Skip to main content
SpringerLink
Log in

Discoidin Domain Receptor Signaling and Pharmacological Inhibitors

  • Chapter
  • First Online:
Discoidin Domain Receptors in Health and Disease

Abstract

Discoidin domain receptors (DDRs) DDR1 and DDR2 are receptor tyrosine kinases (RTKs) with the unique ability among RTKs to specifically bind to and be activated by collagen. Mounting evidence suggests that DDR1 and DDR2 play crucial roles in the regulation of cellular responses under both normal and pathological conditions and has stimulated intense interest in the development of novel therapies to specifically target DDR function. Recent discoveries have shown that DDRs recruit a variety of adaptor and signaling molecules upon collagen stimulation, including ShcA, p85α PI3K, the protein tyrosine kinases PYK2 and CSK, the phosphatases SHP-2 and SHIP-1/2, and STAT1, STAT3 and STAT5β. DDR-associated signaling is not only cell- and collagen-type specific, but DDRs have been shown to trigger different signaling pathways depending on whether they are involved in cell–matrix interactions or collagen-independent cell–cell interactions. Collagen-activated DDR1 signals through NF-kB, PI3K/Akt and p38, JNK, and ERK1/2 MAPKs, while inactive DDR1 appears to interact with E-cadherin promoting cell–cell interactions. DDR1 interacts with several other receptors, including Notch1 and Frizzled5, and has been shown to cooperate or antagonize collagen-binding integrin signaling pathways linked to cell survival and migration, respectively. DDR2 has also been shown to signal through mitogen-activated protein kinases (MAPKs) including p38 and the JAK2/ERK signaling pathway and interact with the insulin receptor, thereby promoting cell migration. In recent years considerable advances have been made in the development of potent inhibitors for these unique collagen receptors.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Alves F, Vogel W, Mossie K, Millauer B, Hofler H, Ullrich A (1995) Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer. Oncogene 10(3):609–618

    CAS  PubMed  Google Scholar 

  2. Vogel W (1999) Discoidin domain receptors: structural relations and functional implications. FASEB J 13:S77–S82

    CAS  PubMed  Google Scholar 

  3. Shrivastava A, Radziejewski C, Campbell E, Kovac L, McGlynn M, Ryan TE, Davis S, Goldfarb MP, Glass DJ, Lemke G, Yancopoulos GD (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 

  4. Vogel W, Gish GD, Alves F, Pawson T (1997) The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1(1):13–23

    Article  CAS  PubMed  Google Scholar 

  5. Labrador JP, Azcoitia V, Tuckermann J, Lin C, Olaso E, Manes S, Bruckner K, Goergen JL, Lemke G, Yancopoulos G, Angel P, Martinez C, Klein R (2001) The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism. EMBO Rep 2(5):446–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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 

  7. Leitinger B, Kwan AP (2006) The discoidin domain receptor DDR2 is a receptor for type X collagen. Matrix Biol 25(6):355–364. doi:10.1016/j.matbio.2006.05.006

    Article  CAS  PubMed  Google Scholar 

  8. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134. doi:10.1016/j.cell.2010.06.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Alves F, Saupe S, Ledwon M, Schaub F, Hiddemann W, Vogel WF (2001) Identification of two novel, kinase-deficient variants of discoidin domain receptor 1: differential expression in human colon cancer cell lines. FASEB J 15(7):1321–1323

    CAS  PubMed  Google Scholar 

  10. Leitinger B (2003) Molecular analysis of collagen binding by the human discoidin domain receptors, DDR1 and DDR2. Identification of collagen binding sites in DDR2. J Biol Chem 278(19):16761–16769. doi:10.1074/jbc.M301370200

    Article  CAS  PubMed  Google Scholar 

  11. Farndale RW, Lisman T, Bihan D, Hamaia S, Smerling CS, Pugh N, Konitsiotis A, Leitinger B, de Groot PG, Jarvis GE, Raynal N (2008) Cell-collagen interactions: the use of peptide toolkits to investigate collagen-receptor interactions. Biochem Soc Trans 36(Pt 2):241–250. doi:10.1042/BST0360241

    Article  CAS  PubMed  Google Scholar 

  12. 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 (2011) Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS One 6(1), e15640. doi:10.1371/journal.pone.0015640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ichikawa O, Osawa M, Nishida N, Goshima N, Nomura N, Shimada I (2007) Structural basis of the collagen-binding mode of discoidin domain receptor 2. EMBO J 26(18):4168–4176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Konitsiotis AD, Raynal N, Bihan D, Hohenester E, Farndale RW, Leitinger B (2008) Characterization of high affinity binding motifs for the discoidin domain receptor DDR2 in collagen. J Biol Chem 283(11):6861–6868

