Skip to main content

Advertisement

SpringerLink
Log in

Discoidin domain receptors: a proteomic portrait

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The discoidin domain receptors (DDRs) are collagen-binding receptor tyrosine kinases that have been implicated in a number of fundamental biological processes ranging from growth and development to immunoregulation. In this review, we examine how recent proteomic technologies have enriched our understanding of DDR signaling mechanisms. We provide an overview on the use of large-scale proteomic profiling and chemical proteomics to reveal novel insights into DDR therapeutics, signaling networks, and receptor crosstalk. A perspective of how proteomics may be harnessed to answer outstanding fundamental questions including the dynamic regulation of receptor activation kinetics is presented. Collectively, these studies present an emerging molecular portrait of these unique receptors and their functional role in health and disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Fu HL et al (2013) Discoidin domain receptors: unique receptor tyrosine kinases in collagen-mediated signaling. J Biol Chem 288(11):7430–7437

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Leitinger B (2011) Transmembrane collagen receptors. Annu Rev Cell Dev Biol 27:265–290

    Article  CAS  PubMed  Google Scholar 

  3. Valiathan RR et al (2012) Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastasis Rev 31(1–2):295–321

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Vogel WF, Abdulhussein R, Ford CE (2006) Sensing extracellular matrix: an update on discoidin domain receptor function. Cell Signal 18(8):1108–1116

    Article  CAS  PubMed  Google Scholar 

  5. Maeyama M et al (2008) Switching in discoid domain receptor expressions in SLUG-induced epithelial–mesenchymal transition. Cancer 113(10):2823–2831

    Article  CAS  PubMed  Google Scholar 

  6. Walsh LA, Nawshad A, Medici D (2011) Discoidin domain receptor 2 is a critical regulator of epithelial–mesenchymal transition. Matrix Biol 30(4):243–247

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Carafoli F, Hohenester E (2013) Collagen recognition and transmembrane signalling by discoidin domain receptors. Biochim Biophys Acta 1834(10):2187–2194

    Article  CAS  PubMed  Google Scholar 

  8. Leitinger B, Hohenester E (2007) Mammalian collagen receptors. Matrix Biol 26(3):146–155

    Article  CAS  PubMed  Google Scholar 

  9. Leitinger B, Kwan AP (2006) The discoidin domain receptor DDR2 is a receptor for type X collagen. Matrix Biol 25(6):355–364

    Article  CAS  PubMed  Google Scholar 

  10. Shrivastava A et al (1997) An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol Cell 1(1):25–34

    Article  CAS  PubMed  Google Scholar 

  11. Vogel W et al (1997) The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1(1):13–23

    Article  CAS  PubMed  Google Scholar 

  12. Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411(6835):355–365

    Article  CAS  PubMed  Google Scholar 

  13. Cohen P, Alessi DR (2013) Kinase drug discovery—what’s next in the field? ACS Chem Biol 8(1):96–104

    Article  CAS  PubMed  Google Scholar 

  14. Lynch TJ et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350(21):2129–2139

    Article  CAS  PubMed  Google Scholar 

  15. Gerber DE, Minna JD (2010) ALK inhibition for non-small cell lung cancer: from discovery to therapy in record time. Cancer Cell 18(6):548–551

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Druker BJ et al (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344(14):1031–1037

    Article  CAS  PubMed  Google Scholar 

  17. Weiner HL et al (2000) Consistent and selective expression of the discoidin domain receptor-1 tyrosine kinase in human brain tumors. Neurosurgery 47(6):1400–1409

    Article  CAS  PubMed  Google Scholar 

  18. Yamanaka R et al (2006) Identification of expressed genes characterizing long-term survival in malignant glioma patients. Oncogene 25(44):5994–6002

    Article  CAS  PubMed  Google Scholar 

  19. Hammerman PS et al (2011) Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov 1(1):78–89

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Ren T et al (2013) Increased expression of discoidin domain receptor 2 (DDR2): a novel independent prognostic marker of worse outcome in breast cancer patients. Med Oncol 30(1):397

    Article  PubMed  Google Scholar 

  21. Ford CE et al (2007) Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma. Br J Cancer 96(5):808–814

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Van Schaeybroeck S et al (2005) Epidermal growth factor receptor activity determines response of colorectal cancer cells to gefitinib alone and in combination with chemotherapy. Clin Cancer Res 11(20):7480–7489

