DDR1 (discoidin domain receptor tyrosine kinase 1)

2011-05-01   Barbara Roig , Elisabet Vilella 

Hospital Psiquiatic Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, C\\\/Sant Llorenc 21, 43201 REUS, Spain

Identity

HGNC
LOCATION
6p21.33
LOCUSID
ALIAS
CAK,CD167,DDR,EDDR1,HGK2,MCK10,NEP,NTRK4,PTK3,PTK3A,RTK6,TRKE
FUSION GENES

DNA/RNA

Atlas Image
Genomic organisation of the DDR1 gene on chromosome 6. Exons that are implicated in the alternative splicing process of the DDR1 gene are represented by open boxes. The alternative splicing process of exon 10 to exon 14 generates 5 DDR1 isoforms, which are affixed a-e.

Description

The DDR1 gene comprises 17 exons and spans 12 kb of the genomic sequence on chromosome 6 (from position 30851861 bp to 30867933 bp in the positive strand orientation).

Transcription

The 3840-bp mRNA is transcribed in a centromeric to telomeric orientation. Alternative splicing can occur, and 5 named isoforms (DDR1a-e) are recognised.

Pseudogene

No pseudogene has been described.

Proteins

Atlas Image
Schematic diagram of the DDR1 protein and localization of the DDR1 Tyrosine phosphorylated sites at intracellular domain.

Description

DDR1 belongs to the DDRs subfamily of tyrosine kinase receptors. This subfamily is composed of only two members, DDR1 and DDR2, and it is distinguished by an extracellular domain that is homologous to the carbohydrate-binding lectin discoidin-I in Dictyostelium discoideum. The Discoidin domain is essential for the ability of DDRs to bind ligands. To-date, collagen is the only unique DDR1 ligand that has been identified. Five isoforms of DDR1 that are generated by alternative splicing have been described. The longest DDR1 transcript codes for the full-length receptor (DDR1c isoform) and is composed of 919 amino acids. DDR1a and DDR1b isoforms lack 37 amino acids in the juxtamembrane domain or 6 amino acids in the kinase domain. DDR1d and DDR1e isoforms are C-terminally truncated receptors. DDR1d lacks exons 11 and 12 causing a frame-shift mutation that generates a stop codon and premature termination of transcription. Finally, DDR1e lacks exons 11 and 12 as well as the first half of exon 10 (Alves et al., 1995).

Expression

DDR1 is ubiquitously expressed in a variety of epithelial tissues (Alves et al., 1995; Curat and Vogel, 2002; Ferri et al., 2004; Hou et al., 2001; Mohan et al., 2001; Sakamoto et al., 2001; Tanaka et al., 1998). DDR1 is also expressed in endothelial blood capillary cells and oligodendrocytes in the human brain (Franco-Pons et al., 2009; Roig et al., 2010). DDR1 is significantly overexpressed in several human cancers (Barker et al., 1995; Colas et al., 2011; Ford et al., 2007; Hajdu et al., 2010; Heinzelmann-Schwarz et al., 2004; Laval et al., 1994; Nemoto et al., 1997; Park et al., 2007; Tun et al., 2011; Weiner et al., 1996; Weiner et al., 2000; Yamanaka et al., 2006; Yoshida et al., 2007) and carcinoma cell lines (Alves et al., 1995; Gu et al., 2011; Park et al., 2007; Sakuma et al., 1996).

Localisation

Transmembrane.

Function

Receptor tyrosine kinases are key components of several signal transduction pathways. These kinases control multiple cellular processes, including motility, proliferation, differentiation, metabolism and survival.
DDR1 is actively involved in tumorigenesis and promotes the proliferation of neoplasic cells. The interaction of DDR1 and Notch1 displays a prosurvival effect (Kim et al., 2011). DDR1 participates in the collective migration of cancer cells by coordinating the cell polarity regulators Par3 and Par6 (Hidalgo-Carcedo et al., 2011).

Homology

- P. troglodytes, discoidin domain receptor tyrosine kinase 1, DDR1
- C. lupus, discoidin domain receptor tyrosine kinase 1, DDR1
- M. musculus, discoidin domain receptor family member 1, Ddr1
- R. norvegicus, discoidin domain receptor tyrosine kinase 1

Mutations

Note

Few somatic mutations have been described. Four mutations (G1486T, A496S, CC2469/2470TT, R824W) have been identified in a cohort of 26 primary lung neoplasms (Davies et al., 2005). One somatic mutation (A803V) was found in 4 acute myeloid leukaemia patients (Tomasson et al., 2008).
Atlas Image

Implicated in

Entity name
Breast cancer
Note
DDR1 overexpression was observed in human primary breast tumours samples compared to that in normal breast tissues (Barker et al., 1995). In addition, invasive ductal and lobular carcinomas showed differential expression of DDR1. DDR1 was downregulated in lobular carcinomas (Turashvili et al., 2007a; Turashvili et al., 2007b).
Entity name
Note
The DDR1 promoter presents a potential p53 binding-site. A previous study has shown that p53 expression upregulated the mRNA expression levels of DDR1 in human osteosarcoma cells (Sakuma et al., 1996).
Entity name
Oesophageal cancer
Note
The overexpression of DDR1 was reported in 12 carcinomatous oesophageal tissues compared to that in normal tissues. Furthermore, a positive correlation was identified between DDR1 mRNA expression and the proliferative activity of the tumoural cells (Nemoto et al., 1997).
Entity name
Ovarian cancer
Note
DDR1 was highly expressed in 158 histological subtypes of primary epithelial ovarian cancers (EOC) compared to that in normal ovarian surface epithelium samples (Heinzelmann-Schwarz et al., 2004).
Entity name
Endometrial cancer
Note
DDR1 has been implicated as a potential molecular marker of endometrial cancer (Colas et al., 2011; Domenyuk et al., 2007). A gene expression screening of 52 carcinomas samples showed differential expression of several genes, including the DDR1 gene. These data were also demonstrated in 50 tumoural and non-tumoural uterine aspirates (Colas et al., 2011).
Entity name
Brain tumours
Note
DDR1 was originally isolated in malignant childhood brain tumours, which overexpressed DDR1 (Weiner et al., 1996). Replicable findings were found in metastatic brain neoplasms and glioma cells (Yamanaka et al., 2006; Weiner et al., 2000). In glioma cells, DDR1 was involved in cell proliferation and invasion via cell interactions with the extracellular matrix (Ram et al., 2005; Yamanaka et al., 2006). Moreover, a study on DDR1a and DDR1b isoforms overexpression in glioma cells has identified distinct roles for each DDR1 isoforms in the cell attachment process, which is mediated by collagen I (Ram et al., 2005). The analysis of the expression profile in mice that had PDGF-induced glioma showed overexpression of DDR1 (Johansson et al., 2005).
Note
A PCNSL pathway analysis revealed upregulation of DDR1 expression in the extracellular matrix and the adhesion-related pathways (Tun et al., 2011).
Entity name
Pituitary adenoma
Note
In different subtypes of pituitary adenoma, DDR1 expression was related to the hormonal background. DDR1 was more highly expressed in macroadenomas, compared to microadenomas, and in PRL- and GH-producing adenomas (Yoshida et al., 2007).
Entity name
Lung cancer
Note
DDR1 was upregulated in tumour lung tissue compared to that in normal tissue and was an independent favourable predictor for prognosis (Ford et al., 2007). Similarly, DDR1 was highly phosphorylated in non-small cell lung cancer (NSCLC) (Rikova et al., 2007).
One study described the presence of DDR1 somatic mutations in lung cancer (Davies et al., 2005). However, no mutations were detected in another lung cancer study (Ford et al., 2007).
Entity name
Liver cancer
Note
DDR1a and DDR1b isoforms were overexpressed in hepatocellular carcinoma cell lines HLE and Huh-7. DDR1 isoform overexpression enhanced the migration and invasion of the hepatocellular carcinoma cell lines in association with the matrix metalloproteinases MMP2 and MMP9 (Park et al., 2007).
The downregulation of miR-199a-5p, which is a direct target of DDR1, deregulated DDR1 functionality and increased cell invasion in human hepatocellular carcinoma (HCC) (Shen et al., 2010).
Finally, a profiling study on receptor tyrosine kinase phosphorylation in cholangiocarcinoma patients showed high levels of phosphorylation of DDR1 and other tyrosine kinases in tumour tissues in comparison to para-tumour tissues (Gu et al., 2011).
Entity name
Mesenchymal neoplasm
Note
Solitary fibrous tumour (SFT) expression profiling of 23 samples showed an over-expression of several receptor tyrosine kinase genes, including DDR1. However, no mutations were identified using cDNA sequencing (Hajdu et al., 2010).

Bibliography

Pubmed IDLast YearTitleAuthors
113441272001Identification of two novel, kinase-deficient variants of discoidin domain receptor 1: differential expression in human colon cancer cell lines.Alves F et al
78456871995Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer.Alves F et al
78456821995Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours.Barker KT et al
212074242011Molecular markers of endometrial carcinoma detected in uterine aspirates.Colas E et al
123970342002Discoidin domain receptor 1 controls growth and adhesion of mesangial cells.Curat CA et al
161409232005Somatic mutations of the protein kinase gene family in human lung cancer.Davies H et al
177047372007Identification of new DNA markers of endometrial cancer in patients from the Ukrainian population.Domenyuk VP et al
151113042004Role of discoidin domain receptors 1 and 2 in human smooth muscle cell-mediated collagen remodeling: potential implications in atherosclerosis and lymphangioleiomyomatosis.Ferri N et al
172993902007Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma.Ford CE et al
188368512009Discoidin domain receptor 1, a tyrosine kinase receptor, is upregulated in an experimental model of remyelination and during oligodendrocyte differentiation in vitro.Franco-Pons N et al
212535782011Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma.Gu TL et al
205270232010IGF2 over-expression in solitary fibrous tumours is independent of anatomical location and is related to loss of imprinting.Hajdu M et al
152405332004Overexpression of the cell adhesion molecules DDR1, Claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer.Heinzelmann-Schwarz VA et al
211700302011Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6.Hidalgo-Carcedo C et al
157506232005Expression analysis of genes involved in brain tumor progression driven by retroviral insertional mutagenesis in mice.Johansson FK et al
213986982011DDR1 receptor tyrosine kinase promotes prosurvival pathway through Notch1 activation.Kim HG et al
93960431997Overexpression of protein tyrosine kinases in human esophageal cancer.Nemoto T et al
179826272007Overexpression of discoidin domain receptor 1 increases the migration and invasion of hepatocellular carcinoma cells in association with matrix metalloproteinase.Park HS et al
86228631996Identification of two isoforms of the Cak receptor kinase that are coexpressed in breast tumor cell lines.Perez JL et al
162349852006Discoidin domain receptor-1a (DDR1a) promotes glioma cell invasion and adhesion in association with matrix metalloproteinase-2.Ram R et al
180831072007Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.Rikova K et al
89770991996Receptor protein tyrosine kinase DDR is up-regulated by p53 protein.Sakuma S et al
207999542010Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion.Shen Q et al
182703282008Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia.Tomasson MH et al
181848682008Pathway analysis of primary central nervous system lymphoma.Tun HW et al
176907412007Novel immunohistochemical markers for the differentiation of lobular and ductal invasive breast carcinomas.Turashvili G et al
111269112000Consistent and selective expression of the discoidin domain receptor-1 tyrosine kinase in human brain tumors.Weiner HL et al
90752491996Pediatric brain tumors express multiple receptor tyrosine kinases including novel cell adhesion kinases.Weiner HL et al
166521502006Identification of expressed genes characterizing long-term survival in malignant glioma patients.Yamanaka R et al
170015182007Enhancement of pituitary adenoma cell invasion and adhesion is mediated by discoidin domain receptor-1.Yoshida D et al

Other Information

Locus ID:

NCBI: 780
MIM: 600408
HGNC: 2730
Ensembl: ENSG00000204580

Variants:

dbSNP: 780
ClinVar: 780
TCGA: ENSG00000204580
COSMIC: DDR1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000204580ENST00000324771Q08345
ENSG00000204580ENST00000324771A0A024RCL1
ENSG00000204580ENST00000376567Q08345
ENSG00000204580ENST00000376567A0A024RCQ1
ENSG00000204580ENST00000376568Q08345
ENSG00000204580ENST00000376568A0A024RCL1
ENSG00000204580ENST00000376569Q08345
ENSG00000204580ENST00000376569A0A024RCQ1
ENSG00000204580ENST00000376570Q08345
ENSG00000204580ENST00000376570A0A024RCQ1
ENSG00000204580ENST00000376575Q08345
ENSG00000204580ENST00000396342A2ABL0
ENSG00000204580ENST00000412274D6RBU7
ENSG00000204580ENST00000417521A2ABM8
ENSG00000204580ENST00000418800Q08345
ENSG00000204580ENST00000418800A0A024RCQ1
ENSG00000204580ENST00000421124A2ABL2
ENSG00000204580ENST00000424544H0Y717
ENSG00000204580ENST00000428153E7EQ30
ENSG00000204580ENST00000437124E7ERI6
ENSG00000204580ENST00000446312A0A0A0MSX3
ENSG00000204580ENST00000452441Q08345
ENSG00000204580ENST00000452441A0A024RCL1
ENSG00000204580ENST00000454612Q08345
ENSG00000204580ENST00000454612A0A024RCQ1
ENSG00000204580ENST00000460944E7EPH4
ENSG00000204580ENST00000482873Q08345
ENSG00000204580ENST00000484556H0Y9F4
ENSG00000204580ENST00000502955D6RB82
ENSG00000204580ENST00000503180D6RB35
ENSG00000204580ENST00000503495E7EUP7
ENSG00000204580ENST00000503628D6RAJ3
ENSG00000204580ENST00000503670D6R9C4
ENSG00000204580ENST00000504651E7EX99
ENSG00000204580ENST00000504679E7ETX3
ENSG00000204580ENST00000504927E7ETI3
ENSG00000204580ENST00000505066E7EVW6
ENSG00000204580ENST00000505534E7EN94
ENSG00000204580ENST00000507046E7EQ23
ENSG00000204580ENST00000507901E7EXB0
ENSG00000204580ENST00000508312Q08345
ENSG00000204580ENST00000508317E7EUD5
ENSG00000204580ENST00000509639E7ES06
ENSG00000204580ENST00000511510E7ESR9
ENSG00000204580ENST00000512336E7EVT1
ENSG00000204580ENST00000512694E7EPN2
ENSG00000204580ENST00000512725E7ERN0
ENSG00000204580ENST00000513043D6RB35
ENSG00000204580ENST00000513240Q08345
ENSG00000204580ENST00000513240A0A024RCJ0
ENSG00000204580ENST00000513749D6RAJ3
ENSG00000204580ENST00000514434H0YAH6
ENSG00000204580ENST00000515219D6RGW5
ENSG00000204580ENST00000515233E7ERN0
ENSG00000204580ENST00000515881E7ENJ2

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
Extracellular matrix organizationREACTOMER-HSA-1474244
Non-integrin membrane-ECM interactionsREACTOMER-HSA-3000171

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
211700302011Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6.126
182703282008Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia.90
183621842008Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor 1.88
207999542010Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion.68
233355072013Discoidin domain receptors: unique receptor tyrosine kinases in collagen-mediated signaling.66
152405332004Overexpression of the cell adhesion molecules DDR1, Claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer.63
273681002016Multi-organ Site Metastatic Reactivation Mediated by Non-canonical Discoidin Domain Receptor 1 Signaling.57
210448842011Collagen binding specificity of the discoidin domain receptors: binding sites on collagens II and III and molecular determinants for collagen IV recognition by DDR1.56
172993902007Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma.51
198514452009High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions.51

Citation

Barbara Roig ; Elisabet Vilella

DDR1 (discoidin domain receptor tyrosine kinase 1)

Atlas Genet Cytogenet Oncol Haematol. 2011-05-01

Online version: http://atlasgeneticsoncology.org/gene/40280/ddr1-(discoidin-domain-receptor-tyrosine-kinase-1)