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Q62371

- DDR2_MOUSE

UniProt

Q62371 - DDR2_MOUSE

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Protein
Discoidin domain-containing receptor 2
Gene
Ddr2, Ntrkr3, Tkt, Tyro10
Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

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.5 Publications

Catalytic activityi

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

Enzyme regulationi

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.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei608 – 6081ATP By similarity
Active sitei709 – 7091Proton acceptor By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi569 – 5779ATP By similarity

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. collagen binding Source: UniProtKB
  3. protein tyrosine kinase collagen receptor activity Source: UniProtKB
  4. transmembrane receptor protein tyrosine kinase activity Source: UniProtKB

GO - Biological processi

  1. biomineral tissue development Source: UniProtKB
  2. cell adhesion Source: InterPro
  3. chondrocyte proliferation Source: UniProtKB
  4. collagen fibril organization Source: UniProtKB
  5. collagen-activated tyrosine kinase receptor signaling pathway Source: UniProtKB
  6. endochondral bone growth Source: UniProtKB
  7. ossification Source: UniProtKB-KW
  8. peptidyl-tyrosine phosphorylation Source: UniProtKB
  9. positive regulation of cell proliferation Source: MGI
  10. positive regulation of extracellular matrix disassembly Source: UniProtKB
  11. positive regulation of fibroblast migration Source: UniProtKB
  12. positive regulation of fibroblast proliferation Source: UniProtKB
  13. positive regulation of osteoblast differentiation Source: UniProtKB
  14. positive regulation of protein kinase activity Source: UniProtKB
  15. positive regulation of sequence-specific DNA binding transcription factor activity Source: UniProtKB
  16. protein autophosphorylation Source: Ensembl
  17. regulation of bone mineralization Source: UniProtKB
  18. transmembrane receptor protein tyrosine kinase signaling pathway Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Receptor, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Osteogenesis

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1. 3474.
ReactomeiREACT_196607. Non-integrin membrane-ECM interactions.

Names & Taxonomyi

Protein namesi
Recommended name:
Discoidin domain-containing receptor 2 (EC:2.7.10.1)
Short name:
Discoidin domain receptor 2
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 namesi
Name:Ddr2
Synonyms:Ntrkr3, Tkt, Tyro10
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 1

Organism-specific databases

MGIiMGI:1345277. Ddr2.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini22 – 399378Extracellular Reviewed prediction
Add
BLAST
Transmembranei400 – 42122Helical; Reviewed prediction
Add
BLAST
Topological domaini422 – 854433Cytoplasmic Reviewed prediction
Add
BLAST

GO - Cellular componenti

  1. apical plasma membrane Source: Ensembl
  2. integral component of membrane Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

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 phenotypei

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.1 Publication

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi471 – 4711Y → F: Reduces tyrosine phosphorylation by 90%; when associated with E-608. 1 Publication
Mutagenesisi608 – 6081K → E: Abolishes kinase activity. Reduces tyrosine phosphorylation by 90%; when associated with F-471. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2121 Reviewed prediction
Add
BLAST
Chaini22 – 854833Discoidin domain-containing receptor 2
PRO_0000016747Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi30 ↔ 185 By similarity
Disulfide bondi73 ↔ 177 By similarity
Glycosylationi121 – 1211N-linked (GlcNAc...) Reviewed prediction
Glycosylationi213 – 2131N-linked (GlcNAc...) Reviewed prediction
Glycosylationi261 – 2611N-linked (GlcNAc...) Reviewed prediction
Glycosylationi280 – 2801N-linked (GlcNAc...) Reviewed prediction
Glycosylationi372 – 3721N-linked (GlcNAc...) Reviewed prediction
Modified residuei461 – 4611Phosphoserine By similarity
Modified residuei471 – 4711Phosphotyrosine; by SRC and autocatalysis1 Publication
Modified residuei674 – 6741Phosphoserine By similarity
Modified residuei735 – 7351Phosphotyrosine; by SRC and autocatalysis By similarity
Modified residuei739 – 7391Phosphotyrosine; by SRC and autocatalysis By similarity
Modified residuei740 – 7401Phosphotyrosine; by SRC and autocatalysis By similarity

Post-translational modificationi

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.1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

PRIDEiQ62371.

