Serine protease inhibitors of the Kazal-type 9 (SPINK9) is a keratinocyte-derived cationic peptide that is found most abundantly in the upper layers of the palmar-plantar epidermis. In vitro, the peptide displays the capacity to inhibit specifically kallikrein-related peptidase 5 (KLK5). Here, we report that cells expressing SPINK9 secrete the peptide constitutively. Recombinant SPINK9 (rSPINK9) provoked transactivation of the EGFR in human keratinocytes, resulting in efficient downstream triggering of cell migration. Transactivation occurred via functional upregulation of a disintegrin and metalloproteases (ADAMs), as evidenced by suppression with a metalloproteinase inhibitor and an EGFR-blocking antibody. SPINK9 preparations isolated from human skin also displayed EGFR-transactivating capacity. The classical purinergic receptor antagonists oxidized ATP and pyridoxalphosphate-6-azophenyl-2',4',-disulfonic acid effectively suppressed EGFR transactivation by rSPINK9, indicating that in analogy to what has recently been reported for the cationic antimicrobial peptides cathelicidin LL-37 and bee venom melittin, purinergic receptors have an essential bridging role in promoting the upregulation of ADAM function by the cationic peptide. SPINK9 could represent an example of how a cationic peptide may subserve multiple and interrelated functions that contribute to the maintenance of the physical and immunological barrier of the skin.

Department of Dermatology University Hospital Schleswig Holstein Christian Albrecht University Kiel Kiel Germany

Department of Transgenic Models of Diseases Institute of Molecular Genetics of the ASCR Prague Czech Republic

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J Invest Dermatol. 2007 Mar;127(3):594-604 PubMed

Lung Cancer. 2008 Jan;59(1):12-23 PubMed

Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11035-9 PubMed

Biol Chem. 2012 Apr;393(5):369-77 PubMed

J Immunol. 2005 Oct 1;175(7):4662-8 PubMed

J Cell Physiol. 1996 Mar;166(3):637-42 PubMed

Mol Cancer Res. 2009 Sep;7(9):1572-81 PubMed

FASEB J. 2010 Dec;24(12):4756-66 PubMed

J Innate Immun. 2012;4(4):377-86 PubMed

Nat Rev Mol Cell Biol. 2005 Jan;6(1):32-43 PubMed

Int Immunol. 2002 Dec;14(12):1415-21 PubMed

J Immunol. 2003 Dec 15;171(12):6690-6 PubMed

FASEB J. 2006 Oct;20(12):2068-80 PubMed

J Invest Dermatol. 2008 Jan;128(1):223-36 PubMed

Blood. 1998 Aug 1;92(3):946-51 PubMed

J Biol Chem. 2010 Mar 5;285(10):7545-55 PubMed

Nat Cell Biol. 2005 Aug;7(8):808-16 PubMed

J Immunol. 2005 Aug 1;175(3):1776-84 PubMed

PLoS One. 2009;4(2):e4372 PubMed

Thromb Haemost. 2013 Sep;110(3):442-9 PubMed

J Invest Dermatol. 2012 Sep;132(9):2129-30 PubMed

J Biol Chem. 1999 Jul 30;274(31):21499-502 PubMed

Immunol Lett. 2006 Jan 15;102(1):98-105 PubMed

Pharmacol Rev. 1998 Sep;50(3):413-92 PubMed

J Invest Dermatol. 2010 Jan;130(1):295-304 PubMed

Nat Commun. 2011;2:229 PubMed

Nat Rev Immunol. 2012 Jun 25;12(7):503-16 PubMed

Med Microbiol Immunol. 2012 Nov;201(4):419-26 PubMed

Int J Biochem Cell Biol. 2002 Jun;34(6):573-6 PubMed

J Invest Dermatol. 2009 Jul;129(7):1656-65 PubMed

J Biol Chem. 2011 Jan 28;286(4):2596-606 PubMed

Science. 1998 Nov 13;282(5392):1281-4 PubMed

Curr Top Microbiol Immunol. 2006;306:27-66 PubMed

J Immunol. 2004 Apr 15;172(8):4987-94 PubMed

J Exp Med. 2012 Jun 4;209(6):1105-19 PubMed

Nat Genet. 2000 Jun;25(2):141-2 PubMed

J Biol Chem. 2008 Nov 7;283(45):30471-81 PubMed

J Biol Chem. 2012 Jul 6;287(28):23678-89 PubMed

Blood. 2001 Jun 15;97(12):3951-9 PubMed

Naunyn Schmiedebergs Arch Pharmacol. 2000 Nov;362(4-5):340-50 PubMed

Science. 1995 Jul 14;269(5221):234-8 PubMed

J Biol Chem. 2005 May 13;280(19):18696-702 PubMed

Cell Immunol. 2012 Nov;280(1):22-35 PubMed