    Article  PubMed  Google Scholar 

  23. Thomson S et al (2005) Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res 65(20):9455–9462

    Article  CAS  PubMed  Google Scholar 

  24. Rikova K et al (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131(6):1190–1203

    Article  CAS  PubMed  Google Scholar 

  25. Amann J et al (2005) Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Res 65(1):226–235

    CAS  PubMed  Google Scholar 

  26. Garofalo M et al (2012) EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat Med 18(1):74–82

    CAS  Google Scholar 

  27. Ishikawa M et al (2012) Higher expression of EphA2 and ephrin-A1 is related to favorable clinicopathological features in pathological stage I non-small cell lung carcinoma. Lung Cancer 76(3):431–438

    Article  PubMed  Google Scholar 

  28. van Kempen LC et al (2003) The tumor microenvironment: a critical determinant of neoplastic evolution. Eur J Cell Biol 82(11):539–548

    Article  PubMed  Google Scholar 

  29. Gu TL et al (2011) Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS One 6(1):e15640

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Bai Y et al (2012) Phosphoproteomics identifies driver tyrosine kinases in sarcoma cell lines and tumors. Cancer Res 72(10):2501–2511

    Article  CAS  PubMed  Google Scholar 

  31. Alitalo K et al (1982) Biosynthesis of type V procollagen by A204, a human rhabdomyosarcoma cell line. J Biol Chem 257(15):9016–9024

    CAS  PubMed  Google Scholar 

  32. Kleman JP et al (1992) The human rhabdomyosarcoma cell line A204 lays down a highly insoluble matrix composed mainly of alpha 1 type-XI and alpha 2 type-V collagen chains. Eur J Biochem 210(1):329–335

    Article  CAS  PubMed  Google Scholar 

  33. Xu AM, Huang PH (2010) Receptor tyrosine kinase coactivation networks in cancer. Cancer Res 70(10):3857–3860

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Huang PH (2012) Phosphoproteomic studies of receptor tyrosine kinases: future perspectives. Mol BioSyst 8(4):1100–1107

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Johnson H et al (2012) Molecular characterization of EGFR and EGFRvIII signaling networks in human glioblastoma tumor xenografts. Mol Cell Proteomics 11(12):1724–1740

    Article  PubMed Central  PubMed  Google Scholar 

  36. Iwai LK, Chang F, Huang PH (2013) Phosphoproteomic analysis identifies insulin enhancement of discoidin domain receptor 2 phosphorylation. Cell Adh Migr 7(2):161–164

    Article  PubMed Central  PubMed  Google Scholar 

  37. Meyer AS et al (2013) The Receptor AXL diversifies EGFR signaling and limits the response to EGFR-targeted inhibitors in triple-negative breast cancer cells. Sci Signal 6(287):ra66

    Article  PubMed Central  PubMed  Google Scholar 

  38. Vajpai N et al (2008) Solution conformations and dynamics of ABL kinase-inhibitor complexes determined by NMR substantiate the different binding modes of imatinib/nilotinib and dasatinib. J Biol Chem 283(26):18292–18302

    Article  CAS  PubMed  Google Scholar 

  39. Bantscheff M et al (2007) Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotech 25(9):1035–1044

    Article  CAS  Google Scholar 

  40. Weisberg E et al (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7(2):129–141

    Article  CAS  PubMed  Google Scholar 

  41. Rix U et al (2007) Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood 110(12):4055–4063

    Article  CAS  PubMed  Google Scholar 

  42. Joensuu H et al (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344(14):1052–1056

    Article  CAS  PubMed  Google Scholar 

  43. Demetri GD et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347(7):472–480

    Article  CAS  PubMed  Google Scholar 

  44. Heinrich MC et al (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21(23):4342–4349

    Article  CAS  PubMed  Google Scholar 

  45. Day E et al (2008) Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib. Eur J Pharmacol 599(1–3):44–53

    Article  CAS  PubMed  Google Scholar 

  46. Taipale M, Jarosz DF, Lindquist S (2010) HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 11(7):515–528

    Article  CAS  PubMed  Google Scholar 

  47. Sharma K et al (2012) Quantitative proteomics reveals that Hsp90 inhibition preferentially targets kinases and the DNA damage response. Mol Cell Proteomics 11(3):M111.014654. doi:10.1074/mcp.M111.014654

    Article  PubMed Central  PubMed  Google Scholar 

  48. Wu Z, Moghaddas Gholami A, Kuster B (2012) Systematic identification of the HSP90 candidate regulated proteome. Mol Cell Proteomics 11(6):M111.016675. doi:10.1074/mcp.M111.016675

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Haupt A et al (2012) Hsp90 inhibition differentially destabilises MAP kinase and TGF-beta signalling components in cancer cells revealed by kinase-targeted chemoproteomics. BMC Cancer 12:38