    Article  CAS  PubMed  Google Scholar 

  15. Xu H, Raynal N, Stathopoulos S, Myllyharju J, Farndale RW, Leitinger B (2011) Collagen binding specificity of the discoidin domain receptors: binding sites on collagens II and III and molecular determinants for collagen IV recognition by DDR1. Matrix Biol 30(1):16–26. doi:10.1016/j.matbio.2010.10.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Carafoli F, Bihan D, Stathopoulos S, Konitsiotis AD, Kvansakul M, Farndale RW, Leitinger B, Hohenester E (2009) Crystallographic insight into collagen recognition by discoidin domain receptor 2. Structure 17(12):1573–1581. doi:10.1016/j.str.2009.10.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Slack BE, Siniaia MS, Blusztajn JK (2006) Collagen type I selectively activates ectodomain shedding of the discoidin domain receptor 1: involvement of Src tyrosine kinase. J Cell Biochem 98(3):672–684. doi:10.1002/jcb.20812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vogel WF (2002) Ligand-induced shedding of discoidin domain receptor 1. FEBS Lett 514(2–3):175–180

    Article  CAS  PubMed  Google Scholar 

  19. Ikeda K, Wang LH, Torres R, Zhao H, Olaso E, Eng FJ, Labrador P, Klein R, Lovett D, Yancopoulos GD, Friedman SL, Lin HC (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 

  20. Finger C, Escher C, Schneider D (2009) The single transmembrane domains of human receptor tyrosine kinases encode self-interactions. Sci Signal 2(89), ra56. doi:10.1126/scisignal.2000547

    Article  PubMed  Google Scholar 

  21. Noordeen NA, Carafoli F, Hohenester E, Horton MA, Leitinger B (2006) A transmembrane leucine zipper is required for activation of the dimeric receptor tyrosine kinase DDR1. J Biol Chem 281(32):22744–22751. doi:10.1074/jbc.M603233200

    Article  CAS  PubMed  Google Scholar 

  22. Agarwal G, Kovac L, Radziejewski C, Samuelsson SJ (2002) Binding of discoidin domain receptor 2 to collagen I: an atomic force microscopy investigation. Biochemistry 41(37):11091–11098

    Article  CAS  PubMed  Google Scholar 

  23. Agarwal G, Mihai C, Iscru DF (2007) Interaction of discoidin domain receptor 1 with collagen type 1. J Mol Biol 367(2):443–455. doi:10.1016/j.jmb.2006.12.073

    Article  CAS  PubMed  Google Scholar 

  24. Chin GS, Lee S, Hsu M, Liu W, Kim WJ, Levinson H, Longaker MT (2001) Discoidin domain receptors and their ligand, collagen, are temporally regulated in fetal rat fibroblasts in vitro. Plast Reconstr Surg 107(3):769–776

    Article  CAS  PubMed  Google Scholar 

  25. Hou G, Vogel WF, Bendeck MP (2002) Tyrosine kinase activity of discoidin domain receptor 1 is necessary for smooth muscle cell migration and matrix metalloproteinase expression. Circ Res 90(11):1147–1149

    Article  CAS  PubMed  Google Scholar 

  26. Ferri N, Carragher NO, Raines EW (2004) Role of discoidin domain receptors 1 and 2 in human smooth muscle cell-mediated collagen remodeling: potential implications in atherosclerosis and lymphangioleiomyomatosis. Am J Pathol 164(5):1575–1585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li W, Zhang YQ, Liu XP, Yao LB, Sun L (2005) Regular expression of discoidin domain receptor 2 in the improved adjuvant-induced animal model for rheumatoid arthritis. Chin Acad Med Sci 20(2):133–137

    CAS  Google Scholar 

  28. Xu L, Peng H, Wu D, Hu K, Goldring MB, Olsen BR, Li Y (2005) Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice. J Biol Chem 280(1):548–555. doi:10.1074/jbc.M411036200

    Article  CAS  PubMed  Google Scholar 

  29. Kamohara H, Yamashiro S, Galligan C, Yoshimura T (2001) Discoidin domain receptor 1 isoform-a (DDR1alpha) promotes migration of leukocytes in three-dimensional collagen lattices. FASEB J 15(14):2724–2726

    CAS  PubMed  Google Scholar 

  30. Valiathan RR, Marco M, Leitinger B, Kleer CG, Fridman R (2012) Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastasis Rev 31(1–2):295–321. doi:10.1007/s10555-012-9346-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee R, Eidman KE, Kren SM, Hostetter TH, Segal Y (2004) Localization of discoidin domain receptors in rat kidney. Nephron Exp Nephrol 97(2):e62–e70. doi:10.1159/000078407