PTM databases

PhosphoSiteiQ62371.

Expressioni

Tissue specificityi

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.3 Publications

Inductioni

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

Gene expression databases

BgeeiQ62371.
CleanExiMM_DDR2.
MM_TKT.
GenevestigatoriQ62371.

Interactioni

Subunit structurei

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 SHC1.1 Publication

Structurei

3D structure databases

ProteinModelPortaliQ62371.
SMRiQ62371. Positions 26-369, 491-850.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini30 – 185156F5/8 type C
Add
BLAST
Domaini563 – 848286Protein kinase
Add
BLAST

Sequence similaritiesi

Contains 1 F5/8 type C domain.

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00750000117362.
HOGENOMiHOG000043102.
HOVERGENiHBG005461.
InParanoidiB2RSD7.
KOiK05125.
OMAiASAIKCQ.
OrthoDBiEOG77Q4W2.
PhylomeDBiQ62371.
TreeFamiTF317840.

Family and domain databases

Gene3Di2.60.120.260. 1 hit.
InterProiIPR000421. Coagulation_fac_5/8-C_type_dom.
IPR029553. DDR2.
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]
PANTHERiPTHR24416:SF297. PTHR24416:SF297. 1 hit.
PfamiPF00754. F5_F8_type_C. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PRINTSiPR00109. TYRKINASE.
SMARTiSM00231. FA58C. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF49785. SSF49785. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS01285. 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]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q62371-1 [UniParc]FASTAAdd to Basket

« Hide

MIPIPRMPLV LLLLLLILGS AKAQVNPAIC RYPLGMSGGH IPDEDITASS    50
QWSESTAAKY GRLDSEEGDG AWCPEIPVQP DDLKEFLQID LRTLHFITLV 100
GTQGRHAGGH GIEFAPMYKI NYSRDGSRWI SWRNRHGKQV LDGNSNPYDV 150
FLKDLEPPIV ARFVRLIPVT DHSMNVCMRV ELYGCVWLDG LVSYNAPAGQ 200
QFVLPGGSII YLNDSVYDGA VGYSMTEGLG QLTDGVSGLD DFTQTHEYHV 250
WPGYDYVGWR NESATNGFIE IMFEFDRIRN FTTMKVHCNN MFAKGVKIFK 300
EVQCYFRSEA SEWEPTAVYF PLVLDDVNPS ARFVTVPLHH RMASAIKCQY 350
HFADTWMMFS EITFQSDAAM YNNSGALPTS PMAPTTYDPM LKVDDSNTRI 400
LIGCLVAIIF ILLAIIVIIL WRQFWQKMLE KASRRMLDDE MTVSLSLPSE 450
SSMFNNNRSS SPSEQESNST YDRIFPLRPD YQEPSRLIRK LPEFAPGEEE 500
SGCSGVVKPA QPNGPEGVPH YAEADIVNLQ GVTGGNTYCV PAVTMDLLSG 550
KDVAVEEFPR KLLAFKEKLG EGQFGEVHLC EVEGMEKFKD KDFALDVSAN 600
QPVLVAVKML RADANKNARN DFLKEIKIMS RLKDPNIIRL LAVCITEDPL 650
CMITEYMENG DLNQFLSRHE PLSSCSSDAT VSYANLKFMA TQIASGMKYL 700
SSLNFVHRDL ATRNCLVGKN YTIKIADFGM SRNLYSGDYY RIQGRAVLPI 750
RWMSWESILL GKFTTASDVW AFGVTLWETF TFCQEQPYSQ LSDEQVIENT 800
GEFFRDQGRQ IYLPQPALCP DSVYKLMLSC WRRETKHRPS FQEIHLLLLQ 850
QGAE 854
Length:854
Mass (Da):96,482
Last modified:November 1, 1997 - v2
Checksum:i45CFD2BE9ED524D4
GO

