title: Proteolytic action of kallikrein-related peptidase 7 produces unique active matrix metalloproteinase-9 lacking the C-terminal hemopexin domains.
abstract: The gelatinases, matrix metalloproteinase (MMP)-9 and -2, are produced as latent, inactive enzymes that can be proteolytically activated by a number of proteases. In many normal and pathological conditions, where the expression of MMPs is deregulated, changes in the expression of other proteases have also been reported. Human kallikrein-related peptidase 7 (KLK7), a chymotryptic-like serine protease, is overexpressed in many different types of neoplastic conditions, which have also been shown to express high levels of both MMP-9 and -2. Since the activation of MMPs by KLK7 has never been examined, we sought to determine whether KLK7 can activate these MMPs. To test this hypothesis KLK7 was incubated with the recombinant MMPs and the products of the reaction were analyzed for their activity. Incubation of proMMP-9 with KLK7 resulted in the production of a novel truncated, active MMP-9 lacking the C-terminal hemopexin domains. In contrast, KLK7 degraded, but did not activate, proMMP-2. The novel activation of proMMP-9 by KLK7 was further confirmed using conditioned medium prepared from an MMP-9-expressing cell line, MDA-MMP-9. Our results clearly establish that KLK7 activates proMMP-9 to produce a novel truncated, active MMP-9 product not generated by other proteases. These findings suggest that KLK7 may play an important role in the activation of MMP-9 in tumors that express high levels of both these proteases and the resulting truncated MMP may possess altered substrate specificities compared with full-length MMP-9 activated by other proteases.
authors: University of Arkansas for Medical Sciences, Departments of Physiology and Biophysics, Little Rock, AR 72205, USA. vpramani@uab.edu
authors: Vishnu C
authors: VC
authors: Ramani
authors: Gur P
authors: GP
authors: Kaushal
authors: Randy S
authors: RS
authors: Haun
references: Protein Expr Purif. 2001 Dec;23(3):447-52
references: 11722182
references: Nat Cell Biol. 2000 Oct;2(10):737-44
references: 11025665
references: J Biol Chem. 1995 Aug 4;270(31):18506-11
references: 7629179
references: Cancer Metastasis Rev. 2006 Mar;25(1):9-34
references: 16680569
references: Cell. 2000 Oct 27;103(3):481-90
references: 11081634
references: Gynecol Oncol. 2004 Aug;94(2):283-8
references: 15297163
references: Cancer Chemother Pharmacol. 1999;43 Suppl:S42-51
references: 10357558
references: Anticancer Res. 1999 Sep-Oct;19(5B):4257-64
references: 10628384
references: Cancer Res. 1996 Nov 15;56(22):5279-84
references: 8912869
references: Surg Today. 1997;27(4):302-4
references: 9086544
references: Thromb Haemost. 2004 Jan;91(1):180-6
references: 14691584
references: Clin Chem. 2008 Oct;54(10):1600-7
references: 18687738
references: J Biol Chem. 1997 Oct 10;272(41):25628-35
references: 9325284
references: Annu Rev Cell Dev Biol. 2001;17:463-516
references: 11687497
references: J Biol Chem. 1989 Oct 15;264(29):17213-21
references: 2551898
references: J Biol Chem. 2002 Jul 26;277(30):27319-27
references: 12004062
references: Clin Cancer Res. 2001 Aug;7(8):2396-404
references: 11489818
references: Clin Exp Metastasis. 1999 Mar;17(2):177-81
references: 10411111
references: Cancer. 2007 May 1;109(9):1811-20
references: 17354228
references: Mol Oncol. 2007 Dec;1(3):269-87
references: 19383303
references: Biochem J. 1998 May 1;331 ( Pt 3):965-72
references: 9560329
references: Proc Natl Acad Sci U S A. 1990 Jan;87(1):364-8
references: 2153297
references: Protein Expr Purif. 2010 Jul;72(1):87-94
references: 20214994
references: Cell. 1999 Jul 23;98(2):137-46
references: 10428026
references: J Surg Oncol. 2000 Feb;73(2):95-9
references: 10694645
references: J Pathol. 1997 Jul;182(3):347-55
references: 9349239
references: Cancer Res. 2003 May 1;63(9):2223-7
references: 12727843
references: Bone. 2007 Dec;41(6):912-27
references: 17945547
references: Invasion Metastasis. 1994-1995;14(1-6):246-58
references: 7657517
references: Int J Cancer. 2005 Jul 20;115(6):849-60
references: 15729716
references: Proc Natl Acad Sci U S A. 1994 May 10;91(10):4293-7
references: 8183903
references: Clin Cancer Res. 2004 Nov 15;10(22):7621-8
references: 15569994
references: Int J Oncol. 2000 Oct;17(4):673-81
references: 10995877
references: Cell. 1998 Aug 7;94(3):353-62
references: 9708737
references: Int J Cancer. 2000 Jan 1;85(1):14-20
references: 10585576
references: Neoplasia. 2001 Nov-Dec;3(6):459-68
references: 11774028
references: Pathol Oncol Res. 2001;7(1):14-23
references: 11349215
references: Clin Cancer Res. 1999 Jan;5(1):25-33
references: 9918199
references: Breast Cancer Res Treat. 2007 Mar;102(1):7-18
references: 16897430
references: Proc Natl Acad Sci U S A. 1990 Jul;87(14):5578-82
references: 2164689
references: J Cancer Res Clin Oncol. 2003 Feb;129(2):123-31
references: 12669237
references: Clin Biochem. 2003 Mar;36(2):135-43
references: 12633763
references: J Biol Chem. 1992 Feb 25;267(6):3581-4
references: 1371271
references: J Clin Oncol. 2001 Feb 15;19(4):1118-27
references: 11181677
references: J Biol Chem. 2006 Sep 1;281(35):25678-88
references: 16740631
references: Clin Cancer Res. 2003 Oct 15;9(13):4935-43
references: 14581368
references: Physiol Rev. 1993 Jan;73(1):161-95
references: 8419965
references: J Biol Chem. 1985 Feb 25;260(4):2493-500
references: 2982822
references: Cell. 1997 Nov 14;91(4):439-42
references: 9390552
references: Biochem Biophys Res Commun. 2008 May 16;369(4):1169-73
references: 18343220
references: Thromb Haemost. 1998 Jun;79(6):1171-6
references: 9657444
references: Am J Pathol. 1996 Jul;149(1):273-82
references: 8686751
references: Clin Cancer Res. 2003 May;9(5):1710-20
references: 12738725
references: J Cell Sci. 2001 Jan;114(Pt 1):111-118
references: 11112695
references: Nat Rev Cancer. 2002 Mar;2(3):161-74
references: 11990853
references: J Biol Chem. 1994 Jul 29;269(30):19420-6
references: 8034709
references: Biochem J. 2007 Aug 1;405(3):547-58
references: 17489740
references: Cancer. 1999 Nov 15;86(10):2074-82
references: 10570434
references: Int J Cancer. 1995 Aug 9;62(4):407-13
references: 7635566
references: Cancer Lett. 2007 Apr 28;249(1):61-79
references: 17275179
references: Eur J Cell Biol. 1997 Oct;74(2):111-22
references: 9352216
references: Cancer. 1998 Feb 15;82(4):642-50
references: 9477095
references: J Biol Chem. 1999 May 7;274(19):13066-76
references: 10224058
references: J Biol Chem. 1992 Mar 5;267(7):4583-91
references: 1311314
references: Proc Natl Acad Sci U S A. 1989 Apr;86(8):2632-6
references: 2468156
references: J Invest Dermatol. 1993 Aug;101(2):200-4
references: 8393902
references: Mol Cancer Res. 2004 May;2(5):257-80
references: 15192120