    Article  CAS  PubMed  Google Scholar 

  32. Olaso E, Ikeda K, Eng FJ, Xu L, Wang LH, Lin HC, Friedman SL (2001) DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J Clin Invest 108(9):1369–1378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Avivi-Green C, Singal M, Vogel WF (2006) Discoidin domain receptor 1-deficient mice are resistant to bleomycin-induced lung fibrosis. Am J Respir Crit Care Med 174(4):420–427

    Article  CAS  PubMed  Google Scholar 

  34. Park HS, Kim KR, Lee HJ, Choi HN, Kim DK, Kim BT, Moon WS (2007) Overexpression of discoidin domain receptor 1 increases the migration and invasion of hepatocellular carcinoma cells in association with matrix metalloproteinase. Oncol Rep 18(6):1435–1441

    CAS  PubMed  Google Scholar 

  35. Shimada K, Nakamura M, Ishida E, Higuchi T, Yamamoto H, Tsujikawa K, Konishi N (2008) Prostate cancer antigen-1 contributes to cell survival and invasion though discoidin receptor 1 in human prostate cancer. Cancer Sci 99(1):39–45. doi:10.1111/j.1349-7006.2007.00655.x

    CAS  PubMed  Google Scholar 

  36. Yoshida D, Teramoto A (2007) Enhancement of pituitary adenoma cell invasion and adhesion is mediated by discoidin domain receptor-1. J Neurooncol 82(1):29–40. doi:10.1007/s11060-006-9246-6

    Article  CAS  PubMed  Google Scholar 

  37. Yang SH, Baek HA, Lee HJ, Park HS, Jang KY, Kang MJ, Lee DG, Lee YC, Moon WS, Chung MJ (2010) Discoidin domain receptor 1 is associated with poor prognosis of non-small cell lung carcinomas. Oncol Rep 24(2):311–319

    CAS  PubMed  Google Scholar 

  38. Nemoto T, Ohashi K, Akashi T, Johnson JD, Hirokawa K (1997) Overexpression of protein tyrosine kinases in human esophageal cancer. Pathobiology 65(4):195–203

    Article  CAS  PubMed  Google Scholar 

  39. Barker KT, Martindale JE, Mitchell PJ, Kamalati T, Page MJ, Phippard DJ, Dale TC, Gusterson BA, Crompton MR (1995) Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours. Oncogene 10(3):569–575

    CAS  PubMed  Google Scholar 

  40. Hidalgo-Carcedo C, Hooper S, Chaudhry SI, Williamson P, Harrington K, Leitinger B, Sahai E (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. doi:10.1038/ncb2133

    Article  CAS  PubMed  Google Scholar 

  41. Laval S, Butler R, Shelling AN, Hanby AM, Poulsom R, Ganesan TS (1994) Isolation and characterization of an epithelial-specific receptor tyrosine kinase from an ovarian cancer cell line. Cell Growth Differ 5(11):1173–1183

    CAS  PubMed  Google Scholar 

  42. Shen Q, Cicinnati VR, Zhang X, Iacob S, Weber F, Sotiropoulos GC, Radtke A, Lu M, Paul A, Gerken G, Beckebaum S (2010) Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion. Mol Cancer 9:227. doi:10.1186/1476-4598-9-227

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Couvelard A, Hu J, Steers G, O'Toole D, Sauvanet A, Belghiti J, Bedossa P, Gatter K, Ruszniewski P, Pezzella F (2006) Identification of potential therapeutic targets by gene-expression profiling in pancreatic endocrine tumors. Gastroenterology 131(5):1597–1610. doi:10.1053/j.gastro.2006.09.007

    Article  CAS  PubMed  Google Scholar 

  44. Ram R, Lorente G, Nikolich K, Urfer R, Foehr E, Nagavarapu U (2006) Discoidin domain receptor-1a (DDR1a) promotes glioma cell invasion and adhesion in association with matrix metalloproteinase-2. J Neurooncol 76(3):239–248

    Article  CAS  PubMed  Google Scholar 

  45. Das S, Ongusaha PP, Yang YS, Park JM, Aaronson SA, Lee SW (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 

  46. Kim HG, Hwang SY, Aaronson SA, Mandinova A, Lee SW (2011) DDR1 receptor tyrosine kinase promotes prosurvival pathway through Notch1 activation. J Biol Chem 286(20):17672–17681. doi:10.1074/jbc.M111.236612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Valencia K, Ormazabal C, Zandueta C, Luis-Ravelo D, Anton I, Pajares MJ, Agorreta J, Montuenga LM, Martinez-Canarias S, Leitinger B, Lecanda F (2012) Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) reduces cell survival, homing, and colonization in lung cancer bone metastasis. Clin Cancer Res 18(4):969–980. doi:10.1158/1078-0432.CCR-11-1686