Sequence cautioni

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

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X76505 mRNA. Translation: CAA54040.1. Different initiation.
BC138826 mRNA. Translation: AAI38827.1.
BC138827 mRNA. Translation: AAI38828.1.
CCDSiCCDS48436.1.
PIRiI48859.
RefSeqiNP_072075.2. NM_022563.2.
XP_006496759.1. XM_006496696.1.
XP_006496760.1. XM_006496697.1.
XP_006496761.1. XM_006496698.1.
UniGeneiMm.229249.

Genome annotation databases

EnsembliENSMUST00000027985; ENSMUSP00000027985; ENSMUSG00000026674.
ENSMUST00000170800; ENSMUSP00000129624; ENSMUSG00000026674.
GeneIDi18214.
KEGGimmu:18214.
UCSCiuc007dlu.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X76505 mRNA. Translation: CAA54040.1 . Different initiation.
BC138826 mRNA. Translation: AAI38827.1 .
BC138827 mRNA. Translation: AAI38828.1 .
CCDSi CCDS48436.1.
PIRi I48859.
RefSeqi NP_072075.2. NM_022563.2.
XP_006496759.1. XM_006496696.1.
XP_006496760.1. XM_006496697.1.
XP_006496761.1. XM_006496698.1.
UniGenei Mm.229249.

3D structure databases

ProteinModelPortali Q62371.
SMRi Q62371. Positions 26-369, 491-850.
ModBasei Search...
MobiDBi Search...

PTM databases

PhosphoSitei Q62371.

Proteomic databases

PRIDEi Q62371.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000027985 ; ENSMUSP00000027985 ; ENSMUSG00000026674 .
ENSMUST00000170800 ; ENSMUSP00000129624 ; ENSMUSG00000026674 .
GeneIDi 18214.
KEGGi mmu:18214.
UCSCi uc007dlu.2. mouse.

Organism-specific databases

CTDi 4921.
MGIi MGI:1345277. Ddr2.

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00750000117362.
HOGENOMi HOG000043102.
HOVERGENi HBG005461.
InParanoidi B2RSD7.
KOi K05125.
OMAi ASAIKCQ.
OrthoDBi EOG77Q4W2.
PhylomeDBi Q62371.
TreeFami TF317840.

Enzyme and pathway databases

BRENDAi 2.7.10.1. 3474.
Reactomei REACT_196607. Non-integrin membrane-ECM interactions.

Miscellaneous databases

NextBioi 293620.
PROi Q62371.
SOURCEi Search...

Gene expression databases

Bgeei Q62371.
CleanExi MM_DDR2.
MM_TKT.
Genevestigatori Q62371.

Family and domain databases

Gene3Di 2.60.120.260. 1 hit.
InterProi IPR000421. Coagulation_fac_5/8-C_type_dom.
IPR029553. DDR2.
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 ]
PANTHERi PTHR24416:SF297. PTHR24416:SF297. 1 hit.
Pfami PF00754. F5_F8_type_C. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view ]
PRINTSi PR00109. TYRKINASE.
SMARTi SM00231. FA58C. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view ]
SUPFAMi SSF49785. SSF49785. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEi PS01285. 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 ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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.

Entry informationi

Entry nameiDDR2_MOUSE
AccessioniPrimary (citable) accession number: Q62371
Secondary accession number(s): B2RSD7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1997
Last modified: September 3, 2014
This is version 145 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Caution

According to 1 Publication 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 (1 Publication). On the other hand, the fertility status of mice with a targeted disruption of the Ddr2 gene has not been mentioned (1 Publication). Thus, the infertility of smallie mice may be due to some additional, not yet identified defect.

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi