Transforming growth factor beta induces rosettes of podosomes in primary aortic endothelial cells.
Cytoskeletal rearrangements are central to endothelial cell physiology and are controlled by soluble factors, matrix proteins, cell-cell interactions, and mechanical forces. We previously reported that aortic endothelial cells can rearrange their cytoskeletons into complex actin-based structures called podosomes when a constitutively active mutant of Cdc42 is expressed. We now report that transforming growth factor beta (TGF-beta) promotes podosome formation in primary aortic endothelial cells. TGF-beta-induced podosomes assembled together into large ring- or crescent-shaped structures. Their formation was dependent on protein synthesis and required functional Src, phosphatidylinositide 3-kinase, Cdc42, RhoA, and Smad signaling. MT1-MMP and metalloprotease 9 (MMP9), both upregulated by TGF-beta, were detected at sites of podosome formation, and MT1-MMP was found to be involved in the local degradation of extracellular matrix proteins beneath the podosomes and required for the invasion of collagen gels by endothelial cells. We propose that TGF-beta plays an important role in endothelial cell physiology by inducing the formation of podosomal structures endowed with metalloprotease activity that may contribute to arterial remodeling.
Varon
Christine
C
European Institute of Chemistry and Biology, 2 rue Robert Escarpit, 33600 Pessac, France.
Tatin
Florence
F
Moreau
Violaine
V
Van Obberghen-Schilling
Ellen
E
Fernandez-Sauze
Samantha
S
Reuzeau
Edith
E
Kramer
Ijsbrand
I
Génot
Elisabeth
E
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002417:Cattle; D003599:Cytoskeleton / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D020780:Matrix Metalloproteinase 9; D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein