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Journal of Biochemistry Advance Access originally published online on August 30, 2007
Journal of Biochemistry 2007 142(4):435-442; doi:10.1093/jb/mvm156
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© 2007 The Japanese Biochemical Society.

SerpinB6 is an Inhibitor of Kallikrein-8 in Keratinocytes

Fiona L. Scott1,*,{dagger}, Jiuru Sun1, James C. Whisstock1, Keiko Kato2 and Phillip I. Bird1

1Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia; and 2Division of Structural Cell Biology, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0101 Japan

{dagger}To whom correspondence should be addressed. Tel: +1-858-646 3100 x3667, Fax: +1-858-646-3199, E-mail: fscott{at}burnham.org

Received March 7, 2007; Accepted June 21, 2007


  Abstract

SerpinB6 (Proteinase inhibitor 6/PI-6) is an intracellular serpin produced by leukocytes, platelets, endothelial cells, keratinocytes and other epithelial cells. It is a potent cathepsin G inhibitor thought to protect monocytes, neutrophils and bystander cells from ectopic cathepsin G during inflammation. Here we show that serpinB6 also inhibits the human serine protease kallikrein-8 (hK8) and that in human and mouse skin, serpinB6 and kallikrein-8 co-localize in differentiated keratinocytes. SerpinB6 inhibits hK8 with an association rate constant (kass) of 1.8 ± 0.2 x 105 M–1s–1 compared to 3.4 ± 0.2 x 106 M–1 s–1 for the interaction between the mouse orthologue of serpinB6 (SPI3/serpinb6a) and mouse kallikrein-8 (mK8). Molecular modelling suggested that the lower efficiency of the serpinB6/hK8 interaction is partly due to the bulkier P2 methionine residue of serpinB6 compared to the smaller P2 valine in SPI3. Taken together, these results suggest that serpinB6 is a physiologically relevant inhibitor of hK8 in skin. We postulate that serpinB6 protects the intracellular compartment of keratinocytes from ectopic hK8.

Key Words: kallikrein, keratinocyte, neuropsin, serpinB6, SPI3

Abbreviations: CatG, cathepsin G; HEK, human epidermal keratinocytes; hK8, human kallikrein-8; kass, association rate constant; mK8, mouse kallikrein-8; RCL, reactive centre loop; SI, stoichiometry of inhibition; SCCA, squamous cell carcinoma antigen

*Present address: Program for Apoptosis and Cell Death Research, Burnham Institute for Medical Research, 10901 North Torrey Pines Rd, La Jolla, CA 92037, USA


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