Skip to main content

Advertisement

SpringerLink
Log in

Migration inhibition of mammary epithelial cells by Syk is blocked in the presence of DDR1 receptors

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

Abstract

The non-receptor tyrosine kinase Syk is a well-characterized hematopoietic signal transducer, which is also expressed in non-hematopoietic cells. In epithelial cells, the function of Syk is not wholly known. It interacts with the receptor tyrosine kinase DDR1 and is frequently lost from metastatic mammary tumors. Here, using genetic tracing, we demonstrate Syk expression in murine mammary epithelium, myoepithelium and skin epithelium, but not in intestinal or lung epithelia. Investigating possible functions of Syk, we found a substantial suppression of cell mobility that depended on Syk kinase activity in trans-well migration and wounding assays. Co-expression of DDR1 resulted in constitutive interaction and strong activation of Syk kinase. Most importantly, Syk-mediated migration inhibition was blocked in the presence of DDR1, while conversely DDR1 knockdown restored migration inhibition. Our study identifies Syk as a potent inhibitor of epithelial migration and describes a first functional consequence of the interaction with the collagen receptor DDR1.

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
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Comoglio PM, Trusolino L (2005) Cancer: the matrix is now in control. Nat Med 11:1156–1159

    Article  PubMed  CAS  Google Scholar 

  2. Sada K, Takano T, Yanagi S, Yamamura H (2001) Structure and function of Syk protein-tyrosine kinase. J Biochem 130:177–186

    PubMed  CAS  Google Scholar 

  3. Fluck M, Zurcher G, Andres AC, Ziemiecki A (1995) Molecular characterization of the murine Syk protein tyrosine kinase cDNA, transcripts and protein. Biochem Biophys Res Commun 213:273–281

    Article  PubMed  CAS  Google Scholar 

  4. Coopman PJ, Mueller SC (2006) The Syk tyrosine kinase: a new negative regulator in tumor growth and progression. Cancer Lett 241:159–173

    Article  PubMed  CAS  Google Scholar 

  5. Mocsai A, Ruland J, Tybulewicz VL (2010) The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol 10:387–402

    Article  PubMed  CAS  Google Scholar 

  6. Moroni M, Soldatenkov V, Zhang L, Zhang Y, Stoica G, Gehan E, Rashidi B, Singh B, Ozdemirli M, Mueller SC (2004) Progressive loss of Syk and abnormal proliferation in breast cancer cells. Cancer Res 64:7346–7354

    Article  PubMed  CAS  Google Scholar 

  7. Yuan Y, Liu H, Sahin A, Dai JL (2005) Reactivation of SYK expression by inhibition of DNA methylation suppresses breast cancer cell invasiveness. Int J Cancer 113:654–659

    Article  PubMed  CAS  Google Scholar 

  8. 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 11:520–528

    PubMed  CAS  Google Scholar 

  9. Toyama T, Iwase H, Yamashita H, Hara Y, Omoto Y, Sugiura H, Zhang Z, Fujii Y (2003) Reduced expression of the Syk gene is correlated with poor prognosis in human breast cancer. Cancer Lett 189:97–102

    Article  PubMed  CAS  Google Scholar 

  10. Coopman PJ, Do MT, Barth M, Bowden ET, Hayes AJ, Basyuk E, Blancato JK, Vezza PR, McLeskey SW, Mangeat PH, Mueller SC (2000) The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature 406:742–747

    Article  PubMed  CAS  Google Scholar 

  11. Li J, Sidell N (2005) Growth-related oncogene produced in human breast cancer cells and regulated by Syk protein-tyrosine kinase. Int JCancer 117:14–20

    Article  CAS  Google Scholar 

  12. Wang L, Devarajan E, He J, Reddy SP, Dai JL (2005) Transcription repressor activity of spleen tyrosine kinase mediates breast tumor suppression. Cancer Res 65:10289–10297

    Article  PubMed  CAS  Google Scholar 

  13. Zyss D, Montcourrier P, Vidal B, Anguille C, Merezegue F, Sahuquet A, Mangeat PH, Coopman PJ (2005) The Syk tyrosine kinase localizes to the centrosomes and negatively affects mitotic progression. Cancer Res 65:10872–10880

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  15. Di ME, Cutuli N, Guerra L, Cancedda R, De LM (1993) Molecular cloning of trkE, a novel trk-related putative tyrosine kinase receptor isolated from normal human keratinocytes and widely expressed by normal human tissues. J Biol Chem 268:24290–24295

    Google Scholar 

  16. 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 10:609–618

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. 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 15:1321–1323

