Cell and Tissue Research

, Volume 351, Issue 2, pp 301–307 | Cite as

Rhomboid proteins: a role in keratinocyte proliferation and cancer

  • Sarah L. Etheridge
  • Matthew A. Brooke
  • David P. Kelsell
  • Diana C. BlaydonEmail author


The Rhomboids represent a relatively recently discovered family of proteins, consisting in a variety of intramembrane serine proteases and their inactive homologues, the iRhoms. Rhomboids typically contain six or seven transmembrane domains (TMD) and have been classified into four subgroups: Secretase A and B, Presenilin-Associated-Rhomboid-Like (PARL) and iRhoms. Although the iRhoms, iRhom1 and iRhom2, have lost their protease activity during evolution, they retain key non-protease functions and have been implicated in the regulation of epidermal growth factor (EGF) signalling. EGF is moreover a substrate of RHBDL2, their active Rhomboid relative. Other substrates of RHBDL2 include members of the EphrinB family and thrombomodulin. RHBDL2 has also previously been demonstrated to be important in wound healing in cutaneous keratinocytes through the cleavage of thrombomodulin. Additional roles for these intriguing proteins seem likely to be revealed in the future. This review focuses on our current understanding of Rhomboids and, in particular, on RHBDL2 and iRhom2 and their roles in cellular processes and human disease.


Rhomboid proteins iRhom2 Tylosis EGFR signalling ADAM17 


  1. Adrain C, Strisovsky K, Zettl M, Hu L, Lemberg MK, Freeman M (2011) Mammalian EGF receptor activation by the rhomboid protease RHBDL2. EMBO Reports 12:421–427PubMedCrossRefGoogle Scholar
  2. Adrain C, Zettl M, Christova Y, Taylor N, Freeman M (2012) Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE. Science 335:225–228PubMedCrossRefGoogle Scholar
  3. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M (2008) Growth factors and cytokines in wound healing. Wound Repair Regen 16:585–601PubMedCrossRefGoogle Scholar
  4. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, et al (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385:729–733PubMedCrossRefGoogle Scholar
  5. Blaydon DC, Biancheri P, Di WL, Plagnol V, Cabral RM, Brooke MA, et al (2011) Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med 365:1502–1508PubMedCrossRefGoogle Scholar
  6. Blaydon DC, Etheridge SL, Risk JM, Hennies HC, Gay LJ, Carroll R, et al (2012) RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Am J Hum Genet 90:340–346PubMedCrossRefGoogle Scholar
  7. Blobel CP (2005) ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol 6:32–43PubMedCrossRefGoogle Scholar
  8. Cheng TL, Wu YT, Lin HY, Hsu FC, Liu SK, Chang BI, Chen WS, Lai CH, Shi GY, Wu HL (2011) Functions of Rhomboid family protease RHBDL2 and thrombomodulin in wound healing. J Invest Dermatol 131:2486–2494PubMedCrossRefGoogle Scholar
  9. Ellis A, Field JK, Field EA, Friedmann PS, Fryer A, Howard P, Leigh IM, Risk J, Shaw JM, Whittaker J (1994) Tylosis associated with carcinoma of the oesophagus and oral leukoplakia in a large Liverpool family—a review of six generations. Eur J Cancer B Oral Oncol 30B:102–112PubMedCrossRefGoogle Scholar
  10. Esmon CT (1995) Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB J 9:946–955PubMedGoogle Scholar
  11. Foltenyi K, Greenspan RJ, Newport JW (2007) Activation of EGFR and ERK by rhomboid signaling regulates the consolidation and maintenance of sleep in Drosophila. Nat Neurosci 10:1160–1167PubMedCrossRefGoogle Scholar
  12. Freeman M (2008) Rhomboid proteases and their biological functions. Annu Rev Genet 42:191–210PubMedCrossRefGoogle Scholar
  13. Freeman M (2009) Rhomboids: 7 years of a new protease family. Semin Cell Dev Biol 20:231–239PubMedCrossRefGoogle Scholar
  14. Hamada H, Ishii H, Sakyo K, Horie S, Nishiki K, Kazama M (1995) The epidermal growth factor-like domain of recombinant human thrombomodulin exhibits mitogenic activity for Swiss 3 T3 cells. Blood 86:225–233PubMedGoogle Scholar
  15. Hennies HC, Hagedorn M, Reis A (1995) Palmoplantar keratoderma in association with carcinoma of the esophagus maps to chromosome 17q distal to the keratin gene cluster. Genomics 29:537–540PubMedCrossRefGoogle Scholar
  16. Huovila AP, Turner AJ, Pelto-Huikko M, Karkkainen I, Ortiz RM (2005) Shedding light on ADAM metalloproteinases. Trends Biochem Sci 30:413–422PubMedCrossRefGoogle Scholar
  17. Hynes NE (2005) Receptor tyrosine kinases as therapeutic targets in cancer. Discov Med 5:483–488PubMedGoogle Scholar
  18. Koonin EV, Makarova KS, Rogozin IB, Davidovic L, Letellier MC, Pellegrini L (2003) The rhomboids: a nearly ubiquitous family of intramembrane serine proteases that probably evolved by multiple ancient horizontal gene transfers. Genome Biol 4:R19PubMedCrossRefGoogle Scholar
  19. Lager DJ, Callaghan EJ, Worth SF, Raife TJ, Lentz SR (1995) Cellular localization of thrombomodulin in human epithelium and squamous malignancies. Am J Pathol 146:933–943PubMedGoogle Scholar
  20. Lei X, Li YM (2009) The processing of human rhomboid intramembrane serine protease RHBDL2 is required for its proteolytic activity. J Mol Biol 394:815–825PubMedCrossRefGoogle Scholar
  21. Lemberg MK, Freeman M (2007a) Cutting proteins within lipid bilayers: Rhomboid structure and mechanism. Mol Cell 28:930–940PubMedCrossRefGoogle Scholar
  22. Lemberg MK, Freeman M (2007b) Functional and evolutionary implications of enhanced genomic analysis of rhomboid intramembrane proteases. Genome Res 17:1634–1646PubMedCrossRefGoogle Scholar
  23. Lemieux MJ, Fischer SJ, Cherney MM, Bateman KS, James MN (2007) The crystal structure of the rhomboid peptidase from Haemophilus influenzae provides insight into intramembrane proteolysis. Proc Natl Acad Sci USA 104:750–754PubMedCrossRefGoogle Scholar
  24. Lohi O, Urban S, Freeman M (2004) Diverse substrate recognition mechanisms for rhomboids; thrombomodulin is cleaved by mammalian rhomboids. Curr Biol 14:236–241PubMedGoogle Scholar
  25. McIlwain DR, Lang PA, Maretzky T, Hamada K, Ohishi K, Maney SK, et al (2012) iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS. Science 335:229–232PubMedCrossRefGoogle Scholar
  26. Mizutani H, Hayashi T, Nouchi N, Ohyanagi S, Hashimoto K, Shimizu M, Suzuki K (1994) Functional and immunoreactive thrombomodulin expressed by keratinocytes. J Invest Dermatol 103:825–828PubMedCrossRefGoogle Scholar
  27. Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, et al (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385:733–736PubMedCrossRefGoogle Scholar
  28. Nakagawa T, Guichard A, Castro CP, Xiao Y, Rizen M, Zhang HZ, Hu D, Bang A, Helms J, Bier E, Derynck R (2005) Characterization of a human rhomboid homolog, p100hRho/RHBDF1, which interacts with TGF-alpha family ligands. Dev Dyn 233:1315–1331PubMedCrossRefGoogle Scholar
  29. Pasquale EB (2005) Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol 6:462–475PubMedCrossRefGoogle Scholar
  30. Pasquale EB (2008) Eph-ephrin bidirectional signaling in physiology and disease. Cell 133:38–52PubMedCrossRefGoogle Scholar
