Q03146 (DDR1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Epithelial discoidin domain-containing receptor 1
Short name=Epithelial discoidin domain receptor 1
EC=2.7.10.1

Alternative name(s):
CD167 antigen-like family member A
Cell adhesion kinase
Discoidin receptor tyrosine kinase
Protein-tyrosine kinase MPK-6
Tyrosine kinase DDR
Tyrosine-protein kinase CAK
CD_antigen=CD167a

Gene names

Name:	Ddr1
Synonyms:	Cak, Eddr1, Mpk6

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	911 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at transcript level

General annotation (Comments)

Function	Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell attachment to the extracellular matrix, remodeling of the extracellular matrix, cell migration, differentiation, survival and cell proliferation. Collagen binding triggers a signaling pathway that involves SRC and leads to the activation of MAP kinases. Regulates remodeling of the extracellular matrix by up-regulation of the matrix metalloproteinases MMP2, MMP7 and MMP9, and thereby facilitates cell migration and wound healing, but also tumor cell invasion. Promotes smooth muscle cell migration, and thereby contributes to arterial wound healing. Phosphorylates PTPN11 By similarity. Required for normal blastocyst implantation during pregnancy, for normal mammary gland differentiation and normal lactation. Required for normal ear morphology and normal hearing. Ref.4
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subunit structure	Homodimer. Interacts (via PPxY motif) with WWC1 (via WW domains) in a collagen-regulated manner. Forms a tripartite complex with WWC1 and PRKCZ, but predominantly in the absence of collagen. Interacts (tyrosine phosphorylated) with SHC1. Interacts with SRC. Interacts with MYH9. Interacts with CDH1. Interacts with PTPN11. Interacts with NCK2 By similarity.
Subcellular location	Cell membrane; Single-pass type I membrane protein.
Tissue specificity	Detected in the cochlea and the organ of Corti in the inner ear. Isoform 1 is predominant and is expressed in developing embryo and adult brain. Isoform 2 is expressed in various epithelial cells. Ref.6
Post-translational modification	Autophosphorylated in response to fibrillar collagen binding By similarity.
Disruption phenotype	Mice are born at the expected Mendelian rate, but female mice are dwarfs and most of them are unable to bear offspring, due to defects in blastocyte implantation in the uterus. About one fifth can bear offspring, but for these the mammary gland fails to undergo proper differentiation during pregnancy, with hyperproliferation and abnormal branching of the mammary ducts, leading to a lactation defect. In addition, mice exhibit hearing loss, due to alterations of the inner ear. Mice display poor calcification of the fibula. They also exhibit defects in the structure of the slit diaphragm in kidney glomeruli, leading to proteinuria, but do not show overt signs of kidney dysfunction. Ref.3 Ref.5 Ref.6
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.

Ontologies

Keywords
Biological process	Lactation Pregnancy
Cellular component	Cell membrane Membrane
Coding sequence diversity	Alternative splicing
Domain	Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Calcium Metal-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	branching involved in mammary gland duct morphogenesis Inferred from mutant phenotype Ref.3. Source: MGI ear development Inferred from mutant phenotype Ref.3. Source: MGI embryo implantation Inferred from mutant phenotype Ref.3. Source: MGI lactation Inferred from electronic annotation. Source: UniProtKB-KW mammary gland alveolus development Inferred from mutant phenotype Ref.3. Source: MGI negative regulation of cell proliferation Inferred from mutant phenotype PubMed 12397034. Source: MGI peptidyl-tyrosine autophosphorylation Inferred from sequence or structural similarity. Source: UniProtKB regulation of cell growth Inferred from mutant phenotype PubMed 12397034. Source: MGI regulation of cell-matrix adhesion Inferred from mutant phenotype PubMed 12397034. Source: MGI regulation of extracellular matrix disassembly Inferred from mutant phenotype Ref.4. Source: UniProtKB smooth muscle cell migration Inferred from mutant phenotype Ref.4. Source: UniProtKB smooth muscle cell-matrix adhesion Inferred from mutant phenotype Ref.4. Source: UniProtKB wound healing, spreading of cells Inferred from mutant phenotype Ref.4. Source: UniProtKB
Cellular_component	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Inferred from direct assay PubMed 12397034. Source: MGI
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW collagen binding Inferred from mutant phenotype Ref.4. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein tyrosine kinase collagen receptor activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q03146-1)

