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Gene Review

DDR1  -  discoidin domain receptor tyrosine kinase 1

Homo sapiens

Synonyms: CAK, CD167, CD167 antigen-like family member A, Cell adhesion kinase, DDR, ...
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Disease relevance of DDR1


Psychiatry related information on DDR1

  • All 27 patients participated in a Dual Diagnosis Relapse Prevention (DDRP) program, which integrates traditional substance-abuse relapse prevention and psychiatric social skills training [7].

High impact information on DDR1

  • Similar results are obtained with CD10+ human polymorphonuclear leukocytes, indicating that CD10/NEP related structures regulate enkephalin-mediated inflammatory responses in organisms whose ancestors diverged approximately 500 million years ago [8].
  • We report here that a structure related to CD10/NEP is expressed by M. edulis haemocytes and that abrogation of CD10/NEP enzymatic activity reduces the amount of Met-enkephalin required for haemocyte activation by five orders of magnitude [8].
  • CD10/NEP hydrolyses several naturally occurring peptides, including the endogenous opioid pentapeptides Met- and Leu-enkephalin [8].
  • Two mammalian receptor tyrosine kinases (DDR1 and DDR2) have extracellular domains closely related to a D. discoideum lectin, discoidin, required for cell aggregation [9].
  • Collagen activation of DDR1 induces phosphorylation of a docking site for the Shc phosphotyrosine binding domain, whose presence is controlled by alternative splicing [9].

Chemical compound and disease context of DDR1


Biological context of DDR1

  • Mutation of this site (Y-->F) eliminated PLCgamma activation (indicating there are no other cryptic binding sites for PLCgamma in the DDR1 sequences) and markedly reduced the differentiative activity of the receptor [15].
  • Furthermore, we created a three-dimensional model of the DDR1 discoidin domain based on the related domains of blood coagulation factors V and VIII [16].
  • Activation of DDR1b on differentiated DDR1b-overexpressing THP-1 cells or DDR1 on mature DCs induced the formation of TNFR associated factor 6 (TRAF6)/TGF-beta-activated kinase 1 binding protein 1beta/p38alpha MAPK complex and p38alpha autophosphorylation [17].
  • CONCLUSIONS: These results suggest that up-regulation of DDR1, CLDN3, and epithelial cell adhesion molecule are early events in the development of EOC and have potential application in the early detection of disease [1].
  • Our studies suggest that DDR1 plays an important role in regulating attachment to collagen, chemotaxis, proliferation, and MMP production in smooth muscle cells [18].

Anatomical context of DDR1

  • A chimeric receptor, containing the extracellular domain of hPDGFRbeta fused to the transmembrane and intracellular regions of DDR1, also fails to mediate neuronal-like differentiation in stably transfected PC12 cells and is only weakly autophosphorylated [15].
  • Finally, we show that overexpression of dominant negative DDR1 in the myoblast cell line C2C12 blocks cellular differentiation and the formation of myofibers [19].
  • Discoidin domain receptor 1 (DDR1) is a nonintegrin collagen receptor constitutively expressed in a variety of epithelial cells, including tumor cells, and is inducible in leukocytes [17].
  • We previously reported that discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor, is expressed during differentiation of human monocytes into macrophages, and the interaction of the DDR1b isoform with collagen facilitates their differentiation via the p38 mitogen-activated protein kinase (MAPK) pathway [20].
  • Taken together, these data provide evidence for the potential roles of DDR1 and DDR2 in the regulation of collagen turnover mediated by SMCs in obstructive diseases of blood vessels and the lung [21].

