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Q62371 (DDR2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 142. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Discoidin domain-containing receptor 2

Short name=Discoidin domain receptor 2
EC=2.7.10.1
Alternative name(s):
CD167 antigen-like family member B
Neurotrophic tyrosine kinase, receptor-related 3
Receptor protein-tyrosine kinase TKT
Tyrosine-protein kinase TYRO10
CD_antigen=CD167b
Gene names
Name:Ddr2
Synonyms:Ntrkr3, Tkt, Tyro10
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length854 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation. Required for normal bone development. Regulates osteoblast differentiation and chondrocyte maturation via a signaling pathway that involves MAP kinases and leads to the activation of the transcription factor RUNX2. Regulates remodeling of the extracellular matrix by up-regulation of the collagenases MMP1, MMP2 and MMP13, and thereby facilitates cell migration and tumor cell invasion. Promotes fibroblast migration and proliferation, and thereby contributes to cutaneous wound healing. Ref.4 Ref.5 Ref.6 Ref.7 Ref.9

Catalytic activity

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

Enzyme regulation

Present in an inactive state in the absence of collagen binding and phosphorylation by SRC. Tyrosine phosphorylation enhances the affinity for ATP and the catalytic activity.

Subunit structure

Binds hydroxyproline-rich sequence motifs in fibrillar, glycosylated collagen, such as the GQOGVMGFO motif, where O stands for hydroxyproline. Interacts with SRC. Interacts (tyrosine phosphorylated) with SHC1. Ref.6

Subcellular location

Cell membrane; Single-pass type I membrane protein.

Tissue specificity

Widely expressed. Detected in lung, ovary, skin and in testis Leydig cells (at protein level). Widely expressed. Detected at high levels in heart, lung, skeletal muscle, central nervous system (CNS) and kidney, and at lower levels in brain and testis. Detected in chondrocytes in tibia growth plates of young mice. Ref.4 Ref.8 Ref.9

Induction

Up-regulated during osteoblast differentiation (in vitro). Up-regulated in cartilage from mice with osteoarthritis.

Post-translational modification

N-glycosylated By similarity.

Tyrosine phosphorylated in response to collagen binding. Phosphorylated by SRC; this is required for activation and subsequent autophosphorylation on additional tyrosine residues By similarity. Ref.6

Involvement in disease

Defects in Ddr2 are the cause of the smallie (sli) phenotype. Smallie mice show distinct dwarfing, with reduced body mass and reduced bone mineral content. Mice also have mild craniofacial deformities, such as protuberant eyes and snub noses. Smallie mice have a reduced life span, with about half of them dying within 6 months. Matings between male and female smallie mice do not yield any offspring. The levels of circulating steroid hormones remain at a level corresponding to prepubertal wild-type mice. Adult testes exhibit much reduced numbers of spermatids with atrophy of spermatogonia, Sertoli and Leydig cells. Ovaries show an absence of corpora lutea.

Disruption phenotype

Mice are born at the expected Mendelian rate, but fail to thrive, resulting in much reduced adult body weight and dwarfing. They exhibit shortening of long bones, irregular growth of flat bones and a shortened snout. Young mice show shortened growth plates in long bones and impaired chondrocyte proliferation. Likewise, cultured fibroblasts from mutant mice show reduced proliferation. Ref.4

Sequence similarities

Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.

Contains 1 F5/8 type C domain.

Contains 1 protein kinase domain.

Caution

According to Ref.8 Ddr2 is required for male and female fertility, since smallie mice with a 150 kb deletion that extends into the Ddr2 gene are sterile. Smallie males have defects in spermatogenesis (Ref.9). On the other hand, the fertility status of mice with a targeted disruption of the Ddr2 gene has not been mentioned (Ref.4). Thus, the infertility of smallie mice may be due to some additional, not yet identified defect.