Also known as: CAK I;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q03146-2)

Also known as: CAK II;

The sequence of this isoform differs from the canonical sequence as follows:
     503-539: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 19	19	Potential
	Chain	20 – 911	892	Epithelial discoidin domain-containing receptor 1		PRO_0000016743
Regions
	Topological domain	22 – 415	394	Extracellular Potential
	Transmembrane	416 – 436	21	Helical; Potential
	Topological domain	437 – 911	475	Cytoplasmic Potential
	Domain	32 – 186	155	F5/8 type C
	Domain	608 – 903	296	Protein kinase
	Nucleotide binding	614 – 622	9	ATP By similarity
	Region	193 – 369	177	DS-like domain By similarity
	Motif	479 – 482	4	PPxY motif
	Compositional bias	379 – 413	35	Gly/Pro-rich
	Compositional bias	474 – 599	126	Gly/Pro-rich
Sites
	Active site	764	1	Proton acceptor By similarity
	Metal binding	213	1	Calcium 1; via carbonyl oxygen By similarity
	Metal binding	232	1	Calcium 1 By similarity
	Metal binding	232	1	Calcium 2; via carbonyl oxygen By similarity
	Metal binding	235	1	Calcium 2 By similarity
	Metal binding	237	1	Calcium 2; via carbonyl oxygen By similarity
	Metal binding	255	1	Calcium 1; via carbonyl oxygen By similarity
	Metal binding	257	1	Calcium 1; via carbonyl oxygen By similarity
	Metal binding	362	1	Calcium 2; via carbonyl oxygen By similarity
	Metal binding	363	1	Calcium 2 By similarity
	Binding site	653	1	ATP By similarity
Amino acid modifications
	Modified residue	511	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	738	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	790	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	794	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	795	1	Phosphotyrosine; by autocatalysis By similarity
	Glycosylation	213	1	N-linked (GlcNAc...) Potential
	Glycosylation	262	1	N-linked (GlcNAc...) Potential
	Glycosylation	372	1	N-linked (GlcNAc...) Potential
	Glycosylation	392	1	N-linked (GlcNAc...) Potential
	Disulfide bond	32 ↔ 186		By similarity
	Disulfide bond	75 ↔ 178		By similarity
	Disulfide bond	305 ↔ 350		By similarity
Natural variations
	Alternative sequence	503 – 539	37	Missing in isoform 2.		VSP_002954

