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Protein

Discoidin domain-containing receptor 2

Gene

Ddr2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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

Caution

According to PubMed:18483174 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 (PubMed:19681157). On the other hand, the fertility status of mice with a targeted disruption of the Ddr2 gene has not been mentioned (PubMed:11375938). Thus, the infertility of smallie mice may be due to some additional, not yet identified defect.2 Publications

Catalytic activityi

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

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)DescriptionActionsGraphical viewLength
Binding sitei608ATPPROSITE-ProRule annotation1
Active sitei709Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi569 – 577ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • collagen binding Source: MGI
  • protein tyrosine kinase collagen receptor activity Source: UniProtKB
  • transmembrane receptor protein tyrosine kinase activity Source: UniProtKB

GO - Biological processi

  • biomineral tissue development Source: UniProtKB
  • chondrocyte proliferation Source: UniProtKB
  • collagen-activated tyrosine kinase receptor signaling pathway Source: UniProtKB
  • collagen fibril organization Source: UniProtKB
  • endochondral bone growth Source: UniProtKB
  • ossification Source: UniProtKB-KW
  • peptidyl-tyrosine phosphorylation Source: UniProtKB
  • positive regulation of cell proliferation Source: MGI
  • positive regulation of DNA binding transcription factor activity Source: UniProtKB
  • positive regulation of extracellular matrix disassembly Source: UniProtKB
  • positive regulation of fibroblast migration Source: UniProtKB
  • positive regulation of fibroblast proliferation Source: UniProtKB
  • positive regulation of osteoblast differentiation Source: UniProtKB
  • positive regulation of protein kinase activity Source: UniProtKB
  • protein autophosphorylation Source: MGI
  • regulation of bone mineralization Source: UniProtKB
  • transmembrane receptor protein tyrosine kinase signaling pathway Source: MGI

Keywordsi

Molecular functionKinase, Receptor, Transferase, Tyrosine-protein kinase
Biological processOsteogenesis
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1 3474
ReactomeiR-MMU-3000171 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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 1

Organism-specific databases

MGIiMGI:1345277 Ddr2

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini22 – 399ExtracellularSequence analysisAdd BLAST378
Transmembranei400 – 421HelicalSequence analysisAdd BLAST22
Topological domaini422 – 854CytoplasmicSequence analysisAdd BLAST433

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)DescriptionActionsGraphical viewLength
Mutagenesisi471Y → F: Reduces tyrosine phosphorylation by 90%; when associated with E-608. 1 Publication1
Mutagenesisi608K → E: Abolishes kinase activity. Reduces tyrosine phosphorylation by 90%; when associated with F-471. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 21Sequence analysisAdd BLAST21
ChainiPRO_000001674722 – 854Discoidin domain-containing receptor 2Add BLAST833

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi30 ↔ 185PROSITE-ProRule annotation
Disulfide bondi73 ↔ 177PROSITE-ProRule annotation
Glycosylationi121N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi213N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi261N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi280N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi372N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei471Phosphotyrosine; by SRC and autocatalysis1 Publication1
Modified residuei735Phosphotyrosine; by SRC and autocatalysisBy similarity1
Modified residuei739Phosphotyrosine; by SRC and autocatalysisBy similarity1
Modified residuei740Phosphotyrosine; by SRC and autocatalysisBy similarity1

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).By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

MaxQBiQ62371
PaxDbiQ62371
PeptideAtlasiQ62371
PRIDEiQ62371

PTM databases

iPTMnetiQ62371
PhosphoSitePlusiQ62371
SwissPalmiQ62371

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

BgeeiENSMUSG00000026674
CleanExiMM_DDR2
MM_TKT
ExpressionAtlasiQ62371 baseline and differential
GenevisibleiQ62371 MM

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

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000027985

Structurei

3D structure databases

ProteinModelPortaliQ62371
SMRiQ62371
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini30 – 185F5/8 type CPROSITE-ProRule annotationAdd BLAST156
Domaini563 – 848Protein kinasePROSITE-ProRule annotationAdd BLAST286

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.PROSITE-ProRule annotation

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1094 Eukaryota
ENOG410XQAI LUCA
GeneTreeiENSGT00760000118818
HOGENOMiHOG000043102
HOVERGENiHBG005461
InParanoidiQ62371
KOiK05125
OMAiMSGGHIP
OrthoDBiEOG091G05Y8
PhylomeDBiQ62371
TreeFamiTF317840

