Skip to main content

Advertisement

SpringerLink
Log in

Relationship between urokinase plasminogen activator receptor (uPAR) and the invasion of human prenatal hair follicle

  • Original Paper
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

During the morphogenesis of hair follicles, the invasive migration of basal keratinocytes resembles cell’s dissemination of tissue remodeling. The urokinase-type plasminogen activator receptor (uPAR) appears to be a key molecule in the metastasis. In order to elucidate the relationship between uPAR and the invasion of the human hair follicle, immunohistochemistry, RT-PCR, plasmids transfection, and western blot were used. The results showed that uPAR was expressed in the outermost epithelial cells of the hair follicle and the basal keratinocytes of epidermis, and that the expression decreased with the development of the hair follicle. The cells of the outer root sheath (ORS) and interfollicle epidermis, which overexpressed uPAR, acquired increased invasiveness; however, they showed decreased invasion with overexpression of the urokinase-type plasminogen activator amino terminal fragment (uPA ATF), which inhibited the combination of uPAR and uPA competitively, and the cell invasive migration with overexpressed uPAR was required activated extracellular signal-regulated kinases (ERK). These results implied that overexpression of uPAR promote the invasive migration of hair follicle into the dermis in uPA-dependent and independent manner during human prenatal development.

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
Fig. 7

Similar content being viewed by others

References

  1. Aguirre Ghiso JA, Alonso DF, Farías EF, Gomez DE, de Kier Joffè EB (1999) Deregulation of the signaling pathways controlling urokinase production Its relationship with the invasive phenotype. Eur J Biochem 263:295–304. doi:10.1046/j.1432-1327.1999.00507.x

    Article  CAS  PubMed  Google Scholar 

  2. Akiyama M, Smith LT, Holbrook KA (1996) Growth factor and growth factor receptor localization in the hair follicle bulge and associated tissue in human fetus. J Invest Dermatol 106:391–396

    Article  CAS  PubMed  Google Scholar 

  3. Akiyama M, Smith LT, Shimizu H (2000) Changing patterns of localization of putative stem cells in developing human hair follicles. J Invest Dermatol 114:321–327. doi:10.1046/j.1523-1747.2000.00857.x

    Article  CAS  PubMed  Google Scholar 

  4. Andreasen PA, Egelund R, Petersen HH (2000) The plasminogen activation system in tumor growth, invasion, and metastasis. Cell Mol Life Sci 57:25–40

    Article  CAS  PubMed  Google Scholar 

  5. Bernard BA (2002) Hair biology: an update. Int J Cosmet Sci 24:13–16. doi:10.1046/j.0412-5463.2001.00109.x

    Article  CAS  PubMed  Google Scholar 

  6. Blasi F, Carmeliet P (2002) uPAR: a versatile signaling orchestrator. Nat Rev Mol Cell Biol 3:932–943. doi:10.1038/nrm977

    Article  CAS  PubMed  Google Scholar 

  7. Botchkarev VA, Paus R (2003) Molecular biology of hair morphogenesis: development and cycling. J Exp Zool B Mol Dev Evol 298:164–180. doi:10.1002/jez.b.33

    PubMed  Google Scholar 

  8. Choong PF, Nadesapillai AP (2003) Urokinase plasminogen activator system: a multifunctional role in tumor progression and metastasis. Clin Orthop 415S:S46–S58. doi:10.1097/01.blo.0000093845.72468.bd

    Google Scholar 

  9. Commo S, Bernard BA (1997) The distribution of α2β1, α3β1 and α6β4 integrins identify as distinct subpopulations of basal keratinocytes in the outer root sheath of the human anagen hair follicle. Cell Mol Life Sci 53:466–471

    Article  CAS  PubMed  Google Scholar 

  10. Cotsarelis G (2006) Gene expression profiling gets to the root of human hair follicle stem cells. J Clin Invest 116:19–22. doi:10.1172/JCI27490

    Article  CAS  PubMed  Google Scholar 

  11. Croucher DR, Saunders DN, Lobov S, Ranson M (2008) Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Nat Rev Cancer 8:535–545. doi:10.1038/nrc2400

    Article  CAS  PubMed  Google Scholar 

  12. Cui ZH, Yang T, Gao QG, Wang Y (2004) Urokinase plasminogen activator (uPA) is a positive regulator of outer root sheath keratinocyte proliferation. Cell Biol Int 28:571–575. doi:10.1016/j.cellbi.2004.04.012

    Article  CAS  PubMed  Google Scholar 

  13. D’Alessio S, Blasi F (2009) The urokinase receptor as an entertainer of signal transduction. Front Biosci 14:4575–4587

    Article  PubMed  Google Scholar 

  14. D’Alessio S, Gerasi L, Blasi F (2008) uPAR-deficient mouse keratinocytes fail to produce EGFR-dependent laminin-5, affecting migration in vivo and in vitro. J Cell Sci 121:3922–3932. doi:10.1242/jcs.037549

    Article  PubMed  Google Scholar 

  15. Dass K, Ahmad A, Azmi AS, Sarkar SH, Sarkar FH (2008) Evolving role of uPA/uPAR system in human cancers. Cancer Treat Rev 34:122–136. doi:10.1016/j.ctrv.2007.10.005

    Article  CAS  PubMed  Google Scholar 

  16. Duffy MJ (2004) The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des 10:39–49

    Article  CAS  PubMed  Google Scholar 

  17. Ellis V, Scully M, Kakkar VV (1989) Plasminogen activation initiated by single chain urokinase-type plasminogen activator. Potentiation by U937 monocytes. J Biol Chem 264:2185–2188

    CAS  PubMed  Google Scholar 

  18. Gu JM, Johns A, Morser J, Dole WP, Greaves DR, Deng GG (2005) Urokinase plasminogen activator receptor promotes macrophage infiltration into the vascular wall of ApoE deficient mice. J Cell Physiol 204:73–82. doi:10.1002/jcp.20262

    Article  CAS  PubMed  Google Scholar 

  19. Hildenbrand R, Gandhari M, Stroebel P, Marx A, Allgayer H, Arens N (2008) The urokinase-system—role of cell proliferation and apoptosis. Histol Histopathol 23:227–236

    CAS  PubMed  Google Scholar 

  20. Holbrook KA, Smith LT, Kaplan ED, Minami SA, Hebert GP, Underwood RA (1993) Expression of morphogenesis during human follicle development in vivo and a model for studying follicle morphogenesis in vitro. J Invest Dermatol 101:39s–49s

    Article  CAS  PubMed  Google Scholar 

  21. Huang C, Jacobson K, Schaller MD (2004) MAP kinases and cell migration. J Cell Sci 117:4619–4628. doi:10.1242/jcs.01481

    Article  CAS  PubMed  Google Scholar 

  22. Jensen PJ, Lavker RM (1999) Urokinase is a positive regulator of epidermal proliferation in vivo. J Invest Dermatol 112:240–244. doi:10.1046/j.1523-1747.1999.00494.x

    Article  CAS  PubMed  Google Scholar 

  23. Kloepper JE, Hendrix S, Bodó E, Bodó E, Tiede S, Humphries MJ, Philpott MP, Fässler R, Paus R (2008) Functional role of beta 1 integrin-mediated signalling in the human hair follicle. Exp Cell Res 314:498–508. doi:10.1016/j.yexcr.2007.10.030

    Article  CAS  PubMed  Google Scholar 

  24. Lademann UA, Rømer MU (2008) Regulation of programmed cell death by plasminogen activator inhibitor type 1 (PAI-1). Thromb Haemost 100:1041–1046

    CAS  PubMed  Google Scholar 

  25. Lavker RM, Risse B, Brown H, Ginsburg D, Pearson J, Baker MS, Jensen PJ (1998) Localization of plasminogen activator inhibitor type 2 (PAI-2) in hair and nail: implications for terminal differentiation. J Invest Dermatol 110:917–922. doi:10.1046/j.1523-1747.1998.00223.x

    Article  CAS  PubMed  Google Scholar 

  26. Li G, Yang T, Yan J (2002) Cyclooxygenase-2 increased the angiogenic and metastatic potential of tumor cells. Biochem Biophys Res Commun 299:886–890

    Article  CAS  PubMed  Google Scholar 

  27. Lund LR, Eriksen J, Ralfkiaer E, Rømer J (1996) Differential expression of urokinase-type plasminogen activator, its receptor, and inhibitors in mouse skin after exposure to a tumor-promoting phorbol ester. J Invest Dermatol 106:622–630

    Article  CAS  PubMed  Google Scholar 

  28. Luparello C, Del Rosso M (1996) In vitro anti-proliferative and anti-invasive role of aminoterminal fragment of urokinase-type plasminogen activator on 8701-BC breast cancer cells. Eur J Cancer 32A:702–707

