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Mol. Biol. Cell 21 (14): 2514-2528

Copyright © 2010 by The American Society for Cell Biology.


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

Angela F. Messmer-Blust*, Sujata Balasubramanian*, Victoria Y. Gorbacheva{dagger}, Jonathan A. Jeyaratnam*, and Deborah J. Vestal*,{dagger}

*Department of Biological Sciences, University of Toledo, Toledo, OH 43606; and {dagger}Department of Molecular Biology of the Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195

Received for publication April 30, 2009. Revision received May 14, 2010. Accepted for publication May 17, 2010.

Monitoring Editor: Josephine Adams

Abstract: 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. Either IFN-{gamma} treatment or mGBP-2 expression inhibits Rac activation during cell spreading. Rac is required for cell spreading. mGBP-2 also inhibits the activation of Akt during cell spreading on fibronectin. mGBP-2 is incorporated into a protein complex containing the catalytic subunit of phosphatidylinositol 3-kinase (PI3-K), p110. The association of mGBP-2 with p110 seems important for the inhibition of cell spreading because S52N mGBP-2, which does not incorporate into the protein complex with p110, is unable to inhibit cell spreading. PI3-K activation during cell spreading on fibronectin was inhibited in the presence of mGBP-2. Both IFN-{gamma} and mGBP-2 also inhibit cell spreading initiated by platelet-derived growth factor treatment, which is also accompanied by inhibition of Rac activation by mGBP-2. This is the first report of a novel mechanism by which IFN-{gamma} can alter how cells respond to subsequent extracellular signals, by the induction of mGBP-2.

This was published online ahead of print in MBoC in Press ( on May 26, 2010.

Address correspondence to: Deborah J. Vestal (deborah.vestal{at}

Abbreviations: ECM, extracellular matrix • FN, fibronectin • GBP, guanylate-binding protein • GST, glutathione transferase • IFN, interferon • IL, interleukin • PAK, p21-activated kinase • PBD, PAK binding domain • PBS, phosphate-buffered saline • PDGF, platelet-derived growth factor • PI3-K, phosphoinositol 3-kinase • PMSF, phenylmethylsulfonyl fluoride • TCL, total cell lysate • TNF, tumor necrosis factor.

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