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (CAK I) [UniParc]. Last modified November 1, 1997. Version 2. Checksum: DBB7FE03DDD79510	FASTA	911	101,161
	10 20 30 40 50 60 MGTGTLSSLL LLLLLVTIGD ADMKGHFDPA KCRYALGMQD RTIPDSDISV SSSWSDSTAA 70 80 90 100 110 120 RHSRLESSDG DGAWCPAGPV FPKEEEYLQV DLRRLHLVAL VGTQGRHAGG LGKEFSRSYR 130 140 150 160 170 180 LRYSRDGRRW MDWKDRWGQE VISGNEDPGG VVLKDLGPPM VARLVRFYPR ADRVMSVCLR 190 200 210 220 230 240 VELYGCLWRD GLLSYTAPVG QTMQLSEVMV HLNDSTYDGY TAGGLQYGGL GQLADGVVGL 250 260 270 280 290 300 DDFRQSQELR VWPGYDYVGW SNQSFPTGYV EMEFEFDRLR TFQTMQVHCN NMHTLGARLP 310 320 330 340 350 360 GGVECRFKRG PAMAWEGEPV RHALGGSLGD PRARAISVPL GGHVGRFLQC RFLFAGPWLL 370 380 390 400 410 420 FSEISFISDV VNDSSDTFPP APWWPPGPPP TNFSSLELEP RGQQPVAKAE GSPTAILIGC 430 440 450 460 470 480 LVAIILLLLL IIALMLWRLH WRRLLSKAER RVLEEELTVH LSVPGDTILI NNRPGPREPP 490 500 510 520 530 540 PYQEPRPRGT PPHSAPCVPN GSALLLSNPA YRLLLATYAR PPRGPGPPTP AWAKPTNTQA 550 560 570 580 590 600 CSGDYMEPEK PGAPLLPPPP QNSVPHYAEA DIVTLQGVTG GNTYAVPALP PGAVGDGPPR 610 620 630 640 650 660 VDFPRSRLRF KEKLGEGQFG EVHLCEVEDP QDLVSSDFPI SVHKGHPLLV AVKILRPDAT 670 680 690 700 710 720 KNARNDFLKE VKIMSRLKDP NIIRLLGVCV QDDPLCMITD YMENGDLNQF LSARQLENKA 730 740 750 760 770 780 TQGLSGDTES DQGPTISYPM LLHVGAQIAS GMRYLATLNF VHRDLATRNC LVGENFTIKI 790 800 810 820 830 840 ADFGMSRNLY AGDYYRVQGR AVLPIRWMAW ECILMGKFTT ASDVWAFGVT LWEVLMLCRS 850 860 870 880 890 900 QPFGQLTDEQ VIENAGEFFR DQGRQVYLSR PPACPQTLYE LMLRCWSREP EQRPPFAQLH 910 RFLADDALNT V
	Isoform 2 (CAK II) [UniParc]. Checksum: A649B2FCE360BA5B	FASTA	874	97,207
	10 20 30 40 50 60 MGTGTLSSLL LLLLLVTIGD ADMKGHFDPA KCRYALGMQD RTIPDSDISV SSSWSDSTAA 70 80 90 100 110 120 RHSRLESSDG DGAWCPAGPV FPKEEEYLQV DLRRLHLVAL VGTQGRHAGG LGKEFSRSYR 130 140 150 160 170 180 LRYSRDGRRW MDWKDRWGQE VISGNEDPGG VVLKDLGPPM VARLVRFYPR ADRVMSVCLR 190 200 210 220 230 240 VELYGCLWRD GLLSYTAPVG QTMQLSEVMV HLNDSTYDGY TAGGLQYGGL GQLADGVVGL 250 260 270 280 290 300 DDFRQSQELR VWPGYDYVGW SNQSFPTGYV EMEFEFDRLR TFQTMQVHCN NMHTLGARLP 310 320 330 340 350 360 GGVECRFKRG PAMAWEGEPV RHALGGSLGD PRARAISVPL GGHVGRFLQC RFLFAGPWLL 370 380 390 400 410 420 FSEISFISDV VNDSSDTFPP APWWPPGPPP TNFSSLELEP RGQQPVAKAE GSPTAILIGC 430 440 450 460 470 480 LVAIILLLLL IIALMLWRLH WRRLLSKAER RVLEEELTVH LSVPGDTILI NNRPGPREPP 490 500 510 520 530 540 PYQEPRPRGT PPHSAPCVPN GSACSGDYME PEKPGAPLLP PPPQNSVPHY AEADIVTLQG 550 560 570 580 590 600 VTGGNTYAVP ALPPGAVGDG PPRVDFPRSR LRFKEKLGEG QFGEVHLCEV EDPQDLVSSD 610 620 630 640 650 660 FPISVHKGHP LLVAVKILRP DATKNARNDF LKEVKIMSRL KDPNIIRLLG VCVQDDPLCM 670 680 690 700 710 720 ITDYMENGDL NQFLSARQLE NKATQGLSGD TESDQGPTIS YPMLLHVGAQ IASGMRYLAT 730 740 750 760 770 780 LNFVHRDLAT RNCLVGENFT IKIADFGMSR NLYAGDYYRV QGRAVLPIRW MAWECILMGK 790 800 810 820 830 840 FTTASDVWAF GVTLWEVLML CRSQPFGQLT DEQVIENAGE FFRDQGRQVY LSRPPACPQT 850 860 870 LYELMLRCWS REPEQRPPFA QLHRFLADDA LNTV

