Q62371 (DDR2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	854 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	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 process	Osteogenesis
Cellular component	Cell membrane Membrane
Domain	Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	biomineral 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 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 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: Compara regulation of bone mineralization Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP 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
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 21	21	Potential
	Chain	22 – 854	833	Discoidin domain-containing receptor 2		PRO_0000016747
Regions
	Topological domain	22 – 399	378	Extracellular Potential
	Transmembrane	400 – 421	22	Helical; Potential
	Topological domain	422 – 854	433	Cytoplasmic Potential
	Domain	30 – 185	156	F5/8 type C
	Domain	563 – 848	286	Protein kinase
	Nucleotide binding	569 – 577	9	ATP By similarity
Sites
	Active site	709	1	Proton acceptor By similarity
	Binding site	608	1	ATP By similarity
Amino acid modifications
	Modified residue	461	1	Phosphoserine By similarity
	Modified residue	471	1	Phosphotyrosine; by SRC and autocatalysis Ref.6
	Modified residue	674	1	Phosphoserine By similarity
	Modified residue	735	1	Phosphotyrosine; by SRC and autocatalysis By similarity
	Modified residue	739	1	Phosphotyrosine; by SRC and autocatalysis By similarity
	Modified residue	740	1	Phosphotyrosine; by SRC and autocatalysis By similarity
	Glycosylation	121	1	N-linked (GlcNAc...) Potential
	Glycosylation	213	1	N-linked (GlcNAc...) Potential
	Glycosylation	261	1	N-linked (GlcNAc...) Potential
	Glycosylation	280	1	N-linked (GlcNAc...) Potential
	Glycosylation	372	1	N-linked (GlcNAc...) Potential
	Disulfide bond	30 ↔ 185		By similarity
	Disulfide bond	73 ↔ 177		By similarity
Experimental info
	Mutagenesis	471	1	Y → F: Reduces tyrosine phosphorylation by 90%; when associated with E-608. Ref.6
	Mutagenesis	608	1	K → E: Abolishes kinase activity. Reduces tyrosine phosphorylation by 90%; when associated with F-471. Ref.6

Sequences

	Sequence		Length	Mass (Da)
	Q62371 [UniParc]. Last modified November 1, 1997. Version 2. Checksum: 45CFD2BE9ED524D4	FASTA	854	96,482
	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

References

	« Hide 'large scale' referencesShow '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.
IPI	IPI00124761.
PIR	I48859.
RefSeq	NP_072075.2. NM_022563.2.
UniGene	Mm.229249.
3D structure databases
ProteinModelPortal	Q62371.
SMR	Q62371. Positions 26-369, 466-848.
ModBase	Search...
PTM databases
PhosphoSite	Q62371.
Proteomic databases
PRIDE	Q62371.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000027985; ENSMUSP00000027985; ENSMUSG00000026674. ENSMUST00000170800; ENSMUSP00000129624; ENSMUSG00000026674.
GeneID	18214.
KEGG	mmu:18214.
UCSC	uc007dlu.2. mouse.
Organism-specific databases
CTD	4921.
MGI	MGI:1345277. Ddr2.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00700000104389.
HOGENOM	HOG000043102.
HOVERGEN	HBG005461.
InParanoid	B2RSD7.
KO	K05125.
OMA	FSEITFQ.
OrthoDB	EOG4KWJS6.
Enzyme and pathway databases
BRENDA	2.7.10.1. 3474.
Gene expression databases
Bgee	Q62371.
CleanEx	MM_DDR2. MM_TKT.
Genevestigator	Q62371.
GermOnline	ENSMUSG00000026674. Mus musculus.
Family and domain databases
InterPro	IPR000421. Coagulation_fac_5/8-C_type_dom. IPR008979. Galactose-bd-like. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_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]
Pfam	PF00754. F5_F8_type_C. 1 hit. PF07714. Pkinase_Tyr. 1 hit. [Graphical view]
PRINTS	PR00109. TYRKINASE.
SMART	SM00231. FA58C. 1 hit. SM00219. TyrKc. 1 hit. [Graphical view]
SUPFAM	SSF49785. Gal_bind_like. 1 hit. SSF56112. Kinase_like. 1 hit.
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. [Graphical view]
ProtoNet	Search...
Other
NextBio	293620.
SOURCE	Search...

Entry information

Entry name

DDR2_MOUSE

Accession

Primary (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:	May 1, 2013
This is version 132 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program