    Article  CAS  PubMed  Google Scholar 

  29. Medcalf RL, Stasinopoulos SJ (2005) The undecided serpin. The ins and outs of plasminogen activator inhibitor type 2. FEBS J 272:4858–4867. doi: 10.1111/j.1742-4658.2005.04879.x

    Article  CAS  PubMed  Google Scholar 

  30. Mondino A, Blasi F (2004) uPA and uPAR in fibrinolysis, immunity and pathology. Trends Immunol 25:450–455. doi:10.1016/j.it.2004.06.004

    Article  CAS  PubMed  Google Scholar 

  31. Montuori N, Carriero MV, Salzano S, Rossi G, Ragno P (2002) The cleavage of the urokinase receptor regulates its multiple functions. J Biol Chem 277:46932–46939. doi:10.1074/jbc.M207494200

    Article  CAS  PubMed  Google Scholar 

  32. Morioka S, Lazarus GS, Baird JL, Jensen PJ (1987) Migrating keratinocytes express urokinase-type plasminogen activator. J Invest Dermatol 88:418–423

    Article  CAS  PubMed  Google Scholar 

  33. Oshima H, Rochat A, Kedzia C, Kobayashi K, Barrandon Y (2001) Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell 104:233–245

    Article  CAS  PubMed  Google Scholar 

  34. Ossowski L, Aguirre-Ghiso JA (2000) Urokinase receptor and integrin partnership: coordination of signaling for cell adhesion, migration and growth. Curr Opin Cell Biol 12:613–620

    Article  CAS  PubMed  Google Scholar 

  35. Ploug M (2003) Structure-function relationships in the interaction between the urokinase-type plasminogen activator and its receptor. Curr Pharm Des 9:1499–1528

    Article  CAS  PubMed  Google Scholar 

  36. Ragno P (2006) The urokinase receptor: a ligand or a receptor? Story of a sociable molecule. Cell Mol Life Sci 63:1028–1037. doi:10.1007/s00018-005-5428-1

    Article  CAS  PubMed  Google Scholar 

  37. Rømer J, Lund LR, Eriksen J, Pyke C, Kristensen P, Danø K (1994) The receptor for urokinase-type plasminogen activator is expressed by keratinocytes at the leading edge during re-epithelialization of mouse skin wounds. J Invest Dermatol 102:519–522

    Article  PubMed  Google Scholar 

  38. Rømer J, Pyke C, Lund LR, Danø K (2001) Cancer cell expression of urokinase-type plasminogen activator receptor mRNA in squamous cell carcinomas of the skin. J Invest Dermatol 116:353–358. doi:10.1046/j.1523-1747.2001.01241.x

    Article  PubMed  Google Scholar 

  39. Satoh Y, Saitoh D, Takeuchi A, Ojima K, Kouzu K, Kawakami S, Ito M, Ishihara M, Sato S, Takishima K (2009) ERK2 dependent signaling contributes to wound healing after a partial-thickness burn. Biochem Biophys Res Commun 381:118–122. doi:10.1016/j.bbrc.2009.02.039

    Article  CAS  PubMed  Google Scholar 

  40. Schaefer BM, Stark HJ, Fusenig NE III, Todd RF, Kramer MD (1995) Differential expression of urokinase-type plasminogen activator (uPA), its receptor (uPA-R), and inhibitor type-2 (PAI-2) during differentiation of keratinocytes in an organotypic coculture system. Exp Cell Res 220:415–423

    Article  CAS  PubMed  Google Scholar 

  41. Schneider MR, Schmidt-Ullrich R, Paus R (2009) The hair follicle as a dynamic miniorgan. Curr Biol 19:R132–R142. doi:10.1016/j.cub.2008.12.005

    Article  CAS  PubMed  Google Scholar 

  42. Solberg H, Ploug M, Høyer-Hansen G, Nielsen BS, Lund LR (2001) The murine receptor for urokinase-type plasminogen activator is primarily expressed in tissues actively undergoing remodeling. J Histochem Cytochem 49:237–246

    CAS  PubMed  Google Scholar 

  43. Song C, Lian XH, Yang T (2000) Biological aspects and progress of tPA/PAI-2 during differentiation of dermatic keratinocyte. Zhong Guo Ke Xue Ji Jin 14:147–150

    Google Scholar 

  44. Stenn KS, Paus R (2001) Controls of hair follicle cycling. Physiol Rev 81:449–494

    CAS  PubMed  Google Scholar 

  45. Tang CH, Wei Y (2008) The urokinase receptor and integrins in cancer progression. Cell Mol Life Sci 65:1916–1932. doi:10.1007/s00018-008-7573-9

