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Cdc42 increases activation of MMP‐2 in endothelial cells
Author(s) -
Serio Damiano,
Ispanovic Eric,
Haas Tara L
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.925.9
Subject(s) - cdc42 , microbiology and biotechnology , stress fiber , actin cytoskeleton , angiogenesis , chemistry , matrix metalloproteinase , cytoskeleton , phosphorylation , actin , biology , focal adhesion , cell , cancer research , biochemistry
Angiogenesis is stimulated by VEGF and requires basement membrane degradation by the matrix metalloproteinases (MMPs). VEGF induces increased membrane type 1‐MMP on the cell surface (required for MMP‐2 activation) and signals through the RhoGTPase family members. The RhoGTPases and the MAPK p38 are known for their roles upstream of actin cytoskeleton reorganization and are purported to regulate angiogenesis. We hypothesize that Cdc42 mediates the effects of VEGF on activation of MMP‐2 via p38 and actin cytoskeleton reorganization. To investigate this we manipulated Cdc42 signaling with a constitutively active Cdc42 (CA‐Cdc42) TAT‐fusion protein and observed the effects in rat skeletal muscle endothelial cells. Confocal microscopy demonstrated that CA‐Cdc42 increased cortical actin and the proportion of retracted or protruded cells similar to VEGF‐induced actin stress fibre depolymerization. CA‐Cdc42 treatments resulted in increased phospho‐p38 levels as seen with VEGF via western blotting. Furthermore, MMP‐2 activation increased in cells treated with CA‐Cdc42 or VEGF independent of new protein synthesis, as tested by gelatin zymography. This evidence suggests that Cdc42 may mediate the effects of VEGF on actin cytoskeleton reorganization, p38 phosphorylation and the levels of active MMP‐2. Funded by NSERC.