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Li J et al (2010) A chemical and phosphoproteomic characterization of dasatinib action in lung cancer. Nat Chem Biol 6(4):291–299

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Gorre ME et al (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293(5531):876–880

    Article  CAS  PubMed  Google Scholar 

  52. Pao W et al (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2(3):e73

    Article  PubMed Central  PubMed  Google Scholar 

  53. Beauchamp EM et al (2013) Acquired resistance to dasatinib in lung cancer cell lines conferred by DDR2 gatekeeper mutation and NF1 loss. Mol Cancer Ther 13(2):475–482

    Article  PubMed  Google Scholar 

  54. Polier S et al (2013) ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system. Nat Chem Biol 9(5):307–312

    CAS  PubMed  Google Scholar 

  55. Siddiqui K et al (2009) Actinomycin D identified as an inhibitor of discoidin domain receptor 2 interaction with collagen through an insect cell-based screening of a drug compound library. Biol Pharm Bull 32(1):136–141

    CAS  PubMed  Google Scholar 

  56. Hu Y et al (2013) Discoipyrroles A-D: isolation, structure determination, and synthesis of potent migration inhibitors from Bacillus hunanensis. J Am Chem Soc 135(36):13387–13392

    Article  CAS  PubMed  Google Scholar 

  57. Potts MB et al (2013) Using functional signature ontology (FUSION) to identify mechanisms of action for natural products. Sci Signal 6(297):ra90

    Article  PubMed Central  PubMed  Google Scholar 

  58. Gao M et al (2013) Discovery and optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamides as novel selective and orally bioavailable discoidin domain receptor 1 (DDR1) inhibitors. J Med Chem 56(8):3281–3295

    Article  CAS  PubMed  Google Scholar 

  59. Kim HG et al (2013) Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor. ACS Chem Biol 8(10):2145–2150

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Duncan JS et al (2012) Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell 149(2):307–321

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Dang CV (2012) MYC on the path to cancer. Cell 149(1):22–35

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. L’Hote CG, Thomas PH, Ganesan TS (2002) Functional analysis of discoidin domain receptor 1: effect of adhesion on DDR1 phosphorylation. FASEB J 16(2):234–236

    PubMed  Google Scholar 

  63. Koo DH et al (2006) Pinpointing phosphotyrosine-dependent interactions downstream of the collagen receptor DDR1. FEBS Lett 580(1):15–22

    Article  CAS  PubMed  Google Scholar 

  64. Wang CZ et al (2006) A discoidin domain receptor 1/SHP-2 signaling complex inhibits alpha2beta1-integrin-mediated signal transducers and activators of transcription 1/3 activation and cell migration. Mol Biol Cell 17(6):2839–2852

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Yang G et al (2009) Proteomic, functional and motif-based analysis of C-terminal Src kinase-interacting proteins. Proteomics 9(21):4944–4961

    Article  CAS  PubMed  Google Scholar 

  66. Lin KL et al (2010) Transcriptional upregulation of DDR2 by ATF4 facilitates osteoblastic differentiation through p38 MAPK-mediated Runx2 activation. J Bone Miner Res 25(11):2489–2503

    Article  CAS  PubMed  Google Scholar 

  67. Zhang Y et al (2011) An essential role of discoidin domain receptor 2 (DDR2) in osteoblast differentiation and chondrocyte maturation via modulation of Runx2 activation. J Bone Miner Res 26(3):604–617

    Article  CAS  PubMed  Google Scholar 

  68. Lemeer S et al (2012) Phosphotyrosine-mediated protein interactions of the discoidin domain receptor 1. J Proteomics 75(12):3465–3477

    Article  CAS  PubMed  Google Scholar 

  69. Faraci-Orf E, McFadden C, Vogel WF (2006) DDR1 signaling is essential to sustain Stat5 function during lactogenesis. J Cell Biochem 97(1):109–121

    Article  CAS  PubMed  Google Scholar 

  70. Kim HG et al (2011) DDR1 receptor tyrosine kinase promotes prosurvival pathway through Notch1 activation. J Biol Chem 286(20):17672–17681

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Dejmek J et al (2005) Expression and signaling activity of Wnt-5a/discoidin domain receptor-1 and Syk plays distinct but decisive roles in breast cancer patient survival. Clin Cancer Res 11(2 Pt 1):520–528

    CAS  PubMed  Google Scholar 

  72. Huang Y et al (2009) The collagen receptor DDR1 regulates cell spreading and motility by associating with myosin IIA. J Cell Sci 122(Pt 10):1637–1646

