Skip to main content

Advertisement

SpringerLink
Log in

Cysteine proteases: mode of action and role in epidermal differentiation

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Desquamation or cell shedding in mammalian skin is known to involve serine proteases, aspartic proteases and glycosidases. In addition, evidence continues to accumulate that papain-like cysteine proteases and an inhibitor cystatin M/E largely confined to the cutaneous epithelia also play key roles in the process. This involves the complete proteolysis of cell adhesive structures of the stratum corneum, the corneodesmosomes and notably of the desmogleins. Continual cell replacement in the epidermis is the result of the balance between the loss of the outer squames and mitosis of the cells in the basal cell layer. This article provides a brief account of the salient features of the characteristics and catalytic mechanism of cysteine proteases, followed by a discussion of the relevant epidermal biology. The proteases include the asparaginyl endopeptidase legumain, which exerts a strict specificity for the hydrolysis of asparaginyl bonds, cathepsin-V and cathepsin-L. The control of these enzymes by cystatin M/E regulates the processing of transglutaminases and is crucial in the biochemical pathway responsible for regulating the cross-linking and desquamation of the stratum corneum. In addition, caspase-14 has now been shown to play a major part in epidermal maturation. Uncontrolled proteolytic activity leads to abnormal hair follicle formation and deleterious effects on the skin barrier function.

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

Similar content being viewed by others

References

  • Abrahamson M, Alvarez-Fernandez M, Nathanson CM (2003) Cystatins. Biochem Soc Symp 70:179–199

    PubMed  CAS  Google Scholar 

  • Akgül B, Cooke JC, Storey A (2006) HPV-associated skin disease. J Pathol 208:165–175

    Article  PubMed  Google Scholar 

  • Barrett AJ, Rawlings ND, Woessner JF (2004) Handbook of proteolytic enzymes. Elsevier, London

    Google Scholar 

  • Benavides F, Starost MF, Flores M, Gimenez-Conti IB, Guenet JL, Conti CJ (2002) Impaired hair follicle morphogenesis and cycling with abnormal epidermal differentiation in nackt mice, a cathepsin L-deficient mutation. Am J Pathol 161:693–703

    Article  PubMed  CAS  Google Scholar 

  • Blaydon DC, Nitoiu D, Eckl KM, Cabral RM, Bland P, Hausser I, Heel DA van, Rajpopat S, Fischer J, Oji V, Zvulunov A, Traupe H, Hennies HC, Kelsell DP (2011) Mutations in CSTA, encoding Cystatin A, underlie exfoliative ichthyosis and reveal a role for this protease inhibitor in cell-cell adhesion. Am J Hum Genet 89:564–571

    Google Scholar 

  • Brocklehurst K (1982) Two–protonic-state electrophiles as probes of enzyme mechanism. Methods Enzymol 87:427–469

    Article  PubMed  CAS  Google Scholar 

  • Brocklehurst K (1994) A sound basis for pH-dependent kinetic studies on enzymes. Protein Eng 7:291–299

    Article  PubMed  CAS  Google Scholar 

  • Brocklehurst K, Little G (1970) A novel reactivity of papain and a convenient active site titration in the presence of other thiols. FEBS Lett 9:113–116

    Article  PubMed  CAS  Google Scholar 

  • Brocklehurst K, Carlsson J, Kierston MPJ, Crook EM (1973) Covalent chromatography: preparation of fully active papain from dried papaya latex. Biochem J 133:573–584

    PubMed  CAS  Google Scholar 

  • Brocklehurst K, Carlsson J, Kierston MPJ, Crook EM (1974) Covalent chromatography by thiol-disulphide interchange. Methods Enzymol 34:531–544

    Article  PubMed  CAS  Google Scholar 

  • Brocklehurst K, Carey PR, Lee H, Salih E, Storer AC (1984) Comparative resonance Raman spectroscopic and kinetic studies of acyl enzymes involving papain, actinidin and papaya peptidase II. Biochem J 233:649–657

    Google Scholar 

  • Brocklehurst K, Willenbrook F, Salih E (1987) Cysteine proteinases. In: Neuberger A, Brocklehurst K (eds) Hydrolytic enzymes. New comprehensive biochemistry, vol 16. Elsevier, Amsterdam, pp 39–158