Sequence caution

The sequence CAA54040.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
   Biological processOsteogenesis
   Cellular componentCell membrane
Membrane
   DomainSignal
Transmembrane
Transmembrane helix
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Receptor
Transferase
Tyrosine-protein kinase
   PTMDisulfide bond
Glycoprotein
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processbiomineral tissue development

Inferred from mutant phenotype PubMed 19900459. Source: UniProtKB

cell adhesion

Inferred from electronic annotation. Source: InterPro

chondrocyte proliferation

Inferred from mutant phenotype Ref.4. Source: UniProtKB

collagen fibril organization

Inferred from mutant phenotype PubMed 19900459. Source: UniProtKB

collagen-activated tyrosine kinase receptor signaling pathway

Inferred from direct assay Ref.5. Source: UniProtKB

endochondral bone growth

Inferred from mutant phenotype Ref.4. Source: UniProtKB

ossification

Inferred from electronic annotation. Source: UniProtKB-KW

peptidyl-tyrosine phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of cell proliferation

Inferred from mutant phenotype Ref.5. Source: MGI

positive regulation of extracellular matrix disassembly

Inferred from mutant phenotype Ref.5. Source: UniProtKB

positive regulation of fibroblast migration

Inferred from mutant phenotype Ref.5. Source: UniProtKB

positive regulation of fibroblast proliferation

Inferred from mutant phenotype Ref.4Ref.5. Source: UniProtKB

positive regulation of osteoblast differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of protein kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of sequence-specific DNA binding transcription factor activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein autophosphorylation

Inferred from electronic annotation. Source: Ensembl

regulation of bone mineralization

Inferred from sequence or structural similarity. Source: UniProtKB

transmembrane receptor protein tyrosine kinase signaling pathway

Inferred from direct assay Ref.5. Source: MGI

   Cellular_componentapical plasma membrane

Inferred from electronic annotation. Source: Ensembl

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

collagen binding

Inferred from sequence or structural similarity. Source: UniProtKB

protein tyrosine kinase collagen receptor activity

Inferred from direct assay Ref.5. Source: UniProtKB

transmembrane receptor protein tyrosine kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2121 Potential
Chain22 – 854833Discoidin domain-containing receptor 2
PRO_0000016747

Regions

Topological domain22 – 399378Extracellular Potential
Transmembrane400 – 42122Helical; Potential
Topological domain422 – 854433Cytoplasmic Potential
Domain30 – 185156F5/8 type C
Domain563 – 848286Protein kinase
Nucleotide binding569 – 5779ATP By similarity

Sites

Active site7091Proton acceptor By similarity
Binding site6081ATP By similarity

Amino acid modifications

Modified residue4611Phosphoserine By similarity
Modified residue4711Phosphotyrosine; by SRC and autocatalysis Ref.6
Modified residue6741Phosphoserine By similarity
Modified residue7351Phosphotyrosine; by SRC and autocatalysis By similarity
Modified residue7391Phosphotyrosine; by SRC and autocatalysis By similarity
Modified residue7401Phosphotyrosine; by SRC and autocatalysis By similarity
Glycosylation1211N-linked (GlcNAc...) Potential
Glycosylation2131N-linked (GlcNAc...) Potential
Glycosylation2611N-linked (GlcNAc...) Potential
Glycosylation2801N-linked (GlcNAc...) Potential
Glycosylation3721N-linked (GlcNAc...) Potential
Disulfide bond30 ↔ 185 By similarity
Disulfide bond73 ↔ 177 By similarity

Experimental info

Mutagenesis4711Y → F: Reduces tyrosine phosphorylation by 90%; when associated with E-608. Ref.6
Mutagenesis6081K → E: Abolishes kinase activity. Reduces tyrosine phosphorylation by 90%; when associated with F-471. Ref.6

Sequences

Sequence LengthMass (Da)Tools
Q62371 [UniParc].

Last modified November 1, 1997. Version 2.
Checksum: 45CFD2BE9ED524D4

FASTA85496,482
        10         20         30         40         50         60 
MIPIPRMPLV LLLLLLILGS AKAQVNPAIC RYPLGMSGGH IPDEDITASS QWSESTAAKY 

        70         80         90        100        110        120 
GRLDSEEGDG AWCPEIPVQP DDLKEFLQID LRTLHFITLV GTQGRHAGGH GIEFAPMYKI 

       130        140        150        160        170        180 
NYSRDGSRWI SWRNRHGKQV LDGNSNPYDV FLKDLEPPIV ARFVRLIPVT DHSMNVCMRV 

       190        200        210        220        230        240 
ELYGCVWLDG LVSYNAPAGQ QFVLPGGSII YLNDSVYDGA VGYSMTEGLG QLTDGVSGLD 

       250        260        270        280        290        300 
DFTQTHEYHV WPGYDYVGWR NESATNGFIE IMFEFDRIRN FTTMKVHCNN MFAKGVKIFK 

       310        320        330        340        350        360 
EVQCYFRSEA SEWEPTAVYF PLVLDDVNPS ARFVTVPLHH RMASAIKCQY HFADTWMMFS 

       370        380        390        400        410        420 
EITFQSDAAM YNNSGALPTS PMAPTTYDPM LKVDDSNTRI LIGCLVAIIF ILLAIIVIIL 

       430        440        450        460        470        480 
WRQFWQKMLE KASRRMLDDE MTVSLSLPSE SSMFNNNRSS SPSEQESNST YDRIFPLRPD 

       490        500        510        520        530        540 
YQEPSRLIRK LPEFAPGEEE SGCSGVVKPA QPNGPEGVPH YAEADIVNLQ GVTGGNTYCV 

       550        560        570        580        590        600 
PAVTMDLLSG KDVAVEEFPR KLLAFKEKLG EGQFGEVHLC EVEGMEKFKD KDFALDVSAN 

       610        620        630        640        650        660 
QPVLVAVKML RADANKNARN DFLKEIKIMS RLKDPNIIRL LAVCITEDPL CMITEYMENG 

       670        680        690        700        710        720 
DLNQFLSRHE PLSSCSSDAT VSYANLKFMA TQIASGMKYL SSLNFVHRDL ATRNCLVGKN 

       730        740        750        760        770        780 
YTIKIADFGM SRNLYSGDYY RIQGRAVLPI RWMSWESILL GKFTTASDVW AFGVTLWETF 

       790        800        810        820        830        840 
TFCQEQPYSQ LSDEQVIENT GEFFRDQGRQ IYLPQPALCP DSVYKLMLSC WRRETKHRPS 