Associations of DDR1 with chemical compounds

  • Here, we provide three lines of evidence suggesting that DDR1 signaling is distinct from integrin activation [19].
  • We expressed glutathione S-transferase fusion proteins containing the discoidin and extracellular domains of DDR1 and DDR2 in insect cells and subjected them to a solid-phase collagen-binding assay [16].
  • The characteristic of the DDR1 sheddase to be blocked by batimastat suggests that it belongs to the membrane-bound matrix metalloproteinase or disintegrin and metalloproteinase family of proteases [22].
  • The expression level of DDR1 in PBMC was increased further by stimulation with tumor necrosis factor-alpha, interleukin-1beta, granulocyte-macrophage colony-stimulating factor, lipopolysaccharide, or phytohemagglutinin, but not with interferon-gamma [23].
  • Furthermore, siRNA against DDR1 significantly inhibited bleomycin-induced P38 MAPK activation in the lungs [11].
  • The identification of DDR1 dimers provides new insights into the molecular structure of receptor tyrosine kinases and suggests distinct signaling mechanisms of each receptor subfamily [24].

Physical interactions of DDR1

  • Inhibition of Raf signalling results in nuclear retention of viral ribonucleoprotein complexes (RNPs), impaired function of the nuclear-export protein (NEP/NS2) and concomitant inhibition of virus production [25].

Enzymatic interactions of DDR1

  • In addition, a chimeric TrkA-DDR1 receptor failed to become phosphorylated on stimulation with nerve growth factor (NGF), although it dimerized normally [26].

Regulatory relationships of DDR1

  • Analysis of the signaling responses of the two chimeras with DDR1 JM sequences (with and without the insert) indicated that the shorter sequence bound and activated FRS2 whereas the insert-containing form activated Shc instead [15].
  • DDR1 activation also induced NF-kappaB nuclear translocation in CD14-positive BALF cells of patients with deteriorated PS [27].
  • In IPF patients, DDR1 activation in fibroblasts inhibited Fas ligand-induced apoptosis and resulted in NF-kappaB nuclear translocation [5].
  • Wnt-5a and G-protein signaling are required for collagen-induced DDR1 receptor activation and normal mammary cell adhesion [28].

Other interactions of DDR1

  • In cells that endogenously express both DDR1 and the EGF receptor, stimulation with EGF does not induce DDR activation [19].
  • Nonetheless, inhibition of DDR1 function resulted in strikingly increased apoptosis of wild-type p53-containing cells in response to genotoxic stress through a caspase-dependent pathway [29].
  • The DDR1 expression level in CD14-positive BALF cells was higher in IPF patients than in chronic obstructive pulmonary disease patients or healthy volunteers [3].
  • These chemokines and MMP-9 contribute to the development of IPF and, therefore, we suggest that DDR1 might be associated with the pathogenesis of IPF in the tissue microenvironment [3].
  • A region in the extracellular domain of DDR1 homologous to the Dictyostelium discoideum protein discoidin-I is also present in the secreted human protein RS1 [4].