    Article  CAS  PubMed  Google Scholar 

  48. Drilon A, Rekhtman N, Ladanyi M, Paik P (2012) Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol 13(10):e418–e426. doi:10.1016/S1470-2045(12)70291-7

    Article  CAS  PubMed  Google Scholar 

  49. Hammerman PS, Sos ML, Ramos AH, Xu C, Dutt A, Zhou W, Brace LE, Woods BA, Lin W, Zhang J, Deng X, Lim SM, Heynck S, Peifer M, Simard JR, Lawrence MS, Onofrio RC, Salvesen HB, Seidel D, Zander T, Heuckmann JM, Soltermann A, Moch H, Koker M, Leenders F, Gabler F, Querings S, Ansen S, Brambilla E, Brambilla C, Lorimier P, Brustugun OT, Helland A, Petersen I, Clement JH, Groen H, Timens W, Sietsma H, Stoelben E, Wolf J, Beer DG, Tsao MS, Hanna M, Hatton C, Eck MJ, Janne PA, Johnson BE, Winckler W, Greulich H, Bass AJ, Cho J, Rauh D, Gray NS, Wong KK, Haura EB, Thomas RK, Meyerson M (2011) Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discovery 1(1):78–89. doi:10.1158/2159-8274.CD-11-0005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ohashi K, Pao W (2011) A new target for therapy in squamous cell carcinoma of the lung. Cancer Discovery 1(1):23–24. doi:10.1158/2159-8274.CD-11-0069

    Article  CAS  PubMed  Google Scholar 

  51. Gao M, Duan L, Luo J, Zhang L, Lu X, Zhang Y, Zhang Z, Tu Z, Xu Y, Ren X, Ding K (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. doi:10.1021/jm301824k

    Article  CAS  PubMed  Google Scholar 

  52. Zhang J, Yang PL, Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9(1):28–39. doi:10.1038/nrc2559

    Article  PubMed  CAS  Google Scholar 

  53. Broekman F, Giovannetti E, Peters GJ (2011) Tyrosine kinase inhibitors: Multi-targeted or single-targeted? World J Clin Oncol 2(2):80–93. doi:10.5306/wjco.v2.i2.80

    Article  PubMed  PubMed Central  Google Scholar 

  54. Rix U, Hantschel O, Durnberger G, Remsing Rix LL, Planyavsky M, Fernbach NV, Kaupe I, Bennett KL, Valent P, Colinge J, Kocher T, Superti-Furga G (2007) Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood 110(12):4055–4063. doi:10.1182/blood-2007-07-102061

    Article  CAS  PubMed  Google Scholar 

  55. Hubbard SR (2004) Juxtamembrane autoinhibition in receptor tyrosine kinases. Nat Rev Mol Cell Biol 5(6):464–471

    Article  CAS  PubMed  Google Scholar 

  56. Flynn LA, Blissett AR, Calomeni EP, Agarwal G (2010) Inhibition of collagen fibrillogenesis by cells expressing soluble extracellular domains of DDR1 and DDR2. J Mol Biol 395(3):533–543. doi:10.1016/j.jmb.2009.10.073

    Article  CAS  PubMed  Google Scholar 

  57. Hachehouche LN, Chetoui N, Aoudjit F (2010) Implication of discoidin domain receptor 1 in T cell migration in three-dimensional collagen. Mol Immunol 47(9):1866–1869. doi:10.1016/j.molimm.2010.02.023

    Article  CAS  PubMed  Google Scholar 

  58. Siddiqui K, Kim GW, Lee DH, Shin HR, Yang EG, Lee NT, Yang BS (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

    Article  CAS  PubMed  Google Scholar 

  59. Mihai C, Chotani M, Elton TS, Agarwal G (2009) Mapping of DDR1 distribution and oligomerization on the cell surface by FRET microscopy. J Mol Biol 385(2):432–445

    Article  CAS  PubMed  Google Scholar 

  60. Margadant C, Monsuur HN, Norman JC, Sonnenberg A (2011) Mechanisms of integrin activation and trafficking. Curr Opin Cell Biol 23(5):607–614. doi:10.1016/j.ceb.2011.08.005