    Article  CAS  PubMed  Google Scholar 

  73. Shintani Y et al (2008) Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor 1. J Cell Biol 180(6):1277–1289

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Hidalgo-Carcedo C et al (2011) Collective cell migration requires suppression of actomyosin at cell–cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nat Cell Biol 13(1):49–58

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Hansen C et al (2006) Phosphorylation of DARPP-32 regulates breast cancer cell migration downstream of the receptor tyrosine kinase DDR1. Exp Cell Res 312(20):4011–4018

    Article  CAS  PubMed  Google Scholar 

  76. Hilton HN et al (2008) KIBRA interacts with discoidin domain receptor 1 to modulate collagen-induced signalling. Biochim Biophys Acta 1783(3):383–393

    Article  CAS  PubMed  Google Scholar 

  77. Das S et al (2006) Discoidin domain receptor 1 receptor tyrosine kinase induces cyclooxygenase-2 and promotes chemoresistance through nuclear factor-kappaB pathway activation. Cancer Res 66(16):8123–8130

    Article  CAS  PubMed  Google Scholar 

  78. Iwai LK et al (2013) Phosphoproteomics of collagen receptor networks reveals SHP-2 phosphorylation downstream of wild-type DDR2 and its lung cancer mutants. Biochem J 454(3):501–513

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Furdui CM et al (2006) Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction. Mol Cell 21(5):711–717

    Article  CAS  PubMed  Google Scholar 

  80. Yang K et al (2005) Tyrosine 740 phosphorylation of discoidin domain receptor 2 by Src stimulates intramolecular autophosphorylation and Shc signaling complex formation. J Biol Chem 280(47):39058–39066

    Article  CAS  PubMed  Google Scholar 

  81. Ikeda K et al (2002) Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen. J Biol Chem 277(21):19206–19212

    Article  CAS  PubMed  Google Scholar 

  82. Su J et al (2009) Discoidin domain receptor 2 is associated with the increased expression of matrix metalloproteinase-13 in synovial fibroblasts of rheumatoid arthritis. Mol Cell Biochem 330(1–2):141–152

    Article  CAS  PubMed  Google Scholar 

  83. Noordeen NA et al (2006) A transmembrane leucine zipper is required for activation of the dimeric receptor tyrosine kinase DDR1. J Biol Chem 281(32):22744–22751

    Article  CAS  PubMed  Google Scholar 

  84. Mihai C et al (2009) Mapping of DDR1 distribution and oligomerization on the cell surface by FRET microscopy. J Mol Biol 385(2):432–445

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Fu, HL et al (2014) Glycosylation at ASN211 regulates the activation state of the discoidin domain receptor 1 (DDR1). J Biol Chem

  86. Lew ED et al (2009) The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations. Sci Signal 2(58):ra6

    Article  PubMed Central  PubMed  Google Scholar 

  87. Payne LS, Huang PH (2013) The pathobiology of collagens in glioma. Mol Cancer Res 11(10):1129–1140

    Article  CAS  PubMed  Google Scholar 

  88. Fu HL et al (2013) Shedding of discoidin domain receptor 1 by membrane-type matrix metalloproteinases. J Biol Chem 288(17):12114–12129

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Carafoli F et al (2009) Crystallographic insight into collagen recognition by discoidin domain receptor 2. Structure 17(12):1573–1581

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Xu H et al (2012) Discoidin domain receptors promote alpha1beta1- and alpha2beta1-integrin-mediated cell adhesion to collagen by enhancing integrin activation. PLoS One 7(12):e52209

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  91. Zheng Y et al (2013) Temporal regulation of EGF signalling networks by the scaffold protein Shc1. Nature 499(7457):166–171

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The work in the authors’ laboratory is funded by the Wellcome Trust (WT089028) and the Biotechnology and Biological Sciences Research Council (BB/I014276/1).

Author information

Author notes

  1. Leo K. Iwai

    Present address: Laboratório Especial de Toxinologia Aplicada/CeTICS, Instituto Butantan, Av Vital Brasil 1500, São Paulo, 05503-000, Brazil

Authors and Affiliations

  1. Protein Networks Team, Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK

    Leo K. Iwai, Maciej T. Luczynski & Paul H. Huang

Authors
  1. Leo K. Iwai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maciej T. Luczynski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul H. Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul H. Huang.

Additional information

L. K. Iwai and M.T. Luczynski contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Iwai, L.K., Luczynski, M.T. & Huang, P.H. Discoidin domain receptors: a proteomic portrait. Cell. Mol. Life Sci. 71, 3269–3279 (2014). https://doi.org/10.1007/s00018-014-1616-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-014-1616-1

Keywords

Search

Navigation