The FHIT tumor suppressor gene is arguably the most commonly altered gene in cancer since it is inactivated in about 60% of human tumors. Despite the fact that Fhit functions as a tumor suppressor, the pathway through which Fhit inhibits growth of cancer cells remains largely unknown. Phosphorylation by Src tyrosine kinases provides a linkage between Fhit and growth factor signaling. Since many G proteins can regulate cell proliferation through multiple signaling components including Src, I explored the relationship between Gα subunits and Fhit. Several members of the Gα_q subfamily (Gα₁₆, Gα₁₄, and Gα_q) have been found to co-immunoprecipitate with Fhit in their GTP-bound active state in HEK293 cells. The binding of activated Gα_q members to Fhit appeared to be direct. The use of G...[ Read more ]

The FHIT tumor suppressor gene is arguably the most commonly altered gene in cancer since it is inactivated in about 60% of human tumors. Despite the fact that Fhit functions as a tumor suppressor, the pathway through which Fhit inhibits growth of cancer cells remains largely unknown. Phosphorylation by Src tyrosine kinases provides a linkage between Fhit and growth factor signaling. Since many G proteins can regulate cell proliferation through multiple signaling components including Src, I explored the relationship between Gα subunits and Fhit. Several members of the Gα_q subfamily (Gα₁₆, Gα₁₄, and Gα_q) have been found to co-immunoprecipitate with Fhit in their GTP-bound active state in HEK293 cells. The binding of activated Gα_q members to Fhit appeared to be direct. The use of Gα_16/z chimeras further enabled the mapping of the Fhit-interacting domain to the α2-β4 region of Gα₁₆. Meanwhile, Fhit was up-regulated specifically by activating Gα subunits of the G_q subfamily but not by those of the other G protein subfamilies. This up-regulation effect was mediated by a PKC/MEK pathway independent of Src-mediated Fhit Tyr¹¹⁴ phosphorylation. I further demonstrated that elevated Fhit expression was due to the specific regulation of Fhit protein synthesis in the ribosome by activated Gα_q, where the regulations of cap-dependent protein synthesis were apparently not required. Stimulation of G_q-coupled receptors in HEK293 and H1299 cells stably overexpressing Fhit led to reduced cell proliferation, as opposed to an enhanced cell proliferation typically seen with parental cells. Moreover, I showed that activated Gα_q could increase cell-cell adhesion through Fhit and this effect did not involve the regulations of the expressions of E-cadherin and MMP2/9, the localizations of adhesive proteins and the the binding of p63RhoGEF to activated Gα_q. These findings provide a possible handle to modulate the level of the Fhit tumor suppressor and tumor suppression by manipulating the activity of G_q-coupled receptors.