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. 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.
Messmer-Blust
Angela F
AF
Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA.
Balasubramanian
Sujata
S
Gorbacheva
Victoria Y
VY
Jeyaratnam
Jonathan A
JA
Vestal
Deborah J
DJ
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005353:Fibronectins / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D039441:Integrin alpha4 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D008545:Melanoma / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017469:Receptors, Fibronectin / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
D005353:Fibronectins; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D017469:Receptors, Fibronectin; D039441:Integrin alpha4; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019204:GTP-Binding Proteins; C452200:Gbp2 protein, mouse; D020744:rac GTP-Binding Proteins