The reprolysin jararhagin, a snake venom metalloproteinase, functions as a fibrillar collagen agonist involved in fibroblast cell adhesion and signaling.
The integrins alpha(2)beta(1) and alpha(1)beta(1) have been shown to modulate cellular activities of fibroblasts on contact with fibrillar collagen. Previously it has been shown that collagen binding to alpha(2)beta(1) regulates matrix metalloproteinase MMP-1 and membrane-type MT1-MMP expression. Jararhagin is a snake venom metalloproteinase of the Reprolysin family of zinc metalloproteinases, containing a metalloproteinase domain followed by disintegrin-like and cysteine-rich domains. Jararhagin blocks type I collagen-induced platelet aggregation by binding to the alpha(2)beta(1) integrin and inhibiting collagen-mediated intracellular signaling events. Here we present evidence that, in contrast to the observations in platelets, jararhagin binding to the integrin receptor alpha(2)beta(1) in fibroblasts produces collagen-like cell signaling events such as up-regulation of MMP-1 and MT1-MMP. Inactivation of the metalloproteinase domain had no effect on these properties of jararhagin. Thus, in fibroblasts the snake venom metalloproteinase jararhagin functions as a collagen-mimetic substrate that binds to and activates integrins. Given the homology between the metalloproteinase, disintegrin-like and cysteine-rich domains of jararhagin and those of the members of the ADAMs (a disintegrin-like and metalloproteinase) family of proteins, this work demonstrates the potential of the disintegrin-like/cysteine-rich domains in the ADAMs as cellular signaling agents to elicit responses relevant to the biological function of these proteins.
Department of Dermatology, University of Cologne, Cologne 50924, Germany.
Paola
P
Zigrino
Aura S
AS
Kamiguti
Johannes
J
Eble
Claudia
C
Drescher
Roswitha
R
Nischt
Jay W
JW
Fox
Cornelia
C
Mauch
D002448:Cell Adhesion / Q000187:drug effects*; D002478:Cells, Cultured; D003094:Collagen / Q000819:agonists*; D003435:Crotalid Venoms / Q000378:metabolism / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D008666:Metalloendopeptidases / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D012910:Snake Venoms / Q000201:enzymology; D000097146:Bothrops jararaca Venom
D003094:Collagen; D003435:Crotalid Venoms; D038982:Integrin alpha2beta1; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D012333:RNA, Messenger; D012910:Snake Venoms; D000097146:Bothrops jararaca Venom