References

[1]	"Identification of two isoforms of the Cak receptor kinase that are coexpressed in breast tumor cell lines." Perez J.L., Jing S.Q., Wong T.W. Oncogene 12:1469-1477(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). Strain: C57BL/6.
[2]	"An Eph-related receptor protein tyrosine kinase gene segmentally expressed in the developing mouse hindbrain." Gilardi-Hebenstreit P., Nieto M.A., Frain M., Mattei M.-G., Chestier A., Wilkinson D.G., Charnay P. Oncogene 7:2499-2506(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 766-822. Strain: C57BL/6. Tissue: Embryonic brain.
[3]	"Discoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development." Vogel W.F., Aszodi A., Alves F., Pawson T. Mol. Cell. Biol. 21:2906-2917(2001) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[4]	"Tyrosine kinase activity of discoidin domain receptor 1 is necessary for smooth muscle cell migration and matrix metalloproteinase expression." Hou G., Vogel W.F., Bendeck M.P. Circ. Res. 90:1147-1149(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[5]	"DDR1-deficient mice show localized subepithelial GBM thickening with focal loss of slit diaphragms and proteinuria." Gross O., Beirowski B., Harvey S.J., McFadden C., Chen D., Tam S., Thorner P.S., Smyth N., Addicks K., Bloch W., Ninomiya Y., Sado Y., Weber M., Vogel W.F. Kidney Int. 66:102-111(2004) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[6]	"Inner ear defects and hearing loss in mice lacking the collagen receptor DDR1." Meyer zum Gottesberge A.M., Gross O., Becker-Lendzian U., Massing T., Vogel W.F. Lab. Invest. 88:27-37(2008) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE, TISSUE SPECIFICITY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	L57509 mRNA. Translation: AAB05209.1. X57240 mRNA. Translation: CAA40516.1.
IPI	IPI00129221. IPI00226685.
PIR	S30502.
RefSeq	NP_001185760.1. NM_001198831.1. NP_001185762.1. NM_001198833.1. NP_031610.1. NM_007584.2. NP_766550.1. NM_172962.1.
UniGene	Mm.5021.
3D structure databases
ProteinModelPortal	Q03146.
SMR	Q03146. Positions 31-369, 583-907.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-5170014.
PTM databases
PhosphoSite	Q03146.
Proteomic databases
PaxDb	Q03146.
PRIDE	Q03146.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000003628; ENSMUSP00000003628; ENSMUSG00000003534. ENSMUST00000097333; ENSMUSP00000094945; ENSMUSG00000003534. ENSMUST00000117301; ENSMUSP00000112570; ENSMUSG00000003534. ENSMUST00000119825; ENSMUSP00000113062; ENSMUSG00000003534. ENSMUST00000166980; ENSMUSP00000133047; ENSMUSG00000003534.
GeneID	12305.
KEGG	mmu:12305.
Organism-specific databases
CTD	780.
MGI	MGI:99216. Ddr1.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00700000104389.
HOGENOM	HOG000043102.
HOVERGEN	HBG005461.
InParanoid	Q03146.
KO	K05124.
OMA	CEVENPQ.
OrthoDB	EOG4H19V5.
Enzyme and pathway databases
BRENDA	2.7.10.1. 3474.
Gene expression databases
ArrayExpress	Q03146.
Bgee	Q03146.
CleanEx	MM_DDR1.
Genevestigator	Q03146.
GermOnline	ENSMUSG00000003534. 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. PS00107. PROTEIN_KINASE_ATP. False negative. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00109. PROTEIN_KINASE_TYR. 1 hit. PS00239. RECEPTOR_TYR_KIN_II. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	DDR1. mouse.
NextBio	280834.
SOURCE	Search...

Entry information

Entry name

DDR1_MOUSE

Accession

Primary (citable) accession number: Q03146

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1994
Last sequence update:	November 1, 1997
Last modified:	May 1, 2013
This is version 134 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program