  31. Pasquale EB (2010) Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer 10:165–180PubMedCrossRefGoogle Scholar
  32. Pascall JC, Brown KD (2004) Intramembrane cleavage of ephrinB3 by the human rhomboid family protease, RHBDL2. Biochem Biophys Res Commun 317:244–252PubMedCrossRefGoogle Scholar
  33. Peterson JJ, Rayburn HB, Lager DJ, Raife TJ, Kealey GP, Rosenberg RD, Lentz SR (1999) Expression of thrombomodulin and consequences of thrombomodulin deficiency during healing of cutaneous wounds. Am J Pathol 155:1569–1575PubMedCrossRefGoogle Scholar
  34. Raife TJ, Demetroulis EM, Lentz SR (1996) Regulation of thrombomodulin expression by all-trans retinoic acid and tumor necrosis factor-alpha: differential responses in keratinocytes and endothelial cells. Blood 88:2043–2049PubMedGoogle Scholar
  35. Raife TJ, Lager DJ, Madison KC, Piette WW, Howard EJ, Sturm MT, Chen Y, Lentz SR (1994) Thrombomodulin expression by human keratinocytes. Induction of cofactor activity during epidermal differentiation. J Clin Invest 93:1846–1851PubMedCrossRefGoogle Scholar
  36. Raife TJ, Lager DJ, Peterson JJ, Erger RA, Lentz SR (1998) Keratinocyte-specific expression of human thrombomodulin in transgenic mice: effects on epidermal differentiation and cutaneous wound healing. J Invest Med 46:127–133Google Scholar
  37. Rechsteiner M (1988) Regulation of enzyme levels by proteolysis: the role of pest regions. Adv Enzym Regul 27:135–151CrossRefGoogle Scholar
  38. Saarinen S, Vahteristo P, Lehtonen R, Aittomäki K, Launonen V, Kiviluoto T, Aaltonen LA (2012) Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer. Fam Cancer 11:525–528PubMedCrossRefGoogle Scholar
  39. Sahin U, Blobel CP (2007) Ectodomain shedding of the EGF-receptor ligand epigen is mediated by ADAM17. FEBS Lett 581:41–44PubMedCrossRefGoogle Scholar
  40. Sahin U, Weskamp G, Kelly K, Zhou HM, Higashiyama S, Peschon J, Hartmann D, Saftig P, Blobel CP (2004) Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J Cell Biol 164:769–779PubMedCrossRefGoogle Scholar
  41. Salomon DS, Brandt R, Ciardiello F, Normanno N (1995) Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183–232PubMedCrossRefGoogle Scholar
  42. Senet P, Peyri N, Berard M, Dubertret L, Boffa MC (1997) Thrombomodulin, a functional surface protein on human keratinocytes, is regulated by retinoic acid. Arch Dermatol Res 289:151–157PubMedCrossRefGoogle Scholar
  43. Shi CS, Shi GY, Chang YS, Han HS, Kuo CH, Liu C, Huang HC, Chang YJ, Chen PS, Wu HL (2005) Evidence of human thrombomodulin domain as a novel angiogenic factor. Circulation 111:1627–1636PubMedCrossRefGoogle Scholar
  44. Stevens HP, Kelsell DP, Bryant SP, Bishop DT, Spurr NK, Weissenbach J, Marger D, Marger RS, Leigh IM (1996) Linkage of an American pedigree with palmoplantar keratoderma and malignancy (palmoplantar ectodermal dysplasia type III) to 17q24. Literature survey and proposed updated classification of the keratodermas. Arch Dermatol 132:640–651PubMedCrossRefGoogle Scholar
  45. Sturtevant MA, Roark M, Bier E (1993) The Drosophila rhomboid gene mediates the localized formation of wing veins and interacts genetically with components of the EGF-R signaling pathway. Genes Dev 7:961–973PubMedCrossRefGoogle Scholar
  46. Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, et al (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 101:6062–6067PubMedCrossRefGoogle Scholar
  47. Tokumaru S, Higashiyama S, Endo T, Nakagawa T, Miyagawa JI, Yamamori K, et al (2000) Ectodomain shedding of epidermal growth factor receptor ligands is required for keratinocyte migration in cutaneous wound healing. J Cell Biol 151:209–220PubMedCrossRefGoogle Scholar
  48. Urban S, Freeman M (2003) Substrate specificity of rhomboid intramembrane proteases is governed by helix-breaking residues in the substrate transmembrane domain. Mol Cell 11:1425–1434PubMedCrossRefGoogle Scholar
  49. Urban S, Lee JR, Freeman M (2001) Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107:173–182PubMedCrossRefGoogle Scholar
  50. Vembar SS, Brodsky JL (2008) One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 9:944–957PubMedCrossRefGoogle Scholar
  51. Wang Y, Zhang Y, Ha Y (2006) Crystal structure of a rhomboid family intramembrane protease. Nature 444:179–180PubMedCrossRefGoogle Scholar
  52. Wasserman JD, Urban S, Freeman M (2000) A family of rhomboid-like genes: Drosophila rhomboid-1 and roughoid/rhomboid-3 cooperate to activate EGF receptor signaling. Genes Dev 14:1651–1663PubMedGoogle Scholar
  53. Weiler H, Isermann BH (2003) Thrombomodulin. J Thromb Haemost 1:1515–1524PubMedCrossRefGoogle Scholar
  54. Yan Z, Zou H, Tian F, Grandis JR, Mixson AJ, Lu PY, Li LY (2008) Human rhomboid family-1 gene silencing causes apoptosis or autophagy to epithelial cancer cells and inhibits xenograft tumor growth. Mol Cancer Ther 7:1355–1364PubMedCrossRefGoogle Scholar
  55. Zettl M, Adrain C, Strisovsky K, Lastun V, Freeman M (2011) Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular signaling. Cell 145:79–91PubMedCrossRefGoogle Scholar
  56. Zou H, Thomas SM, Yan ZW, Grandis JR, Vogt A, Li LY (2009) Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation of EGFR growth signals in head and neck squamous cancer cells. FASEB J 23:425–432PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Sarah L. Etheridge
    • 1
  • Matthew A. Brooke
    • 1
  • David P. Kelsell
    • 1
  • Diana C. Blaydon
    • 1
    Email author
  1. 1.Centre for Cutaneous Research, Blizard InstituteBarts and the London School of Medicine and Dentistry, Queen Mary University of LondonLondonUK

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