Analytical, diagnostic and therapeutic context of DDR1


  1. Overexpression of the cell adhesion molecules DDR1, Claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer. Heinzelmann-Schwarz, V.A., Gardiner-Garden, M., Henshall, S.M., Scurry, J., Scolyer, R.A., Davies, M.J., Heinzelmann, M., Kalish, L.H., Bali, A., Kench, J.G., Edwards, L.S., Vanden Bergh, P.M., Hacker, N.F., Sutherland, R.L., O'Brien, P.M. Clin. Cancer Res. (2004) [Pubmed]
  2. An extracellular matrix-specific microarray allowed the identification of target genes downstream of discoidin domain receptors. Faraci, E., Eck, M., Gerstmayer, B., Bosio, A., Vogel, W.F. Matrix Biol. (2003) [Pubmed]
  3. Activation of discoidin domain receptor 1 on CD14-positive bronchoalveolar lavage fluid cells induces chemokine production in idiopathic pulmonary fibrosis. Matsuyama, W., Watanabe, M., Shirahama, Y., Oonakahara, K., Higashimoto, I., Yoshimura, T., Osame, M., Arimura, K. J. Immunol. (2005) [Pubmed]
  4. Mapping of epitopes in discoidin domain receptor 1 critical for collagen binding. Curat, C.A., Eck, M., Dervillez, X., Vogel, W.F. J. Biol. Chem. (2001) [Pubmed]
  5. Discoidin domain receptor 1 contributes to the survival of lung fibroblast in idiopathic pulmonary fibrosis. Matsuyama, W., Watanabe, M., Shirahama, Y., Mitsuyama, H., Higashimoto, I., Osame, M., Arimura, K. Am. J. Pathol. (2006) [Pubmed]
  6. Inhibition of Collagen Receptor Discoidin Domain Receptor-1 (DDR1) Reduces Cell Survival, Homing, and Colonization in Lung Cancer Bone Metastasis. Valencia, K., Ormazábal, C., Zandueta, C., Luis-Ravelo, D., Antón, I., Pajares, M.J., Agorreta, J., Montuenga, L.M., Martínez-Canarias, S., Leitinger, B., Lecanda, F. Clin. Cancer Res. (2012) [Pubmed]
  7. Adjunctive desipramine in the treatment of cocaine abusing schizophrenics. Ziedonis, D., Richardson, T., Lee, E., Petrakis, I., Kosten, T. Psychopharmacology bulletin. (1992) [Pubmed]
  8. Downregulation of enkephalin-mediated inflammatory responses by CD10/neutral endopeptidase 24.11. Shipp, M.A., Stefano, G.B., D'Adamio, L., Switzer, S.N., Howard, F.D., Sinisterra, J., Scharrer, B., Reinherz, E.L. Nature (1990) [Pubmed]
  9. The discoidin domain receptor tyrosine kinases are activated by collagen. Vogel, W., Gish, G.D., Alves, F., Pawson, T. Mol. Cell (1997) [Pubmed]
  10. Consistent and selective expression of the discoidin domain receptor-1 tyrosine kinase in human brain tumors. Weiner, H.L., Huang, H., Zagzag, D., Boyce, H., Lichtenbaum, R., Ziff, E.B. Neurosurgery (2000) [Pubmed]
  11. Suppression of discoidin domain receptor 1 by RNA interference attenuates lung inflammation. Matsuyama, W., Watanabe, M., Shirahama, Y., Hirano, R., Mitsuyama, H., Higashimoto, I., Osame, M., Arimura, K. J. Immunol. (2006) [Pubmed]
  12. Phosphorylation of DARPP-32 regulates breast cancer cell migration downstream of the receptor tyrosine kinase DDR1. Hansen, C., Greengard, P., Nairn, A.C., Andersson, T., Vogel, W.F. Exp. Cell Res. (2006) [Pubmed]
  13. CD10/neutral endopeptidase inhibition augments pulmonary neuroendocrine cell hyperplasia in hamsters treated with diethylnitrosamine and hyperoxia. Willett, C.G., Shahsafei, A., Graham, S.A., Sunday, M.E. Am. J. Respir. Cell Mol. Biol. (1999) [Pubmed]
  14. Neutral endopeptidase inhibits prostate cancer cell migration by blocking focal adhesion kinase signaling. Sumitomo, M., Shen, R., Walburg, M., Dai, J., Geng, Y., Navarro, D., Boileau, G., Papandreou, C.N., Giancotti, F.G., Knudsen, B., Nanus, D.M. J. Clin. Invest. (2000) [Pubmed]
  15. Discoidin domain receptor 1 (DDR1) signaling in PC12 cells: activation of juxtamembrane domains in PDGFR/DDR/TrkA chimeric receptors. Foehr, E.D., Tatavos, A., Tanabe, E., Raffioni, S., Goetz, S., Dimarco, E., De Luca, M., Bradshaw, R.A. FASEB J. (2000) [Pubmed]
  16. Exploring the collagen-binding site of the DDR1 tyrosine kinase receptor. Abdulhussein, R., McFadden, C., Fuentes-Prior, P., Vogel, W.F. J. Biol. Chem. (2004) [Pubmed]
  17. Activation of discoidin domain receptor 1 facilitates the maturation of human monocyte-derived dendritic cells through the TNF receptor associated factor 6/TGF-beta-activated protein kinase 1 binding protein 1 beta/p38 alpha mitogen-activated protein kinase signaling cascade. Matsuyama, W., Faure, M., Yoshimura, T. J. Immunol. (2003) [Pubmed]
  18. The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair. Hou, G., Vogel, W., Bendeck, M.P. J. Clin. Invest. (2001) [Pubmed]
  19. Discoidin domain receptor 1 is activated independently of beta(1) integrin. Vogel, W., Brakebusch, C., Fässler, R., Alves, F., Ruggiero, F., Pawson, T. J. Biol. Chem. (2000) [Pubmed]
  20. Activation of discoidin domain receptor 1 isoform b with collagen up-regulates chemokine production in human macrophages: role of p38 mitogen-activated protein kinase and NF-kappa B. Matsuyama, W., Wang, L., Farrar, W.L., Faure, M., Yoshimura, T. J. Immunol. (2004) [Pubmed]
  21. 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, N.O., Raines, E.W. Am. J. Pathol. (2004) [Pubmed]
  22. Ligand-induced shedding of discoidin domain receptor 1. Vogel, W.F. FEBS Lett. (2002) [Pubmed]
  23. Discoidin domain receptor 1 isoform-a (DDR1alpha) promotes migration of leukocytes in three-dimensional collagen lattices. Kamohara, H., Yamashiro, S., Galligan, C., Yoshimura, T. FASEB J. (2001) [Pubmed]
  24. Identification of disulfide-linked dimers of the receptor tyrosine kinase DDR1. Abdulhussein, R., Koo, D.H., Vogel, W.F. J. Biol. Chem. (2008) [Pubmed]
  25. Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. Pleschka, S., Wolff, T., Ehrhardt, C., Hobom, G., Planz, O., Rapp, U.R., Ludwig, S. Nat. Cell Biol. (2001) [Pubmed]
  26. Functional analysis of discoidin domain receptor 1: effect of adhesion on DDR1 phosphorylation. L'hôte, C.G., Thomas, P.H., Ganesan, T.S. FASEB J. (2002) [Pubmed]
  27. Involvement of discoidin domain receptor 1 in the deterioration of pulmonary sarcoidosis. Matsuyama, W., Mitsuyama, H., Watanabe, M., Shirahama, Y., Higashimoto, I., Osame, M., Arimura, K. Am. J. Respir. Cell Mol. Biol. (2005) [Pubmed]
  28. Wnt-5a and G-protein signaling are required for collagen-induced DDR1 receptor activation and normal mammary cell adhesion. Dejmek, J., Dib, K., Jönsson, M., Andersson, T. Int. J. Cancer (2003) [Pubmed]
  29. p53 induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop. Ongusaha, P.P., Kim, J.I., Fang, L., Wong, T.W., Yancopoulos, G.D., Aaronson, S.A., Lee, S.W. EMBO J. (2003) [Pubmed]
  30. Discoidin domain receptor (DDR) 1 and 2: collagen-activated tyrosine kinase receptors in the cornea. Mohan, R.R., Mohan, R.R., Wilson, S.E. Exp. Eye Res. (2001) [Pubmed]
  31. Linkage and association studies of discoidin domain receptor 1 (DDR1) single nucleotide polymorphisms (SNPs) in juvenile oligoarthritis. Zeggini, E., Reginato, A.M., Prais, A., Thomson, W., McLean, W., Donn, R. Rheumatology (Oxford, England) (2004) [Pubmed]
  32. Cellular signaling by tyrosine phosphorylation in keloid and normal human dermal fibroblasts. Chin, G.S., Liu, W., Steinbrech, D., Hsu, M., Levinson, H., Longaker, M.T. Plast. Reconstr. Surg. (2000) [Pubmed]
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