    Article  CAS  PubMed  Google Scholar 

  61. Wang CZ, Su HW, Hsu YC, Shen MR, Tang MJ (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. doi:10.1091/mbc.E05-11-1068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yeh YC, Wang CZ, Tang MJ (2009) Discoidin domain receptor 1 activation suppresses alpha2beta1 integrin-dependent cell spreading through inhibition of Cdc42 activity. J Cell Physiol 218(1):146–156. doi:10.1002/jcp.21578

    Article  CAS  PubMed  Google Scholar 

  63. Amit I, Citri A, Shay T, Lu Y, Katz M, Zhang F, Tarcic G, Siwak D, Lahad J, Jacob-Hirsch J, Amariglio N, Vaisman N, Segal E, Rechavi G, Alon U, Mills GB, Domany E, Yarden Y (2007) A module of negative feedback regulators defines growth factor signaling. Nat Genet 39(4):503–512. doi:10.1038/ng1987

    Article  CAS  PubMed  Google Scholar 

  64. Gordus A, Krall JA, Beyer EM, Kaushansky A, Wolf-Yadlin A, Sevecka M, Chang BH, Rush J, MacBeath G (2009) Linear combinations of docking affinities explain quantitative differences in RTK signaling. Mol Syst Biol 5:235. doi:10.1038/msb.2008.72

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Fu HL, Valiathan RR, Arkwright R, Sohail A, Mihai C, Kumarasiri M, Mahasenan KV, Mobashery S, Huang P, Agarwal G, Fridman R (2013) Discoidin domain receptors: unique receptor tyrosine kinases in collagen-mediated signaling. J Biol Chem 288(11):7430–7437. doi:10.1074/jbc.R112.444158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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 

  67. Huang Y, Arora P, McCulloch CA, Vogel WF (2009) The collagen receptor DDR1 regulates cell spreading and motility by associating with myosin IIA. J Cell Sci 122(Pt 10):1637–1646. doi:10.1242/jcs.046219

    Article  CAS  PubMed  Google Scholar 

  68. Shintani Y, Fukumoto Y, Chaika N, Svoboda R, Wheelock MJ, Johnson KR (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  PubMed Central  Google Scholar 

  69. Koo DH, McFadden C, Huang Y, Abdulhussein R, Friese-Hamim M, Vogel WF (2006) Pinpointing phosphotyrosine-dependent interactions downstream of the collagen receptor DDR1. FEBS Lett 580(1):15–22

    Article  CAS  PubMed  Google Scholar 

  70. Yang G, Li Q, Ren S, Lu X, Fang L, Zhou W, Zhang F, Xu F, Zhang Z, Zeng R, Lottspeich F, Chen Z (2009) Proteomic, functional and motif-based analysis of C-terminal Src kinase-interacting proteins. Proteomics 9(21):4944–4961. doi:10.1002/pmic.200800762

    Article  CAS  PubMed  Google Scholar 

  71. Dejmek J, Dib K, Jonsson M, Andersson T (2003) Wnt-5a and G-protein signaling are required for collagen-induced DDR1 receptor activation and normal mammary cell adhesion. Int J Cancer 103(3):344–351. doi:10.1002/ijc.10752

    Article  CAS  PubMed  Google Scholar 

  72. Lemeer S, Bluwstein A, Wu Z, Leberfinger J, Muller K, Kramer K, Kuster B (2012) Phosphotyrosine mediated protein interactions of the discoidin domain receptor 1. J Proteome 75(12):3465–3477. doi:10.1016/j.jprot.2011.10.007

    Article  CAS  Google Scholar 

  73. Thalappilly S, Soubeyran P, Iovanna JL, Dusetti NJ (2010) VAV2 regulates epidermal growth factor receptor endocytosis and degradation. Oncogene 29(17):2528–2539. doi:10.1038/onc.2010.1

    Article  CAS  PubMed  Google Scholar 

  74. 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 

  75. Xi S, Zhang Q, Gooding WE, Smithgall TE, Grandis JR (2003) Constitutive activation of Stat5b contributes to carcinogenesis in vivo. Cancer Res 63(20):6763–6771

    CAS  PubMed  Google Scholar 

  76. Dejmek J, Leandersson K, Manjer J, Bjartell A, Emdin SO, Vogel WF, Landberg G, Andersson T (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 

  77. Hansen C, Greengard P, Nairn AC, Andersson T, Vogel WF (2006) Phosphorylation of DARPP-32 regulates breast cancer cell migration downstream of the receptor tyrosine kinase DDR1. Exp Cell Res 312(20):4011–4018. doi:10.1016/j.yexcr.2006.09.003