    PubMed  CAS  Google Scholar 

  19. Mullenbach E, Walter L, Dressel R (2006) A novel discoidin domain receptor 1 (Ddr1) transcript is expressed in postmeiotic germ cells of the rat testis depending on the major histocompatibility complex haplotype. Gene 372:53–61

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  21. 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 22:1289–1301

    Article  PubMed  CAS  Google Scholar 

  22. Hou G, Vogel W, Bendeck MP (2001) The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair. J Clin Invest 107:727–735

    Article  PubMed  CAS  Google Scholar 

  23. 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 15:2724–2726

    PubMed  CAS  Google Scholar 

  24. Yoshimura T, Matsuyama W, Kamohara H (2005) Discoidin domain receptor 1: a new class of receptor regulating leukocyte-collagen interaction. Immunol Res 31:219–230

    Article  PubMed  CAS  Google Scholar 

  25. Weiner HL, Huang H, Zagzag D, Boyce H, Lichtenbaum R, Ziff EB (2000) Consistent and selective expression of the discoidin domain receptor-1 tyrosine kinase in human brain tumors. Neurosurgery 47:1400–1409

    Article  PubMed  CAS  Google Scholar 

  26. Wang L, Duke L, Zhang PS, Arlinghaus RB, Symmans WF, Sahin A, Mendez R, Dai JL (2003) Alternative splicing disrupts a nuclear localization signal in spleen tyrosine kinase that is required for invasion suppression in breast cancer. Cancer Res 63:4724–4730

    PubMed  CAS  Google Scholar 

  27. Gatalica Z, Bing Z (2005) Syk tyrosine kinase expression during multistep mammary carcinogenesis. Croat Med J 46:372–376

    PubMed  Google Scholar 

  28. Ulanova M, Puttagunta L, Marcet-Palacios M, Duszyk M, Steinhoff U, Duta F, Kim MK, Indik ZK, Schreiber AD, Befus AD (2005) Syk tyrosine kinase participates in beta1-integrin signaling and inflammatory responses in airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 288:L497–L507

    Article  PubMed  CAS  Google Scholar 

  29. Nakashima H, Natsugoe S, Ishigami S, Okumura H, Matsumoto M, Hokita S, Aikou T (2006) Clinical significance of nuclear expression of spleen tyrosine kinase (Syk) in gastric cancer. Cancer Lett 236:89–94

    Article  PubMed  CAS  Google Scholar 

  30. Bohmer R, Neuhaus B, Buhren S, Zhang D, Stehling M, Bock B, Kiefer F (2010) Regulation of developmental lymphangiogenesis by Syk(+) leukocytes. Dev Cell 18:437–449

    Article  PubMed  Google Scholar 

  31. Srinivas S, Watanabe T, Lin CS, William CM, Tanabe Y, Jessell TM, Costantini F (2001) Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol 1:4

    Article  PubMed  CAS  Google Scholar 

  32. Saouaf SJ, Mahajan S, Rowley RB, Kut SA, Fargnoli J, Burkhardt AL, Tsukada S, Witte ON, Bolen JB (1994) Temporal differences in the activation of three classes of non-transmembrane protein tyrosine kinases following B-cell antigen receptor surface engagement. Proc Natl Acad Sci USA 91:9524–9528

    Article  PubMed  CAS  Google Scholar 

  33. Luangdilok S, Box C, Patterson L, Court W, Harrington K, Pitkin L, Rhys-Evans P, Charoenrat P, Eccles S (2007) Syk tyrosine kinase is linked to cell motility and progression in squamous cell carcinomas of the head and neck. Cancer Res 67:7907–7916

    Article  PubMed  CAS  Google Scholar 

  34. Mahabeleshwar GH, Kundu GC (2003) Syk, a protein-tyrosine kinase, suppresses the cell motility and nuclear factor kappa B-mediated secretion of urokinase type plasminogen activator by inhibiting the phosphatidylinositol 3′-kinase activity in breast cancer cells. J Biol Chem 278:6209–6221

    Article  PubMed  CAS  Google Scholar 

  35. Zhang X, Shrikhande U, Alicie BM, Zhou Q, Geahlen RL (2009) Role of the protein tyrosine kinase Syk in regulating cell–cell adhesion and motility in breast cancer cells. Mol Cancer Res 7:634–644

    Article  PubMed  CAS  Google Scholar 

  36. Law DA, Nannizzi-Alaimo L, Ministri K, Hughes PE, Forsyth J, Turner M, Shattil SJ, Ginsberg MH, Tybulewicz VL, Phillips DR (1999) Genetic and pharmacological analyses of Syk function in alphaIIbbeta3 signaling in platelets. Blood 93:2645–2652

