The interferon-gamma-induced GTPase, mGBP-2, inhibits tumor necrosis factor alpha (TNF-alpha) induction of matrix metalloproteinase-9 (MMP-9) by inhibiting NF-kappaB and Rac protein.

Matrix metalloproteinase-9 (MMP-9) is important in numerous normal and pathological processes, including the angiogenic switch during tumor development and tumor metastasis. Whereas TNF-α and other cytokines up-regulate MMP-9 expression, interferons (IFNs) inhibit MMP-9 expression. We found that IFN-γ treatment or forced expression of the IFN-induced GTPase, mGBP-2, inhibit TNF-α-induced MMP-9 expression in NIH 3T3 fibroblasts, by inhibiting MMP-9 transcription.

The guanylate-binding proteins: emerging insights into the biochemical properties and functions of this family of large interferon-induced guanosine triphosphatase.

Originally identified by their unusual ability to bind guanosine monophosphate (GMP) nucleotide agarose, the guanylate-binding proteins (GBPs) were used extensively to promote our understanding of interferon-induced gene transcription and as markers of interferon responsiveness. Structural and biochemical analyses of human GBP-1 subsequently demonstrated that the GBPs are a unique subfamily of guanosine triphosphatase (GTPases) that hydrolyze guanosine triphosphate (GTP) to both guanosine diphosphate (GDP) and GMP. As members of the larger dynamin superfamily of GTPases, GBPs exhibit such properties as nucleotide-dependent oligomerization and concentration-dependent GTPase activity.

Role of GTP binding, isoprenylation, and the C-terminal α-helices in the inhibition of cell spreading by the interferon-induced GTPase, mouse guanylate-binding protein-2.

Interferon-γ pre-exposure inhibits Rac activation by either integrin engagement or platelet-derived growth factor treatment. Interferon-γ does this by inducing expression of the large guanosine triphosphatase (GTPase) mouse guanylate-binding protein (mGBP-2). Inhibiting Rac results in the retardation of cell spreading.

The interferon-gamma-induced murine guanylate-binding protein-2 inhibits rac activation during cell spreading on fibronectin and after platelet-derived growth factor treatment: role for phosphatidylinositol 3-kinase.

Exposure of cells to certain cytokines can alter how these same cells respond to later cues from other agents, such as extracellular matrix or growth factors. Interferon (IFN)-gamma pre-exposure inhibits the spreading of fibroblasts on fibronectin. Expression of the IFN-gamma-induced GTPase murine guanylate-binding protein-2 (mGBP-2) can phenocopy this inhibition and small interfering RNA knockdown of mGBP-2 prevents IFN-gamma-mediated inhibition of cell spreading.