title: Proteolytic processing regulates placental growth factor activities.
abstract: Placental growth factor (PlGF) is a critical mediator of blood vessel formation, yet mechanisms of its action and regulation are incompletely understood. Here we demonstrate that proteolytic processing regulates the biological activity of PlGF. Specifically, we show that plasmin processing of PlGF-2 yields a protease-resistant core fragment comprising the vascular endothelial growth factor receptor-1 binding site but lacking the carboxyl-terminal domain encoding the heparin-binding domain and an 8-amino acid peptide encoded by exon 7. We have identified plasmin cleavage sites, generated a truncated PlGF118 isoform mimicking plasmin-processed PlGF, and explored its biological function in comparison with that of PlGF-1 and -2. The angiogenic responses induced by the diverse PlGF forms were distinct. Whereas PlGF-2 increased endothelial cell chemotaxis, vascular sprouting, and granulation tissue formation upon skin injury, these activities were abrogated following plasmin digestion. Investigation of PlGF/Neuropilin-1 binding and function suggests a critical role for heparin-binding domain/Neuropilin-1 interaction and its regulation by plasmin processing. Collectively, here we provide new mechanistic insights into the regulation of PlGF-2/Neuropilin-1-mediated tissue vascularization and growth.
authors: Department of Dermatology, University of Cologne, Cologne, Germany.
authors: Daniel C
authors: DC
authors: Hoffmann
authors: Sebastian
authors: S
authors: Willenborg
authors: Manuel
authors: M
authors: Koch
authors: Daniela
authors: D
authors: Zwolanek
authors: Stefan
authors: S
authors: Müller
authors: Ann-Kathrin A
authors: AK
authors: Becker
authors: Stephanie
authors: S
authors: Metzger
authors: Martin
authors: M
authors: Ehrbar
authors: Peter
authors: P
authors: Kurschat
authors: Martin
authors: M
authors: Hellmich
authors: Jeffrey A
authors: JA
authors: Hubbell
authors: Sabine A
authors: SA
authors: Eming
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism*; D057809:HEK293 Cells; D006493:Heparin / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology; D039942:Neuropilin-1 / Q000378:metabolism; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism; D000072483:Placenta Growth Factor; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D061987:Sf9 Cells; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D020033:Protein Isoforms; D000072483:Placenta Growth Factor; D039942:Neuropilin-1; D006493:Heparin; D040281:Vascular Endothelial Growth Factor Receptor-1; D005341:Fibrinolysin
keywords: Angiogenesis; Mechanism of Growth Factor Regulation; PlGF; Plasmin; Protease; Vascular Biology; Vascular Endothelial Growth Factor (VEGF)
references: Cell Growth Differ. 1996 Feb;7(2):213-21
references: 8822205
references: J Biol Chem. 1996 Mar 8;271(10):5761-7
references: 8621443
references: J Cell Biol. 2003 Jun 23;161(6):1163-77
references: 12810700
references: Genes Dev. 2002 Oct 15;16(20):2684-98
references: 12381667
references: J Biol Chem. 1996 Mar 29;271(13):7788-95
references: 8631822
references: Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6152-7
references: 17405859
references: Nat Med. 2003 Jul;9(7):936-43
references: 12796773
references: J Invest Dermatol. 2006 Dec;126(12):2731-3
references: 16826165
references: J Cell Biol. 2005 May 23;169(4):681-91
references: 15911882
references: J Biol Chem. 2002 Jul 5;277(27):24818-25
references: 11986311
references: PLoS One. 2011;6(9):e24872
references: 21969865
references: Biochem J. 2001 Nov 15;360(Pt 1):255-64
references: 11696015
references: Nat Med. 2001 May;7(5):575-83
references: 11329059
references: Growth Factors. 1993;9(4):259-68
references: 8148155
references: Cell. 2010 Apr 2;141(1):178-90
references: 20371353
references: Nat Med. 2002 Aug;8(8):831-40
references: 12091877
references: J Invest Dermatol. 2000 Jul;115(1):12-8
references: 10886501
references: EMBO J. 2006 Jul 12;25(13):3045-55
references: 16763549
references: Biochem Soc Trans. 2011 Dec;39(6):1583-91
references: 22103491
references: J Biol Chem. 1992 Dec 25;267(36):26031-7
references: 1464614
references: Am J Pathol. 2006 Feb;168(2):670-84
references: 16436680
references: J Biol Chem. 2006 Mar 3;281(9):5702-10
references: 16371354
references: EMBO J. 1997 Jul 1;16(13):3898-911
references: 9233800
references: Biochim Biophys Acta. 2010 Mar;1804(3):567-80
references: 19761875
references: Nat Med. 2008 Sep;14(9):973-8
references: 18660817
references: Nat Med. 2003 Jun;9(6):694-701
references: 12778168
references: Blood. 2003 Jan 15;101(2):560-7
references: 12393422
references: Blood. 2008 Nov 1;112(9):3638-49
references: 18664627
references: Exp Dermatol. 1993 Feb;2(1):29-37
references: 8156167
references: Nat Rev Cancer. 2008 Dec;8(12):942-56
references: 19029957
references: J Biol Chem. 2007 Aug 17;282(33):24049-56
references: 17575273
references: Oncogene. 1993 Apr;8(4):925-31
references: 7681160
references: Endocr Rev. 2004 Aug;25(4):581-611
references: 15294883
references: Nat Med. 2002 Aug;8(8):841-9
references: 12091880
references: J Clin Invest. 2006 May;116(5):1230-42
references: 16614757
references: Mamm Genome. 1996 Jan;7(1):6-12
references: 8903720
references: Blood. 2011 Jul 21;118(3):816-26
references: 21586748
references: FASEB J. 2008 Aug;22(8):3078-86
references: 18467594
references: J Biol Chem. 2012 Mar 30;287(14):11082-9
references: 22318724
references: Am J Pathol. 2006 Oct;169(4):1167-82
references: 17003476
references: Mol Biol Cell. 2011 Aug 1;22(15):2766-76
references: 21653826
references: J Biol Chem. 1998 Aug 28;273(35):22272-8
references: 9712843
references: J Biol Chem. 2004 Jan 23;279(4):2927-36
references: 14585835