    PubMed  CAS  Google Scholar 

  37. Inoue O, Suzuki-Inoue K, Dean WL, Frampton J, Watson SP (2003) Integrin alpha2beta1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLCgamma2. J Cell Biol 160:769–780

    Article  PubMed  CAS  Google Scholar 

  38. Larive RM, Urbach S, Poncet J, Jouin P, Mascre G, Sahuquet A, Mangeat PH, Coopman PJ, Bettache N (2009) Phosphoproteomic analysis of Syk kinase signaling in human cancer cells reveals its role in cell–cell adhesion. Oncogene 28:2337–2347

    Article  PubMed  CAS  Google Scholar 

  39. Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N, Settleman J (2009) A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell 15:489–500

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  41. 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 90:1147–1149

    Article  PubMed  CAS  Google Scholar 

  42. Katz E, Dubois-Marshall S, Sims AH, Faratian D, Li J, Smith ES, Quinn JA, Edward M, Meehan RR, Evans EE, Langdon SP, Harrison DJ (2010) A gene on the HER2 amplicon, C35, is an oncogene in breast cancer whose actions are prevented by inhibition of Syk. Br J Cancer 103:401–410

    Article  PubMed  CAS  Google Scholar 

  43. Evans EE, Henn AD, Jonason A, Paris MJ, Schiffhauer LM, Borrello MA, Smith ES, Sahasrabudhe DM, Zauderer M (2006) C35 (C17orf37) is a novel tumor biomarker abundantly expressed in breast cancer. Mol Cancer Ther 5:2919–2930

    Article  PubMed  CAS  Google Scholar 

  44. Katz E, Lareef MH, Rassa JC, Grande SM, King LB, Russo J, Ross SR, Monroe JG (2005) MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture. J Exp Med 201:431–439

    Article  PubMed  CAS  Google Scholar 

  45. Grande SM, Katz E, Crowley JE, Bernardini MS, Ross SR, Monroe JG (2006) Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells. Oncogene 25:2748–2757

    Article  PubMed  CAS  Google Scholar 

  46. Kiefer F, Tibbles LA, Anafi M, Janssen A, Zanke BW, Lassam N, Pawson T, Woodgett JR, Iscove NN (1996) HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway. EMBO J 15:7013–7025

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (Ki492/2-1, SFB 629) and the Max Planck Society to F.K., the Fritz-Thyssen Stiftung für Wissenschaftsförderung to B.N. and from the National Cancer Institute of Canada and the Canada Research Chair Program to W.F.V.

Author information

Author notes

  1. Barbara Böck

    Present address: Division of Vascular Oncology and Metastasis (A190), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

  2. Brit Neuhaus

    Present address: Department of Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, 50931, Cologne, Germany

Authors and Affiliations

  1. Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstr. 20, 48149, Münster, Germany

    Brit Neuhaus, Sebastian Bühren, Barbara Böck & Friedemann Kiefer

  2. Department of Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany

    Frauke Alves

  3. Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, 37075, Göttingen, Germany

    Frauke Alves

  4. Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Science Building, Room 7334A, 1 King’s College Circle, Toronto, ON, M5S 1A8, Canada

    Wolfgang F. Vogel

Authors
  1. Brit Neuhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sebastian Bühren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barbara Böck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Frauke Alves
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wolfgang F. Vogel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Friedemann Kiefer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Friedemann Kiefer.

Additional information

B. Neuhaus and S. Bühren contributed equally to this work.

Wolfgang F. Vogel (deceased on 5 December 2007).

Electronic supplementary material

Below is the link to the electronic supplementary material.

18_2011_676_MOESM1_ESM.pdf

Suppl. Fig. 1. Syk is not expressed in murine epithelial cells of the intestinum or the airway epithelium of the lungs. To genetically trace Syk expression in murine epithelial cells of the intestinum or lung, cryosections of tissue samples derived from Syk-CreΔ/+ //R26R-YFP/YFP double transgenic mice were prepared and counterstained for YFP (Alexa 488, green) and E-cadherin (Alexa 568, red). (a–e) Syk promotor activity, indicated by YFP staining, was neither detected in the columnar epithelium of the intestinum (a–c) nor in the airway epithelium of the lungs (D + E). Syk-positive cells in the lacteal of the intestine (asterisk) and surrounding lung alveolar epithelium (arrowhead) served as positive controls (PDF 881 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Neuhaus, B., Bühren, S., Böck, B. et al. Migration inhibition of mammary epithelial cells by Syk is blocked in the presence of DDR1 receptors. Cell. Mol. Life Sci. 68, 3757–3770 (2011). https://doi.org/10.1007/s00018-011-0676-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-011-0676-8

Keywords

Search

Navigation