic databases

PaxDb

Q06418.

PRIDE

Q06418.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000263798; ENSP00000263798; ENSG00000092445.

GeneID

7301.

KEGG

hsa:7301.

UCSC

uc001zof.2. human.

Organism-specific databases

CTD

7301.

GeneCards

GC15P041851.

HGNC

HGNC:12446. TYRO3.

MIM

600341. gene.

neXtProt

NX_Q06418.

PharmGKB

PA37097.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOVERGEN

HBG006346.

InParanoid

Q06418.

KO

K05116.

OMA

HAGQQGP.

OrthoDB

EOG4H4639.

PhylomeDB

Q06418.

Enzyme and pathway databases

BRENDA

2.7.10.1. 2681.

Gene expression databases

ArrayExpress

Q06418.

Bgee

Q06418.

CleanEx

HS_TYRO3.

Genevestigator

Q06418.

GermOnline

ENSG00000092445. Homo sapiens.

Family and domain databases

Gene3D

2.60.40.10. 4 hits.

InterPro

IPR003961. Fibronectin_type3.
IPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR013098. Ig_I-set.
IPR003599. Ig_sub.
IPR003598. Ig_sub2.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
[Graphical view]

Pfam

PF00041. fn3. 2 hits.
PF07679. I-set. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]

PRINTS

PR00109. TYRKINASE.

SMART

SM00060. FN3. 2 hits.
SM00409. IG. 1 hit.
SM00408. IGc2. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]

SUPFAM

SSF49265. FN_III-like. 2 hits.
SSF56112. Kinase_like. 1 hit.

PROSITE

PS50853. FN3. 2 hits.
PS50835. IG_LIKE. 2 hits.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q06418.

ChEMBL

CHEMBL5314.

EvolutionaryTrace

Q06418.

GenomeRNAi

7301.

NextBio

28553.

SOURCE

Search...

Entry information

Entry name

TYRO3_HUMAN

Accession

Primary (citable) accession number: Q06418
Secondary accession number(s): O14953, Q86VR3

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	May 1, 2013
This is version 137 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.