Family and domain databases

Gene3Di2.60.120.2601 hit
InterProiView protein in InterPro
IPR034299 DDR2
IPR000421 FA58C
IPR008979 Galactose-bd-like_sf
IPR011009 Kinase-like_dom_sf
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
PANTHERiPTHR24416:SF295 PTHR24416:SF295, 1 hit
PfamiView protein in Pfam
PF00754 F5_F8_type_C, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PRINTSiPR00109 TYRKINASE
SMARTiView protein in SMART
SM00231 FA58C, 1 hit
SM00219 TyrKc, 1 hit
SUPFAMiSSF49785 SSF49785, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
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

Sequencei

Sequence statusi: Complete.

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

Q62371-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MIPIPRMPLV LLLLLLILGS AKAQVNPAIC RYPLGMSGGH IPDEDITASS
60 70 80 90 100
QWSESTAAKY GRLDSEEGDG AWCPEIPVQP DDLKEFLQID LRTLHFITLV
110 120 130 140 150
GTQGRHAGGH GIEFAPMYKI NYSRDGSRWI SWRNRHGKQV LDGNSNPYDV
160 170 180 190 200
FLKDLEPPIV ARFVRLIPVT DHSMNVCMRV ELYGCVWLDG LVSYNAPAGQ
210 220 230 240 250
QFVLPGGSII YLNDSVYDGA VGYSMTEGLG QLTDGVSGLD DFTQTHEYHV
260 270 280 290 300
WPGYDYVGWR NESATNGFIE IMFEFDRIRN FTTMKVHCNN MFAKGVKIFK
310 320 330 340 350
EVQCYFRSEA SEWEPTAVYF PLVLDDVNPS ARFVTVPLHH RMASAIKCQY
360 370 380 390 400
HFADTWMMFS EITFQSDAAM YNNSGALPTS PMAPTTYDPM LKVDDSNTRI
410 420 430 440 450
LIGCLVAIIF ILLAIIVIIL WRQFWQKMLE KASRRMLDDE MTVSLSLPSE
460 470 480 490 500
SSMFNNNRSS SPSEQESNST YDRIFPLRPD YQEPSRLIRK LPEFAPGEEE
510 520 530 540 550
SGCSGVVKPA QPNGPEGVPH YAEADIVNLQ GVTGGNTYCV PAVTMDLLSG
560 570 580 590 600
KDVAVEEFPR KLLAFKEKLG EGQFGEVHLC EVEGMEKFKD KDFALDVSAN
610 620 630 640 650
QPVLVAVKML RADANKNARN DFLKEIKIMS RLKDPNIIRL LAVCITEDPL
660 670 680 690 700
CMITEYMENG DLNQFLSRHE PLSSCSSDAT VSYANLKFMA TQIASGMKYL
710 720 730 740 750
SSLNFVHRDL ATRNCLVGKN YTIKIADFGM SRNLYSGDYY RIQGRAVLPI
760 770 780 790 800
RWMSWESILL GKFTTASDVW AFGVTLWETF TFCQEQPYSQ LSDEQVIENT
810 820 830 840 850
GEFFRDQGRQ IYLPQPALCP DSVYKLMLSC WRRETKHRPS FQEIHLLLLQ

QGAE
Length:854
Mass (Da):96,482
Last modified:November 1, 1997 - v2
Checksum:i45CFD2BE9ED524D4
GO

Sequence cautioni

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

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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_006496696.3
XP_006496760.1, XM_006496697.3
XP_006496761.1, XM_006496698.3
UniGeneiMm.229249

Genome annotation databases

EnsembliENSMUST00000027985; ENSMUSP00000027985; ENSMUSG00000026674
ENSMUST00000170800; ENSMUSP00000129624; ENSMUSG00000026674
ENSMUST00000194690; ENSMUSP00000141443; ENSMUSG00000026674
GeneIDi18214
KEGGimmu:18214
UCSCiuc007dlu.2 mouse

Similar proteinsi

Entry informationi

Entry nameiDDR2_MOUSE
AccessioniPrimary (citable) accession number: Q62371
Secondary accession number(s): B2RSD7
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1997
Last modified: February 28, 2018
This is version 173 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome