Atlas of Genetics and Cytogenetics in Oncology and Haematology
DDR1 (discoidin domain receptor tyrosine kinase 1)
| Identity |
| Other names | CAK |
| CD167 | |
| DDR | |
| EDDR1 | |
| HGK2 | |
| MCK10 | |
| NEP | |
| NTRK4 | |
| PTK3 | |
| PTK3A | |
| RTK6 | |
| TRKE | |
| HGNC (Hugo) | DDR1 |
| LocusID (NCBI) | 780 |
| Location | 6p21.33 |
| Location_base_pair | Starts at 30856465 and ends at 30867933 bp from pter ( according to hg19-Feb_2009) [Mapping] |
| DNA/RNA |
 | |
| 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. |
| Protein |
 | |
| 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). |
 | |
| Implicated in |
| Entity | 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 | Osteosarcoma |
| 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 | 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 | 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 | 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 | 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). |
| Entity | Primary central nervous system lymphoma (PCNSL) |
| Note | A PCNSL pathway analysis revealed upregulation of DDR1 expression in the extracellular matrix and the adhesion-related pathways (Tun et al., 2011). |
| Entity | 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 | 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 | 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 | 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). |
| External links |
| Bibliography |
| Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer. |
| Alves F, Vogel W, Mossie K, Millauer B, Hofler H, Ullrich A. |
| Oncogene. 1995 Feb 2;10(3):609-18. |
| PMID 7845687 |
| Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours. |
| Barker KT, Martindale JE, Mitchell PJ, Kamalati T, Page MJ, Phippard DJ, Dale TC, Gusterson BA, Crompton MR. |
| Oncogene. 1995 Feb 2;10(3):569-75. |
| PMID 7845682 |
| Identification of two isoforms of the Cak receptor kinase that are coexpressed in breast tumor cell lines. |
| Perez JL, Jing SQ, Wong TW. |
| Oncogene. 1996 Apr 4;12(7):1469-77. |
| PMID 8622863 |
| Receptor protein tyrosine kinase DDR is up-regulated by p53 protein. |
| Sakuma S, Saya H, Tada M, Nakao M, Fujiwara T, Roth JA, Sawamura Y, Shinohe Y, Abe H. |
| FEBS Lett. 1996 Dec 2;398(2-3):165-9. |
| PMID 8977099 |
| Pediatric brain tumors express multiple receptor tyrosine kinases including novel cell adhesion kinases. |
| Weiner HL, Rothman M, Miller DC, Ziff EB. |
| Pediatr Neurosurg. 1996 Aug;25(2):64-71; discussion 71-2. |
| PMID 9075249 |
| Overexpression of protein tyrosine kinases in human esophageal cancer. |
| Nemoto T, Ohashi K, Akashi T, Johnson JD, Hirokawa K. |
| Pathobiology. 1997;65(4):195-203. |
| PMID 9396043 |
| Consistent and selective expression of the discoidin domain receptor-1 tyrosine kinase in human brain tumors. |
| Weiner HL, Huang H, Zagzag D, Boyce H, Lichtenbaum R, Ziff EB. |
| Neurosurgery. 2000 Dec;47(6):1400-9. |
| PMID 11126911 |
| Identification of two novel, kinase-deficient variants of discoidin domain receptor 1: differential expression in human colon cancer cell lines. |
| Alves F, Saupe S, Ledwon M, Schaub F, Hiddemann W, Vogel WF. |
| FASEB J. 2001 May;15(7):1321-3. |
| PMID 11344127 |
| Discoidin domain receptor 1 controls growth and adhesion of mesangial cells. |
| Curat CA, Vogel WF. |
| J Am Soc Nephrol. 2002 Nov;13(11):2648-56. |
| PMID 12397034 |
| Role of discoidin domain receptors 1 and 2 in human smooth muscle cell-mediated collagen remodeling: potential implications in atherosclerosis and lymphangioleiomyomatosis. |
| Ferri N, Carragher NO, Raines EW. |
| Am J Pathol. 2004 May;164(5):1575-85. |
| PMID 15111304 |
| Overexpression of the cell adhesion molecules DDR1, Claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer. |
| Heinzelmann-Schwarz VA, Gardiner-Garden M, Henshall SM, Scurry J, Scolyer RA, Davies MJ, Heinzelmann M, Kalish LH, Bali A, Kench JG, Edwards LS, Vanden Bergh PM, Hacker NF, Sutherland RL, O'Brien PM. |
| Clin Cancer Res. 2004 Jul 1;10(13):4427-36. |
| PMID 15240533 |
| Somatic mutations of the protein kinase gene family in human lung cancer. |
| Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G, Teague J, Butler A, Edkins S, Stevens C, Parker A, O'Meara S, Avis T, Barthorpe S, Brackenbury L, Buck G, Clements J, Cole J, Dicks E, Edwards K, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Shepherd R, Small A, Solomon H, Stephens Y, Tofts C, Varian J, Webb A, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Green A, Knowles M, Leung SY, Looijenga LH, Malkowicz B, Pierotti MA, Teh BT, Yuen ST, Lakhani SR, Easton DF, Weber BL, Goldstraw P, Nicholson AG, Wooster R, Stratton MR, Futreal PA. |
| Cancer Res. 2005 Sep 1;65(17):7591-5. |
| PMID 16140923 |
| Expression analysis of genes involved in brain tumor progression driven by retroviral insertional mutagenesis in mice. |
| Johansson FK, Goransson H, Westermark B. |
| Oncogene. 2005 Jun 2;24(24):3896-905. |
| PMID 15750623 |
| Discoidin domain receptor-1a (DDR1a) promotes glioma cell invasion and adhesion in association with matrix metalloproteinase-2. |
| Ram R, Lorente G, Nikolich K, Urfer R, Foehr E, Nagavarapu U. |
| J Neurooncol. 2006 Feb;76(3):239-48. |
| PMID 16234985 |
| Identification of expressed genes characterizing long-term survival in malignant glioma patients. |
| Yamanaka R, Arao T, Yajima N, Tsuchiya N, Homma J, Tanaka R, Sano M, Oide A, Sekijima M, Nishio K. |
| Oncogene. 2006 Sep 28;25(44):5994-6002. Epub 2006 May 1. |
| PMID 16652150 |
| Identification of new DNA markers of endometrial cancer in patients from the Ukrainian population. |
| Domenyuk VP, Litovkin KV, Verbitskaya TG, Dubinina VG, Bubnov VV. |
| Exp Oncol. 2007 Jun;29(2):152-5. |
| PMID 17704737 |
| Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma. |
| Ford CE, Lau SK, Zhu CQ, Andersson T, Tsao MS, Vogel WF. |
| Br J Cancer. 2007 Mar 12;96(5):808-14. Epub 2007 Feb 13. |
| PMID 17299390 |
| Overexpression of discoidin domain receptor 1 increases the migration and invasion of hepatocellular carcinoma cells in association with matrix metalloproteinase. |
| Park HS, Kim KR, Lee HJ, Choi HN, Kim DK, Kim BT, Moon WS. |
| Oncol Rep. 2007 Dec;18(6):1435-41. |
| PMID 17982627 |
| Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. |
| Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ. |
| Cell. 2007 Dec 14;131(6):1190-203. |
| PMID 18083107 |
| Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. |
| Turashvili G, Bouchal J, Baumforth K, Wei W, Dziechciarkova M, Ehrmann J, Klein J, Fridman E, Skarda J, Srovnal J, Hajduch M, Murray P, Kolar Z. |
| BMC Cancer. 2007a Mar 27;7:55. |
| PMID 17389037 |
| Novel immunohistochemical markers for the differentiation of lobular and ductal invasive breast carcinomas. |
| Turashvili G, Bouchal J, Ehrmann J, Fridman E, Skarda J, Kolar Z. |
| Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2007b Jun;151(1):59-64. |
| PMID 17690741 |
| Enhancement of pituitary adenoma cell invasion and adhesion is mediated by discoidin domain receptor-1. |
| Yoshida D, Teramoto A. |
| J Neurooncol. 2007 Mar;82(1):29-40. Epub 2006 Sep 26. |
| PMID 17001518 |
| Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. |
| Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T, Ries RE, Lubman O, Fremont DH, McLellan MD, Payton JE, Westervelt P, DiPersio JF, Link DC, Walter MJ, Graubert TA, Watson M, Baty J, Heath S, Shannon WD, Nagarajan R, Bloomfield CD, Mardis ER, Wilson RK, Ley TJ. |
| Blood. 2008 May 1;111(9):4797-808. Epub 2008 Feb 12. |
| PMID 18270328 |
| Pathway analysis of primary central nervous system lymphoma. |
| Tun HW, Personett D, Baskerville KA, Menke DM, Jaeckle KA, Kreinest P, Edenfield B, Zubair AC, O'Neill BP, Lai WR, Park PJ, McKinney M. |
| Blood. 2008 Mar 15;111(6):3200-10. Epub 2008 Jan 9. |
| PMID 18184868 |
| Discoidin domain receptor 1, a tyrosine kinase receptor, is upregulated in an experimental model of remyelination and during oligodendrocyte differentiation in vitro. |
| Franco-Pons N, Tomas J, Roig B, Auladell C, Martorell L, Vilella E. |
| J Mol Neurosci. 2009 May;38(1):2-11. Epub 2008 Oct 4. |
| PMID 18836851 |
| IGF2 over-expression in solitary fibrous tumours is independent of anatomical location and is related to loss of imprinting. |
| Hajdu M, Singer S, Maki RG, Schwartz GK, Keohan ML, Antonescu CR. |
| J Pathol. 2010 Jul;221(3):300-7. |
| PMID 20527023 |
| Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion. |
| Shen Q, Cicinnati VR, Zhang X, Iacob S, Weber F, Sotiropoulos GC, Radtke A, Lu M, Paul A, Gerken G, Beckebaum S. |
| Mol Cancer. 2010 Aug 27;9:227. |
| PMID 20799954 |
| Molecular markers of endometrial carcinoma detected in uterine aspirates. |
| Colas E, Perez C, Cabrera S, Pedrola N, Monge M, Castellvi J, Eyzaguirre F, Gregorio J, Ruiz A, Llaurado M, Rigau M, Garcia M, Ertekin T, Montes M, Lopez-Lopez R, Carreras R, Xercavins J, Ortega A, Maes T, Rosell E, Doll A, Abal M, Reventos J, Gil-Moreno A. |
| Int J Cancer. 2011 Jan 4. [Epub ahead of print] |
| PMID 21207424 |
| Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. |
| Gu TL, Deng X, Huang F, Tucker M, Crosby K, Rimkunas V, Wang Y, Deng G, Zhu L, Tan Z, Hu Y, Wu C, Nardone J, MacNeill J, Ren J, Reeves C, Innocenti G, Norris B, Yuan J, Yu J, Haack H, Shen B, Peng C, Li H, Zhou X, Liu X, Rush J, Comb MJ. |
| PLoS One. 2011 Jan 6;6(1):e15640. |
| PMID 21253578 |
| Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. |
| Hidalgo-Carcedo C, Hooper S, Chaudhry SI, Williamson P, Harrington K, Leitinger B, Sahai E. |
| Nat Cell Biol. 2011 Jan;13(1):49-58. Epub 2010 Dec 19. |
| PMID 21170030 |
| DDR1 receptor tyrosine kinase promotes prosurvival pathway through Notch1 activation. |
| Kim HG, Hwang SY, Aaronson SA, Mandinova A, Lee SW. |
| J Biol Chem. 2011 May 20;286(20):17672-81. Epub 2011 Mar 13. |
| PMID 21398698 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 05-2011 | Barbara Roig, Elisabet Vilella |
| Hospital Psiquiatic Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, C/Sant Llorenc 21, 43201 REUS, Spain |
| Citation |
| This paper should be referenced as such : |
| Roig B, Vilella E . DDR1 (discoidin domain receptor tyrosine kinase 1). Atlas Genet Cytogenet Oncol Haematol. May 2011 . URL : http://AtlasGeneticsOncology.org/Genes/DDR1ID40280ch6p21.html |
This paper is referenced by INIST as such : |
| http://documents.irevues.inist.fr/bitstream/handle/2042/46052/05-2011-DDR1ID40280ch6p21.pdf [ Bibliographic record ] |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed May 1 13:00:42 CEST 2013 |
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