The Fragile Histidine Triad (FHIT) gene is a tumor suppressor gene which is frequently inactivated in various human cancers. Recently Fhit has demonstrated as a target of tyrosine phosphorylation by Src, providing insight into the biochemical control of Fhit signaling. Various G proteins and GPCRs are capable of inducing Src activity and regulating cell proliferation and oncogenesis, the possible involvement of Fhit in G protein-mediated signaling pathways was examined in the present study. Here, in co-immunoprecipitation assay, Fhit specifically associates with constitutively active Gα_q subfamily members (except Gα₁₁); such differential association appears to be dependent on the active status of Gα_q subunits. Fhit has also been shown to bind Gα_s and Gα₁₃ (but not Gα_i2) regardless of th...[ Read more ]

The Fragile Histidine Triad (FHIT) gene is a tumor suppressor gene which is frequently inactivated in various human cancers. Recently Fhit has demonstrated as a target of tyrosine phosphorylation by Src, providing insight into the biochemical control of Fhit signaling. Various G proteins and GPCRs are capable of inducing Src activity and regulating cell proliferation and oncogenesis, the possible involvement of Fhit in G protein-mediated signaling pathways was examined in the present study. Here, in co-immunoprecipitation assay, Fhit specifically associates with constitutively active Gα_q subfamily members (except Gα₁₁); such differential association appears to be dependent on the active status of Gα_q subunits. Fhit has also been shown to bind Gα_s and Gα₁₃ (but not Gα_i2) regardless of their active status. Fhit/Gα_qRC association is independent of Y114 phosphorylated conformation or AP₃A-bound conformation of Fhit. Due to Src activation by constitutively active Gα₁₆QL, Fhit/Src complex formation and Fhit phosphorylation on Y114 is greatly enhanced when constitutively active Gα₁₆QL was co-transfected. Activated recombinant Gα₁₆ protein, however, does not interfere with the intrinsic AP₃A hydrolase activity of Fhit. On the other hand, in NIH/3T3 cells stably co-expressing Fhit and RasGV (oncogenic Ras), Fhit partially attenuated the RasGV-induced cell growth, indicating that Fhit may play a role in regulating RasGV-mediated cell proliferation. However, such suppression seems to be independent of Gα_q subfamily since Gα₁₆QL-mediated Ras activation was not affected by transient expression of Fhit. Furthermore, in various Gα_q-mediated molecular pathways examined, Fhit seems to show no involvement in any of these Gα_q-mediated pathways. The present study provides a novel finding that Fhit, a tumor suppressor protein, can associate with several Gα proteins which are linked to a wide variety of signaling cascades, thus providing new avenues for Fhit proteins to carry out its function as a tumor suppressor.