       850 
FQEIHLLLLQ QGAE 

« Hide

References

« Hide 'large scale' references
[1]"Structure, expression and chromosomal mapping of TKT from man and mouse: a new subclass of receptor tyrosine kinases with a factor VIII-like domain."
Karn T., Holtrich U., Braeuninger A., Boehme B., Wolf G., Ruebsamen-Waigmann H., Strebhardt K.
Oncogene 8:3433-3440(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"Structure and expression of the Tyro 10 receptor tyrosine kinase."
Lai C., Lemke G.E.
Oncogene 9:877-883(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: C57BL/6.
Tissue: Brain.
[3]"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].
Tissue: Embryo.
[4]"The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism."
Labrador J.P., Azcoitia V., Tuckermann J., Lin C., Olaso E., Manes S., Bruckner K., Goergen J.L., Lemke G., Yancopoulos G., Angel P., Martinez C., Klein R.
EMBO Rep. 2:446-452(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, FUNCTION, TISSUE SPECIFICITY.
[5]"Discoidin domain receptor 2 regulates fibroblast proliferation and migration through the extracellular matrix in association with transcriptional activation of matrix metalloproteinase-2."
Olaso E., Labrador J.-P., Wang L., Ikeda K., Eng F.J., Klein R., Lovett D.H., Lin H.C., Friedman S.L.
J. Biol. Chem. 277:3606-3613(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen."
Ikeda K., Wang L.H., Torres R., Zhao H., Olaso E., Eng F.J., Labrador P., Klein R., Lovett D., Yancopoulos G.D., Friedman S.L., Lin H.C.
J. Biol. Chem. 277:19206-19212(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH SRC AND SHC1, MUTAGENESIS OF TYR-471 AND LYS-608, PHOSPHORYLATION AT TYR-471.
[7]"Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice."
Xu L., Peng H., Wu D., Hu K., Goldring M.B., Olsen B.R., Li Y.
J. Biol. Chem. 280:548-555(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN UP-REGULATION OF MMP13.
[8]"A novel dwarfism with gonadal dysfunction due to loss-of-function allele of the collagen receptor gene, Ddr2, in the mouse."
Kano K., Marin de Evsikova C., Young J., Wnek C., Maddatu T.P., Nishina P.M., Naggert J.K.
Mol. Endocrinol. 22:1866-1880(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN SLI, TISSUE SPECIFICITY.
[9]"Discoidin domain receptor 2 (DDR2) is required for maintenance of spermatogenesis in male mice."
Kano K., Kitamura A., Matsuwaki T., Morimatsu M., Naito K.
Mol. Reprod. Dev. 77:29-37(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN SLI, FUNCTION, TISSUE SPECIFICITY.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X76505 mRNA. Translation: CAA54040.1. Different initiation.
BC138826 mRNA. Translation: AAI38827.1.
BC138827 mRNA. Translation: AAI38828.1.
PIRI48859.
RefSeqNP_072075.2. NM_022563.2.
XP_006496759.1. XM_006496696.1.
XP_006496760.1. XM_006496697.1.
XP_006496761.1. XM_006496698.1.
UniGeneMm.229249.

3D structure databases

ProteinModelPortalQ62371.
SMRQ62371. Positions 26-369, 466-850.
ModBaseSearch...
MobiDBSearch...

PTM databases

PhosphoSiteQ62371.

Proteomic databases

PRIDEQ62371.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000027985; ENSMUSP00000027985; ENSMUSG00000026674.
ENSMUST00000170800; ENSMUSP00000129624; ENSMUSG00000026674.
GeneID18214.
KEGGmmu:18214.
UCSCuc007dlu.2. mouse.

Organism-specific databases

CTD4921.
MGIMGI:1345277. Ddr2.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00750000117362.
HOGENOMHOG000043102.
HOVERGENHBG005461.
InParanoidB2RSD7.
KOK05125.
OMAASAIKCQ.
OrthoDBEOG77Q4W2.
PhylomeDBQ62371.
TreeFamTF317840.

Enzyme and pathway databases

BRENDA2.7.10.1. 3474.

Gene expression databases

BgeeQ62371.
CleanExMM_DDR2.
MM_TKT.
GenevestigatorQ62371.

Family and domain databases

Gene3D2.60.120.260. 1 hit.
InterProIPR000421. Coagulation_fac_5/8-C_type_dom.
IPR008979. Galactose-bd-like.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR002011. Tyr_kinase_rcpt_2_CS.
[Graphical view]
PfamPF00754. F5_F8_type_C. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PRINTSPR00109. TYRKINASE.
SMARTSM00231. FA58C. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF49785. SSF49785. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS01285. FA58C_1. 1 hit.
PS01286. FA58C_2. 1 hit.
PS50022. FA58C_3. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS00239. RECEPTOR_TYR_KIN_II. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio293620.
PROQ62371.
SOURCESearch...

Entry information

Entry nameDDR2_MOUSE
AccessionPrimary (citable) accession number: Q62371
Secondary accession number(s): B2RSD7
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1997
Last modified: April 16, 2014
This is version 142 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot