G3BP (Ras-GTPase-activating protein SH3 domain binding protein), a protein which binds to RasGAP SH3 domain, belongs to RNA-binding protein family, implicating in the downstream of Ras signaling. G3BP harbors the activities of endoribonuclease and DNA helicase, and can induce stress granules formation. G3BP plays a general role in the signal pathways of cell proliferation, differentiation, apoptosis and RNA metabolism. It has been shown to be over-expressed in a number of human malignancies and has a close relationship with tumor invasion and metastasis. Given that it has been implicated in several pathways that are known to be involved in cancer biology, G3BP may provide a new target for cancer therapy.
Animals ; Carrier Proteins ; genetics ; metabolism ; DNA Helicases ; Drug Delivery Systems ; GTPase-Activating Proteins ; therapeutic use ; Humans ; Molecular Sequence Data ; Neoplasms ; drug therapy ; metabolism ; pathology ; Peptide Fragments ; therapeutic use ; Phosphorylation ; Poly-ADP-Ribose Binding Proteins ; RNA Helicases ; RNA Recognition Motif Proteins ; Signal Transduction ; ras GTPase-Activating Proteins ; metabolism ; src Homology Domains ; genetics

The scaffold protein IQGAP1 shows elevated levels in several cancer types, but its expression in hepatocellular carcinoma is unknown. We found that 58% of human hepatocellular carcinoma tissue samples had increased IQGAP1 expression compared to adjacent normal tissue. Overexpressing IQGAP1 raised the in vivo tumorigenicity of hepatocellular carcinoma cells, and forced overexpression of IQGAP1 in vitro stimulated cell proliferation. Cell growth was reduced by knockdown or mutation of IQGAP1, or by treatment of cells with a phosphotidylinositol 3-kinase inhibitor. To determine the mechanism by which IQGAP1 overexpression affected hepatocellular carcinoma cells, we confirmed its interaction in these cells with mammalian target of rapamycin (mTOR), a serine/threonine kinase that integrates signals about nutrient and energy status with downstream effectors that influence cell division. In addition, we discovered a new interaction involving IQGAP1, mTOR and Akt, which is a downstream target of mTOR. Akt phosphorylation on Ser-473, which is catalyzed by mTOR and required for Akt activation, increased with increasing amounts of IQGAP1, and decreased with IQGAP1 mutation. We hypothesize that IQGAP1 is a scaffold that facilitates mTOR and Akt interaction.
Animals ; Carcinoma, Hepatocellular/*enzymology/*pathology ; Cell Proliferation ; Enzyme Activation ; *Gene Expression Regulation, Neoplastic ; Hep G2 Cells ; Humans ; Liver Neoplasms/*enzymology/*pathology ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Binding ; Proto-Oncogene Proteins c-akt/*metabolism ; TOR Serine-Threonine Kinases/metabolism ; Up-Regulation ; ras GTPase-Activating Proteins/genetics/*metabolism