    Chapter  Google Scholar 

  • Brocklehurst K, Watts AB, Patel M, Verma C, Thomas EW (1998) Cysteine proteinases. In: Sinnott ML (ed) Comprehensive biological catalysis, vol 1. Academic Press, London, pp 381–423

    Google Scholar 

  • Brocklehurst K, Courey AJ, Gul S, Lin S-H, Moritz RL (2004) Affinity and immunoaffinity chromatography. In: Simpson RJ (ed) Purifying proteins for proteomics. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 221–273

    Google Scholar 

  • Brocklehurst K, Gul S, Pickersgill RW (2009) Substrate recognition. In: Hughes AB (ed) Amino acids peptides and proteins in organic chemistry, vol 2. Modified amino acids organocatalysis and enzymes. Wiley—VCH, Weinheim, pp 473–504

    Google Scholar 

  • Candi E, Schmidt R, Melina G (2005) The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol 6:328–340

    Article  PubMed  CAS  Google Scholar 

  • Cheng T, Hitomi K, Ivonne MJ, Van Wlijmen-Willems J, Le Jongh GJ, Yamamoto K, Nishi K, Watts C, Reinheckel T, Schalkwijk J, Zeeuwen PL (2006) Cystatin M/E is a high affirmity inhibitor of cathepsin V and cathepsin L by a reactive site that is distinct from the legumain—binding site. A novel clue for the role of cystatin M/E in epidermal cornification. J Biol Chem 281:15893–15899

    Article  PubMed  CAS  Google Scholar 

  • Cheng T, Tjabringa GS, Van Vlijmen-Willems IM, Hitomi K, Van Erp PE, Schalkwijk J, Zeeuwen PL (2009) The cystatin M/E controlled pathway of skin barrier formation: expression of its key components in psoriasis and atopic dermatitis. Br J Dermatol 161:253–264

    Google Scholar 

  • Cornish-Bowden A (2002) Enthalpy-entropy compensation: a phantom phenomenon. J Biosci 27:121–126

    Article  PubMed  Google Scholar 

  • Denecker G, Hoste E, Gilbert B, Hochepied T, Ovaere P, Lippens S (2007) Caspase-14 protects against epidermal UVB photo damage and water loss. Nat Cell Biol 9:666–674

    Article  PubMed  CAS  Google Scholar 

  • Denecker G, Ovaere P, Petal V (2008) Caspase-14 reveals its secrets. J Cell Biol 180:451–458

    Article  PubMed  CAS  Google Scholar 

  • Dennemärker J, Lohmüller T, Mayerle J, Tacke M, Lerch MM, Coussens LM, Peters C, Reinheckel T (2010) Deficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermis. Oncogene 29:1611–1621

    Article  PubMed  Google Scholar 

  • Devos M, Prawitt J, Staumont-Salle D, Hoste E, Fleury S, Bouchaert E, Gilbert B, Lippens S, Vandenabeele P, Dombrowicz D, Declercq W (2012) Filaggrin degradation by caspase-14 is required for UVB photoprotection but does not influence allergic sensitization in a mouse model of atopic dermatitis. J Invest Dermatol 132:2857-2860

    Article  PubMed  CAS  Google Scholar 

  • Drenth J, Kalk KH, Swen HM (1976) Binding of chloromethyl ketone substrate analogues to crystalline papain. Biochemistry 15:3731–3738

    Article  PubMed  CAS  Google Scholar 

  • Dunitz JD (1995) Win some lose some: enthalpy-entropy compensation in weak intermolecular interactions. Chem Biol 2:709–712

    Article  PubMed  CAS  Google Scholar 

  • Eckhart L, Declercq W, Ban J, Rendl M, Lengauer B, Mayer C, Lippens S, Vandenabeele P, Tschachler E (2000) Terminal differentiation of human keratinocytes and stratum corneum formation is associated with caspase-14 activation. J Invest Dermatol 115:1148–1151

    Article  PubMed  CAS  Google Scholar 

  • Eckhart L, Ballaun C, Uthman A, Kittel C, Stichenwirth M, Buchberger M, Fischer H, Sipos W, Tschachler E (2005) Identification and characterization of a novel mammalian caspase with proapoptotic activity. J Biol Chem 280:35077–35080

    Article  PubMed  CAS  Google Scholar 

  • Fischer H, Stichenwirth M, Dockal M, Ghannadan M, Buchberger M, Bach J, Kapetanopoulos A, Declercq W, Tschachler E, Eckhart L (2004) Stratum corneum-derived caspase-14 is catalytically active. FEBS Lett 577:446–450

    Article  PubMed  CAS  Google Scholar 

  • Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nuñez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon HU, Vandenabeele P, White E, Yuan J, Zhivotovsky B, Melino G, Kroemer G (2012) Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ 19:107–120

    Article  PubMed  CAS  Google Scholar 

  • Gul G, Mellor GW, Thomas EW, Brocklehurst K (2006) Temperature dependences of the kinetics of the reactions of papain and actinidin with a series of recovering probes differing in key molecular recognition features. Biochem J 396:17–21

    Article  PubMed  CAS  Google Scholar 

  • Gul G, Hussain S, Thomas MP, Resmini M, Verma CS, Thomas EW, Brocklehurst K (2008) Generation of nucleophilic character in the Cys 25/His 159 ion-pair of papain involves Trp177 but not Asp158. Biochemistry 47:2025–2035

    Article  PubMed  CAS  Google Scholar 

  • Hagemann S, Gunther T, Dennemarker J, Lohmuller T, Bromme D, Schule R (2004) The human cysteine protease cathepsin V can compensate for murine cathepsin L in mouse epidermis and hair follicles. Eur J Cell Biol 83:775–780

    Article  PubMed  CAS  Google Scholar 

  • Hene IB, Mattis JA, Fruton JS (1979) Interaction of papain with derivatives of phenylalanylglycinal: fluorescence studies. Proc Natl Acad Sci USA 76:1131–1134

    Article  Google Scholar 

  • Hussain S, Khan A, Brocklehurst K (2002) A review of developments in the study of cysteine proteinase mechanism: opportunities for investigation of electrostatic effects and dynamic aspects of molecular recognition in enzyme chemistry. Recent Res Dev Biochem 3:653–677

    CAS  Google Scholar 

  • Hussain S, Pinitglang S, Bailey TSF, Reid JD, Noble MA, Resmini M, Thomas EW, Greaves RB, Verma CS, Brocklehurst K (2003) Variation in the pH-dependent pre-steady-state and steady-state kinetic characteristics of cysteine-proteinase mechanism: evidence for electrostatic modulation of catalytic-site function by the neighbouring carboxylate anion. Biochem J 372:735–746

    Article  PubMed  CAS  Google Scholar 

  • Hussain S, Khan A, Gul S, Resmini M, Verma CS, Thomas EW, Brocklehurst K (2011) Identification of interactions involved in the generation of nucleophilic reactivity and of catalytic competence in the catalytic site Cys/His ion-pair of papain. Biochemistry 50:10732–10742

    Article  PubMed  CAS  Google Scholar 

  • Huber CP, Ozaki Y, Pliura DH, Storer AC, Carey PR (1982) Precise structural information for transient enzyme-substrate complexes by a combined X-ray crystallographic-resonance Raman spectroscopic approach. Biochemisrry 21:3109-3115

    Article  CAS  Google Scholar 

  • Kato T, Takai T, Mitsuishi K, Okumura K, Ogawa H (2005) Cystatin A inhibits IL-8 production by keratinocytes stimulated with Der p 1 and Der f 1: biochemical skin barrier against mite cysteine proteases. J Allergy Clin Immunol 116:169–176

    Article  PubMed  CAS  Google Scholar 

  • Kazem S, Meijden E van der, Struijk L, Gruijl FR de, Feltkamp MC (2012) Human papillomavirus 8 E6 disrupts terminal skin differentiation and prevents pro-Caspase-14 cleavage. Virus Res 163:609–616

    Google Scholar 

  • Koenig U, Eckhart L, Tschachler E (2001) Evidence that caspase-13 is not a human but a bovine gene. Biochem Biophys Res Commun 285:1150–1154

    Article  PubMed  CAS  Google Scholar 

  • Kovalenko A, Kim JC, Kang TB, Rajput A, Bogdanov K, Dittrich-Breiholz O, Kracht M, Brenner O, Wallach D (2009) Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease. J Exp Med 206:2161–2177

    Article  PubMed  CAS  Google Scholar 

  • Kowlessur D, Topham CM, Thomas EW, O’Driscoll M, Templeton W, Brocklehurst K (1989) Identification of signalling and non-signalling binding contributions to enzyme reactivity. Alternate contributions of binding interactions provide for change in transition state geometry in reaction of papain. Biochem J 258:755–764

    PubMed  CAS  Google Scholar 

  • Krug RR, Hunter WG, Greiger RA (1976a) Enthalpy-entropy compensation. 1. Some fundamental statistical problems associated with the analysis of Van’t Hoff and Arrhenius data. J Phys Chem 80:2335–2340

    Article  CAS  Google Scholar 

  • Krug RR, Hunter WG, Greiger RA (1976b) Enthalpy-entropy compensation. 2. Separation of the chemical from the statistical effect. J Phys Chem 80:2341–2351

    Article  CAS  Google Scholar 

  • Lee P, Lee DJ, Chan C, Chen SW, Chen I, Jamora C (2009) Dynamic expression of epidermal caspase 8 simulates a wound healing response. Nature 458:519–523

    Article  PubMed  CAS  Google Scholar 

  • Lippens S, Kockx M, Knaapen M, Mortier L, Polakowska R, Verheyen A, Garmyn M, Zwijsen A, Formstecher P, Huylebroeck D, Vandenabeele P, Declercq W (2000) Epidermal differentiation does not involve the pro-apoptotic executioner caspases, but is associated with caspase-14 induction and processing. Cell Death Differ 7:1218–1224

    Article  PubMed  CAS  Google Scholar 

  • Lippens S, Kockx M, Denecker G, Knaapen M, Verheyen A, Christiaen R, Tschachler E, Vandenabeele P, Declercq W (2004) Vitamin D3 induces caspase-14 expression in psoriatic lesions and enhances caspase-14 processing in organotypic skin cultures. Am J Pathol 165:833–841

    Article  PubMed  CAS  Google Scholar 

  • Lowe G (1976) The cysteine proteinases. Tetrahedron 32:291–302

    Article  CAS  Google Scholar 

  • Lowe G, Williams A (1965) Direct evidence for an acylated thiol as an intermediate in papain– and ficin–catalysed hydrolysis. Biochem J 96:189–193

    PubMed  CAS  Google Scholar 

  • Mellor GW, Thomas EW, Topham CM, Brocklehurst K (1993) The ionization characteristics of the Cys 25–His 159 interactive system and of the modulatory group of papain. Resolution of ambiguity by electronic perturbation of the quasi-2-mercaptopyridine leaving group in a new pyrimidyl disulphide reactivity probe. Biochem J 290:75–83

    PubMed  CAS  Google Scholar 

  • Menard R, Carriere J, Laflamme P, Plouffe C, Khouri H, Vernet T, Tessier DC, Thomas DY, Storer AC (1991) Contribution of the glutamine 19 sidechain to transition state stabilization in the oxyarion hole of papain. Biochemistry 30:8924–8928

    Article  PubMed  CAS  Google Scholar 

  • Menard R, Plouffe C, Laflamme P, Vernet T, Tessier DC, Thomas DY, Storer AC (1995) Modification of the electrostatic environment is tolerated in the oxyarion hole of the cysteine protease papain. Biochemistry 34:464–471

    Article  PubMed  CAS  Google Scholar 

  • Mielgo A, Torres VA, Schmid MC, Graf R, Zeitlin SG, Lee P, Shields DJ, Barbero S, Jamora C, Stupack DG (2009) The death effector domains of caspase-8 induce terminal differentiation. PLoS One 4:e7879

    Article  PubMed  Google Scholar 

  • Noble MA, Gul S, Verma CS, Brocklehurst K (2000) The ionization characteristics and chemical influences of aspartic acid residue 158 of papain and caricain determined by structure-related kinetic and computational techniques: multiple electrostatic modulators of active centre chemistry. Biochem J 351:723–733

    Article  PubMed  CAS  Google Scholar 

  • Patel M, Kayani S, Templeton W, Mellor GW, Thomas EW, Brocklehurst K (1992) Evaluation of hydrogen bonding and enantiomeric P2-S2 hydrophobic contacts in dynamic aspects of molecular recognition by papain. Biochem J 287:881–889

    PubMed  CAS  Google Scholar 

  • Pinitglang S, Watts AB, Patel M, Reid JD, Noble MA, Gul S, Bokth A, Naeem A, Patel H, Thomas EW, Sreedharan S, Verma C, Brocklehurst K (1997) A classical enzyme active centre motif lacks catalytic competence until modulated electrostatically. Biochemistry 36:9968–9982

    Article  PubMed  CAS  Google Scholar 

  • Raymond AA, Méchin MC, Nachat R, Toulza E, Tazi-Ahnini R, Serre G, Simon M (2007) Nine procaspases are expressed in normal human epidermis, but only caspase-14 is fully processed. Br J Dermatol 156:420–427

    Article  PubMed  CAS  Google Scholar 

  • Reid JD, Hussain S, Sreedharan SK, Bailey TSF, Pinitglan S, Thomas EW, Verma CS, Brocklehurst K (2001) Variation in aspects of cysteine proteinase catalytic mechanism deduced spectroscopic observation of dithioester intermediates, kinetic analysis and molecular dynamics simulations. Biochem J 357:343–352

    Article  PubMed  CAS  Google Scholar 

  • Reinheckel T, Hagemann S, Dollwet-Mack S, Martinez E, Lohmuller T, Zlatkovic G (2005) The lysosomal cysteine protease cathepsin L regulates keratinocyte proliferation by control of growth factor recycling. J Cell Sci 118:3387–3395

    Article  PubMed  CAS  Google Scholar 

  • Roth W, Deussing J, Botchkarev VA, Pauly-Evers M, Saftig P, Hafner A (2000) Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling. FASEB J 14:2075–2086

    Article  PubMed  CAS  Google Scholar 

  • Rubach JK, Cui G, Schneck JL, Taylor AN, Zhao B, Smallwood A, Nevins N, Wisnoski D, Thrall SH, Meek TD (2012) The amino-acid substituents of dipeptide substrates of cathepsin C can determine the rate-limiting steps of catalysis.Biochemistry (in press)

  • Samuelsson L, Stiller C, Friberg C, Nilsson C, Inerot A, Wahlström J (2004) Association analysis of cystatin A and zinc finger protein 148, two genes located at the psoriasis susceptibility locus PSORS5. J Invest Dermatol 122:1399–1400

    Article  PubMed  CAS  Google Scholar 

  • Simpson RJ (2004) Purifying proteins for proteomics: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY

    Google Scholar 

  • Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y (2006) Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 38:337–342

    Article  PubMed  CAS  Google Scholar 

  • Steven AC, Steinert PM (1994) Protein composition of cornified cell envelopes of epidermal keratinocytes. J Cell Sci 107:693–700

    PubMed  CAS  Google Scholar 

  • Storer AC, Lee H, Carey PR (1983) Relaxed and perturbed substrate conformations in enzyme active sites: evidence from multichannel resonance Raman spectra.Biochemistry 22:4789-4796

    Article  PubMed  CAS  Google Scholar 

  • Sundberg JP, Boggess D, Hogan ME, Sundberg BA, Rourk MH, Harris B (1997) Harlequin ichthyosis (ichq): a juvenile lethal mouse mutation with ichthyosiform dermatitis. Am J Pathol 151:293–310

    PubMed  CAS  Google Scholar 

  • Tholen S, Biniossek ML, Gansz M, Gomez-Auli A, Werner F, Noel A, Kizhakkedathu JN, Boerries M, Busch H, Reinheckel T, Schilling O (2012) Deletion of cysteine cathepsins B or L yields differential impacts on murine skin proteome and degradome. Mol Cell Proteomics (in press)

  • Turk V, Turk B, Turk D (2001) Lysosomal cysteine proteases: facts and opportunities.EMBO J 20:4629-4633

    Article  PubMed  CAS  Google Scholar 

  • Van de Craen M, Vandenabeele P, Declercq W, Van den Brande I, Van Loo G, Molemans F, Schotte P, Van Criekinge W, Beyaert R, Fiers W (1997) Characterization of seven murine caspase family members. FEBS Lett 403:61–69

    Article  PubMed  Google Scholar 

  • Vasilopoulos Y, Sagoo GS, Cork MJ, Walters K, Tazi-Ahnini R (2011) HLA-C, CSTA and DS12346 susceptibility alleles confer over 100-fold increased risk of developing psoriasis: evidence of gene interaction. J Hum Genet 56:423–427

    Article  PubMed  CAS  Google Scholar 

  • Wu NL, Lee TA, Tsai TL, Lin WW (2011) TRAIL-induced keratinocyte differentiation requires caspase activation and p63 expression. J Invest Dermatol 131:874–883

    Article  PubMed  CAS  Google Scholar 

  • Yuan J (2006) Divergence from a dedicated cellular suicide mechanism: exploring the evolution of cell death. Mol Cell 23:1–12

    Article  PubMed  Google Scholar 

  • Zeeuwen PL, Vlijmen-Willems IM, Jansen BJ, Sotiropoulou G, Curfs JH, Meis JF (2001) Cystatin M/E expression is restricted to differentiated epidermal keratinocytes and sweat glands: a new skin-specific proteinase inhibitor that is a target for cross-linking by transglutaminase. J Invest Dermatol 116:693–701

    Article  PubMed  CAS  Google Scholar 

  • Zeeuwen PL, Vlijmen-Willems IM, Hendriks W (2002) A null mutation in the cystatin M/E gene of ichq mice causes juvenile lethality and defects in epidermal cornification. Hum Mol Genet 11:2867–2875

    Article  PubMed  CAS  Google Scholar 

  • Zeeuwen PL, Dale BA, De Jongh G, Vlijmen-Willems IM, Fleckman P, Kimball JR (2003) The human cystatin M/E gene (CST6): exclusion as a candidate gene for harlequin ichthyosis. Invest Dermatol 121:65–68

    Article  CAS  Google Scholar 

  • Zeeuwen PL, Van Vlijmen-Willems IM, Olthuis D, Johansen HT, Hitomi K, Hara-Nishimura I, Powers JC, James KE, Camp HJ op den, Lemmens R, Schalkwijk J (2004) Evidence that unrestricted legumain activity is involved in disturbed epidermal cornification in cystatin M/E deficient mice.Hum Mol Genet 13:1069-1079

    Google Scholar 

  • Zeeuwen PLJM, Ishida-Yamamoto A, Van Vlijmen-Willems IMJJ, Cheng T, Berges M, Iizuka H, Schalwijk J (2007) Colocalization of cystatin M/E and cathepsin V in lamellar granules and corneodesmosomes suggests a functional role in epidermal differentiation. J Invest Dermatol 127:120–128

    Article  PubMed  CAS  Google Scholar 

  • Zeeuwen PL, Cheng T, Schalwijk J (2009) The biology of cystatin M/E and its cognate target protease. J Invest Dermatol 129:1327–1338

    Article  PubMed  CAS  Google Scholar 

  • Zeeuwen PL, Van Vlijmen-Willems IM, Cheng T, Rodijk-Olthuis D, Hitomi K, Hara-Nishimura I, John S, Smyth N, Reinheckel T, Hendriks WJ, Schalkwijk J (2010) The cystatin M/E-cathepsin L balance is essential for tissue homeostasis in epidermis, hair follicles, and cornea. FASEB J 24:3744–3755

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Biological and Chemical Sciences, Queen Mary University of London, London, UK

    Keith Brocklehurst

  2. Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Mike P. Philpott

Authors
  1. Keith Brocklehurst
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mike P. Philpott
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mike P. Philpott.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brocklehurst, K., Philpott, M.P. Cysteine proteases: mode of action and role in epidermal differentiation. Cell Tissue Res 351, 237–244 (2013). https://doi.org/10.1007/s00441-013-1557-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-013-1557-2

Keywords

Search

Navigation