Dr. Patrick Zeeuwen, PhD
Laboratory
of Skin Biology and Experimental Dermatology
Radboud University Nijmegen Medical Centre
Nijmegen Centre for Molecular Life Sciences
PO Box 9101, 6500 HB Nijmegen
The Netherlands
phone: ++31-24-3617245
p.zeeuwen@ncmls.ru.nl
http://www.ncmls.nl/ncmls/menustructures/pi/theme1/patrickzeeuwen.asp
http://www.n4i.nl/page/312/dr.-patrick-zeeuwen.html
Research
focus
- The role of proteases and protease inhibitors in epidermal differentiation
and desquamation
- The role of transglutaminases in epidermal cornification
- Mouse models (transgenic and knockout) to study the role of proteases,
protease inhibitors and transglutaminases in skin and other epithelia
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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.