European Epidermal Barrier Research Network

European Epidermal Barrier Research Network

European Epidermal Barrier Research Network

European Epidermal Barrier Research Network

Research Focus

  1. The role of proteases and protease inhibitors in epidermal differentiation and desquamation

  2. The role of transglutaminases in epidermal cornification

  3. Mouse models (transgenic and knockout) to study the role of proteases, protease inhibitors and transglutaminases in skin and other epithelia



e2brn - Research Focus Picture
A tentative model of the regulatory role of cystatin M/E in processes that control epidermal cornification and desquamation. Human cystatin M/E is an inhibitor of legumain (LGMN), cathepsin L (CTSL) and cathepsin V (CTSV). Inhibition of legumain regulates the processing of (pro)-cathepsins. Inhibition of cathepsin V regulates desquamation, as cathepsin V is able to degrade (corneo)-desmosomal proteins like desmoglein-1, desmocollin-1, and corneodesmosin. Inhibition of human cathepsin L activity by cystatin M/E is thought to be important in the cornification process, as cathepsin L is the elusive processing and activating enzyme for transglutaminase-3 (TGM3). Cathepsin L is also able to process cathepsin D (CTSD), which in turn can activate transglutaminase-1 (TGM1). As cathepsin V is only expressed in humans (pale blue oval), murine cathepsin L probably controls the specific functional enzymatic activities of both human cathepsin L and cathepsin V. Solid lines represent biochemical functions that are known from literature (grey) or deduced from our studies (black). Dashed lines represent unknown functions. BM, basal membrane; SB, stratum basale; SS, stratum spinosum; SG, stratum granulosum; SC, stratum corneum.

Figure from Zeeuwen et al 2010 FASEB J.24:3744-55


Important Publications

  1. de Koning,H.D., Kamsteeg,M., Rodijk-Olthuis,D., van Vlijmen-Willems,I.M., van Erp,P.E., Schalkwijk,J. and Zeeuwen,P.L. (2010) Epidermal expression of host response genes upon skin barrier disruption in normal skin and uninvolved skin of psoriasis and atopic dermatitis patients. J. Invest. Dermatol. Published online September 23, doi: 10.1038/jid.2010.278

  2. de Koning,H.D., Rodijk-Olthuis,D., van Vlijmen-Willems,I.M., Jooste,L.A., Netea,M.G., Schalkwijk,J. and Zeeuwen,P.L. (2010) A comprehensive analysis of pattern recognition receptors in normal and inflamed human epidermis: upregulation of dectin-1 in psoriasis. J. Invest. Dermatol. 130: 2611-20

  3. Zeeuwen,P.L., van Vlijmen-Willems,I.M., Rodijk-Olthuis,D., Cheng,T., Hitomi,K., Hara-Nishimura,I., John,S., Smyth,N., Reinheckel,T., Hendriks,W.J., and Schalkwijk,J. (2010) The cystatin M/E - cathepsin L balance is essential for tissue homeostasis in epidermis, hair follicles and cornea. FASEB J. 24:3744-55

  4. Cheng,T., Tjabringa,G.S., van Vlijmen-Willems,I.M., Hitomi,K., van Erp,P.E., Schalkwijk,J., and Zeeuwen,P.L. (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

  5. Zeeuwen,P.L., Cheng,T., and Schalkwijk,J. (2009) The biological role of cystatin M/E and its cognate target proteases. J.Invest.Dermatol. 129:1327-38

  6. de Cid,R.*, Riveira-Munoz,E*., Zeeuwen,P.L.*, Robarge,J.*, Liao,W., Dannhauser,E.N., Giardina,E., Stuart,P.E., Nair,R., Helms,S., Escaramis,G., Ballana,E., Martin-Ezquerra,G., den Heijer,M., Kamsteeg,M., Eichler,E.E., Lazara,C., Pujol,R.M., Armengol,L., Abecasis,G., Elder,J.T., Novelli,G., Armour,J.A., Kwok,P., Bowcock,A., Schalkwijk,J., and Estivill,X. (2009) Deletion of the late cornified envelope (LCE) 3C and 3B genes as a susceptibility factor for psoriasis. Nat Genet. 41:211-215. *shared first-authorship

  7. Cheng,T., van Vlijmen-Willems,I.M., Hitomi,K., Pash,M.C., van Erp,P.E., Schalkwijk,J., and Zeeuwen,P.L. (2008) Colocalization of cystatin M/E and its target proteases suggests a role in terminal differentiation of the human hair follicle and nail. J.Invest.Dermatol. 129:1232-42

  8. Zeeuwen,P.L., de Jongh,G.J., Rodijk-Olthuis,D., Kamsteeg,M., Verhoosel,R.M., van Rossum,M.M., Hiemstra,P.S., and Schalkwijk,J. (2008) Genetically programmed differences in epidermal host defense between psoriasis and atopic dermatitis. PLoS ONE 3(6): e2301

  9. Zeeuwen,P.L., Ishida-Yamamoto,A., van Vlijmen-Willems,I.M., Cheng,T., Bergers,M., Iizuka,H., and Schalkwijk,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

  10. Cheng,T., Hitomi,K., van Vlijmen-Willems,I.M., de Jongh,G.J., Yamamoto,K., Nishi,K., Watts,C., Reinheckel,T., Schalkwijk,J., and Zeeuwen,P.L. (2006) Cystatin M/E is a high affinity 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. 281:15893-99

last update: 2013, February