    Article  CAS  PubMed  Google Scholar 

  46. Tucker TA, Dean C, Komissarov A, Koenig K, Mazar A, Pendurthi U, Allen TC, Idell S (2009) The Urokinase Receptor Supports Tumorigenesis of Human Malignant Pleural Mesothelioma Cells. Am J Respir Cell Mol Biol Jul 27. [Epub ahead of print] doi: 10.1165/rcmb.2008-0433OC

  47. Vassalli JD, Sappino AP, Belin D (1991) The plasminogen activator/plasmin system. J Clin Invest 88:1067–1072

    Article  CAS  PubMed  Google Scholar 

  48. Waltz DA, Fujita RM, Yang X, Natkin L, Zhuo S, Gerard CJ, Rosenberg S, Chapman HA (2000) Nonproteolytic role for the urokinase receptor in cellular migration in vivo. Am J Respir Cell Mol Biol 22:316–322

    CAS  PubMed  Google Scholar 

  49. Watt FM (2002) Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J 21:3919–3926. doi:10.1093/emboj/cdf399

    Article  CAS  PubMed  Google Scholar 

  50. Wei Y, Lukashev M, Simon DI, Bodary SC, Rosenberg S, Doyle MV, Chapman HA (1996) Regulation of integrin function by the urokinase receptor. Science 273:1551–1555

    Article  CAS  PubMed  Google Scholar 

  51. Wei Y, Yang X, Liu Q, Wilkins JA, Chapman HA (1999) A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling. J Cell Biol 144:1285–1294

    Article  CAS  PubMed  Google Scholar 

  52. Xing RH, Rabbani SA (1996) Overexpression of urokinase receptor in breast cancer cells results in increased tumor invasion, growth and metastasis. Int J Cancer 67:423–429

    Article  CAS  PubMed  Google Scholar 

  53. Xue A, Xue M, Jackson C, Smith RC (2009) Suppression of urokinase plasminogen activator receptor inhibits proliferation and migration of pancreatic adenocarcinoma cells via regulation of ERK/p38 signaling. Int J Biochem Cell Biol 41:1731–1738. doi:10.1016/j.biocel.2009.03.004

    Article  CAS  PubMed  Google Scholar 

  54. Xue W, Mizukami I III, Todd RF, Petty HR (1997) Urokinase-type plasminogen activator receptors associate with beta1 and beta3 integrins of fibrosarcoma cells: dependence on extracellular matrix components. Cancer Res 57:1682–1689

    CAS  PubMed  Google Scholar 

  55. Zhou HM, Nichols A, Meda P, Vassalli JD (2000) Urokinase-type plasminogen activator and its receptor synergize to promote pathogenic proteolysis. EMBO J 19:4817–4826. doi:10.1093/emboj/19.17.4817

    Article  CAS  PubMed  Google Scholar 

  56. Zhou HM, Nichols A, Wohlwend A, Bolon I, Vassalli JD (1999) Extracellular proteolysis alters tooth development in transgenic mice expressing urokinase-type plasminogen activator in the enamel organ. Development 126:903–912

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the grants from the National Nature Science Foundation of China (No. 30471568) and the Scientific Research & Innovation Fund of the Third Military Medical University of China (XG 2006).

Conflict of interest statement

The authors state no conflict interest.

Author information

Authors and Affiliations

  1. Department of Cell Biology, College of Basic Medicine, Third Military Medical University, 400038, Chongqing, People’s Republic of China

    Qiangguo Gao, Xiaohua Lian, Jin Yu & Tian Yang

  2. Department of Haematology of Southwest Hospital, Third Military Medical University, 400038, Chongqing, People’s Republic of China

    Gang Fu

  3. Department of Medical Genetics, College of Basic Medicine, Third Military Medical University, 400038, Chongqing, People’s Republic of China

    Gang Huang

Authors
  1. Qiangguo Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gang Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaohua Lian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jin Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tian Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tian Yang.

Additional information

Q. Gao, G. Fu and G. Huang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gao, Q., Fu, G., Huang, G. et al. Relationship between urokinase plasminogen activator receptor (uPAR) and the invasion of human prenatal hair follicle. Arch Dermatol Res 302, 409–418 (2010). https://doi.org/10.1007/s00403-009-1010-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-009-1010-2

Keywords

Search

Navigation