    Article  CAS  PubMed  Google Scholar 

  78. Hilton HN, Stanford PM, Harris J, Oakes SR, Kaplan W, Daly RJ, Ormandy CJ (2008) KIBRA interacts with discoidin domain receptor 1 to modulate collagen-induced signalling. Biochim Biophys Acta 1783(3):383–393. doi:10.1016/j.bbamcr.2007.12.007

    Article  CAS  PubMed  Google Scholar 

  79. Wang CZ, Yeh YC, Tang MJ (2009) DDR1/E-cadherin complex regulates the activation of DDR1 and cell spreading. Am J Physiol Cell Physiol 297(2):C419–C429. doi:10.1152/ajpcell.00101.2009

    Article  CAS  PubMed  Google Scholar 

  80. Bryant DM, Stow JL (2004) The ins and outs of E-cadherin trafficking. Trends Cell Biol 14(8):427–434. doi:10.1016/j.tcb.2004.07.007

    Article  CAS  PubMed  Google Scholar 

  81. Takeichi M (1991) Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251(5000):1451–1455

    Article  CAS  PubMed  Google Scholar 

  82. Eswaramoorthy R, Wang CK, Chen WC, Tang MJ, Ho ML, Hwang CC, Wang HM, Wang CZ (2010) DDR1 regulates the stabilization of cell surface E-cadherin and E-cadherin-mediated cell aggregation. J Cell Physiol 224(2):387–397. doi:10.1002/jcp.22134

    Article  CAS  PubMed  Google Scholar 

  83. Benink HA, Bement WM (2005) Concentric zones of active RhoA and Cdc42 around single cell wounds. J Cell Biol 168(3):429–439. doi:10.1083/jcb.200411109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Etienne-Manneville S, Manneville JB, Nicholls S, Ferenczi MA, Hall A (2005) Cdc42 and Par6-PKC zeta regulate the spatially localized association of Dlg1 and APC to control cell polarization. J Cell Biol 170(6):895–901. doi:10.1083/jcb.200412172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wood W, Jacinto A, Grose R, Woolner S, Gale J, Wilson C, Martin P (2002) Wound healing recapitulates morphogenesis in Drosophila embryos. Nat Cell Biol 4(11):907–912. doi:10.1038/ncb875

    Article  CAS  PubMed  Google Scholar 

  86. Yang K, Kim JH, Kim HJ, Park IS, Kim IY, Yang BS (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. doi:10.1074/jbc.M506921200

    Article  CAS  PubMed  Google Scholar 

  87. Iwai LK, Chang F, Huang PH (2013) Phosphoproteomic analysis identifies insulin enhancement of discoidin domain receptor 2 phosphorylation. Cell Adhes Migr 7(2):161–164. doi:10.4161/cam.22572

    Article  Google Scholar 

  88. Suh HN, Han HJ (2011) Collagen I regulates the self-renewal of mouse embryonic stem cells through alpha2beta1 integrin- and DDR1-dependent Bmi-1. J Cell Physiol 226(12):3422–3432. doi:10.1002/jcp.22697

    Article  CAS  PubMed  Google Scholar 

  89. Xu H, Bihan D, Chang F, Huang PH, Farndale RW, Leitinger B (2012) Discoidin domain receptors promote alpha1beta1- and alpha2beta1-integrin mediated cell adhesion to collagen by enhancing integrin activation. PLoS One 7(12), e52209. doi:10.1371/journal.pone.0052209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ongusaha PP, Kim JI, Fang L, Wong TW, Yancopoulos GD, Aaronson SA, Lee SW (2003) p53 induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop. EMBO J 22(6):1289–1301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sakuma S, Saya H, Tada M, Nakao M, Fujiwara T, Roth JA, Sawamura Y, Shinohe Y, Abe H (1996) Receptor protein tyrosine kinase DDR is up-regulated by p53 protein. FEBS Lett 398(2–3):165–169

    Article  CAS  PubMed  Google Scholar 

  92. Kim SH, Lee S, Suk K, Bark H, Jun CD, Kim DK, Choi CH, Yoshimura T (2007) Discoidin domain receptor 1 mediates collagen-induced nitric oxide production in J774A.1 murine macrophages. Free Radic Biol Med 42(3):343–352. doi:10.1016/j.freeradbiomed.2006.10.052

    Article  PubMed  CAS  Google Scholar 

  93. Curat CA, Vogel WF (2002) Discoidin domain receptor 1 controls growth and adhesion of mesangial cells. J Am Soc Nephrol 13(11):2648–2656

    Article  CAS  PubMed  Google Scholar 

  94. Lu KK, Trcka D, Bendeck MP (2011) Collagen stimulates discoidin domain receptor 1-mediated migration of smooth muscle cells through Src. Cardiovasc Pathol 20(2):71–76. doi:10.1016/j.carpath.2009.12.006

    Article  CAS  PubMed  Google Scholar 

  95. Chetoui N, El Azreq MA, Boisvert M, Bergeron ME, Aoudjit F (2011) Discoidin domain receptor 1 expression in activated T cells is regulated by the ERK MAP kinase signaling pathway. J Cell Biochem 112(12):3666–3674. doi:10.1002/jcb.23300

    Article  CAS  PubMed  Google Scholar 

  96. Chen SC, Wang BW, Wang DL, Shyu KG (2008) Hypoxia induces discoidin domain receptor-2 expression via the p38 pathway in vascular smooth muscle cells to increase their migration. Biochem Biophys Res Commun 374(4):662–667

    Article  CAS  PubMed  Google Scholar 

  97. Lin KL, Chou CH, Hsieh SC, Hwa SY, Lee MT, Wang FF (2010) Transcriptional upregulation of DDR2 by ATF4 facilitates osteoblastic differentiation through p38 MAPK-mediated Runx2 activation. J Bone Miner Res 25(11):2489–2503. doi:10.1002/jbmr.159

    Article  CAS  PubMed  Google Scholar 

  98. Zhang Y, Su J, Yu J, Bu X, Ren T, Liu X, Yao L (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 

  99. Su J, Yu J, Ren T, Zhang W, Zhang Y, Liu X, Sun T, Lu H, Miyazawa K, Yao L (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 

  100. Poudel B, Ki HH, Lee YM, Kim DK (2013) Induction of IL-12 production by the activation of discoidin domain receptor 2 via NF-kappaB and JNK pathway. Biochem Biophys Res Commun 434(3):584–588. doi:10.1016/j.bbrc.2013.03.118

    Article  CAS  PubMed  Google Scholar 

  101. Lee JE, Kang CS, Guan XY, Kim BT, Kim SH, Lee YM, Moon WS, Kim DK (2007) Discoidin domain receptor 2 is involved in the activation of bone marrow-derived dendritic cells caused by type I collagen. Biochem Biophys Res Commun 352(1):244–250. doi:10.1016/j.bbrc.2006.11.010

    Article  CAS  PubMed  Google Scholar 

  102. Poudel B, Yoon DS, Lee JH, Lee YM, Kim DK (2012) Collagen I enhances functional activities of human monocyte-derived dendritic cells via discoidin domain receptor 2. Cell Immunol 278(1–2):95–102. doi:10.1016/j.cellimm.2012.07.004

    Article  CAS  PubMed  Google Scholar 

  103. Ruiz PA, Jarai G (2011) Collagen I induces discoidin domain receptor (DDR) 1 expression through DDR2 and a JAK2-ERK1/2-mediated mechanism in primary human lung fibroblasts. J Biol Chem 286(15):12912–12923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ruiz PA, Jarai G (2012) Discoidin domain receptors regulate the migration of primary human lung fibroblasts through collagen matrices. Fibrogenesis Tissue Repair 5:3. doi:10.1186/1755-1536-5-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Jonsson M, Andersson T (2001) Repression of Wnt-5a impairs DDR1 phosphorylation and modifies adhesion and migration of mammary cells. J Cell Sci 114(Pt 11):2043–2053

    CAS  PubMed  Google Scholar 

  106. Roarty K, Serra R (2007) Wnt5a is required for proper mammary gland development and TGF-beta-mediated inhibition of ductal growth. Development 134(21):3929–3939. doi:10.1242/dev.008250

    Article  CAS  PubMed  Google Scholar 

  107. Kato K, Yazawa T, Taki K, Mori K, Wang S, Nishioka T, Hamaguchi T, Itoh T, Takenawa T, Kataoka C, Matsuura Y, Amano M, Murohara T, Kaibuchi K (2012) The inositol 5-phosphatase SHIP2 is an effector of RhoA and is involved in cell polarity and migration. Mol Biol Cell 23(13):2593–2604. doi:10.1091/mbc.E11-11-0958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kelber JA, Klemke RL (2010) PEAK1, a novel kinase target in the fight against cancer. Oncotarget 1(3):219–223

    Article  PubMed  PubMed Central  Google Scholar 

  109. Prasad N, Topping RS, Decker SJ (2001) SH2-containing inositol 5'-phosphatase SHIP2 associates with the p130(Cas) adapter protein and regulates cellular adhesion and spreading. Mol Cell Biol 21(4):1416–1428. doi:10.1128/MCB.21.4.1416-1428.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  111. Comoglio PM, Boccaccio C, Trusolino L (2003) Interactions between growth factor receptors and adhesion molecules: breaking the rules. Curr Opin Cell Biol 15(5):565–571

    Article  CAS  PubMed  Google Scholar 

  112. Vogel W, Brakebusch C, Fassler R, Alves F, Ruggiero F, Pawson T (2000) Discoidin domain receptor 1 is activated independently of beta(1) integrin. J Biol Chem 275(8):5779–5784

    Article  CAS  PubMed  Google Scholar 

  113. Neel BG, Gu H, Pao L (2003) The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci 28(6):284–293. doi:10.1016/S0968-0004(03)00091-4

    Article  CAS  PubMed  Google Scholar 

  114. Yeh YC, Wu CC, Wang YK, Tang MJ (2011) DDR1 triggers epithelial cell differentiation by promoting cell adhesion through stabilization of E-cadherin. Mol Biol Cell 22(7):940–953. doi:10.1091/mbc.E10-08-0678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Palacios F, Schweitzer JK, Boshans RL, D'Souza-Schorey C (2002) ARF6-GTP recruits Nm23-H1 to facilitate dynamin-mediated endocytosis during adherens junctions disassembly. Nat Cell Biol 4(12):929–936. doi:10.1038/ncb881

    Article  CAS  PubMed  Google Scholar 

  116. Staudinger LA, Spano SJ, Lee W, Coelho N, Rajshankar D, Bendeck MP, Moriarty T, McCulloch CA (2013) Interactions between the discoidin domain receptor 1 and beta1 integrin regulate attachment to collagen. Biol Open 2(11):1148–1159. doi:10.1242/bio.20135090

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, Mathieson T, Perrin J, Raida M, Rau C, Reader V, Sweetman G, Bauer A, Bouwmeester T, Hopf C, Kruse U, Neubauer G, Ramsden N, Rick J, Kuster B, Drewes G (2007) Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol 25(9):1035–1044. doi:10.1038/nbt1328

    Article  CAS  PubMed  Google Scholar 

  118. Day E, Waters B, Spiegel K, Alnadaf T, Manley PW, Buchdunger E, Walker C, Jarai G (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 

  119. Rix U, Remsing Rix LL, Terker AS, Fernbach NV, Hantschel O, Planyavsky M, Breitwieser FP, Herrmann H, Colinge J, Bennett KL, Augustin M, Till JH, Heinrich MC, Valent P, Superti-Furga G (2010) A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells. Leukemia 24(1):44–50. doi:10.1038/leu.2009.228

    Article  CAS  PubMed  Google Scholar 

  120. Kotz J (2011) The DDR is in. SciBX 4(20):1–2. doi:10.1038/scibx.2011.559

    Google Scholar 

  121. Kim HG, Tan L, Weisberg EL, Liu F, Canning P, Choi HG, Ezell SA, Wu H, Zhao Z, Wang J, Mandinova A, Griffin JD, Bullock AN, Liu Q, Lee SW, Gray NS (2013) Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor. ACS Chem Biol 8(10):2145–2150. doi:10.1021/cb400430t

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Bae I-H, Son J-B, Han S, Kwak E-J, Kim H-S, Song J-Y, Byun E-Y, Jun S-A, Ahn Y-G, Suh, K-H WO 2013/100632 A1

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Novartis Institutes for Biomedical Research, Respiratory Diseases, Wimblehurst Road, Horsham, RH12 5AB, UK

    Pedro A. Ruiz-Castro, Duncan Shaw Ph.D. & Gabor Jarai Ph.D.

  2. Sanford-Burnham Medical Research Institute, 10901 N Torrey Pines Rd, La Jolla, CA, 92037, USA

    Pedro A. Ruiz-Castro

  3. Division of Gastroenterology and Hepatology, Novartis Institutes for Biomedical Research, Rämistrasse 100, Zurich, 8091, Switzerland

    Pedro A. Ruiz-Castro

  4. Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA, 02039, USA

    Duncan Shaw Ph.D.

  5. Fibrotic Diseases, Disease Sciences and Biology, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA

    Gabor Jarai Ph.D.

Authors
  1. Pedro A. Ruiz-Castro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Duncan Shaw Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gabor Jarai Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gabor Jarai Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Pathology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, Michigan, USA

    Rafael Fridman

  2. Division of Cancer Biology, The Institute of Cancer Research, London, United Kingdom

    Paul H. Huang

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this chapter

Cite this chapter

Ruiz-Castro, P.A., Shaw, D., Jarai, G. (2016). Discoidin Domain Receptor Signaling and Pharmacological Inhibitors. In: Fridman, R., Huang, P. (eds) Discoidin Domain Receptors in Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-6383-6_12

Download citation

Publish with us

Policies and ethics

Search

Navigation