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Background  The  FHIT  tumor suppressor gene is arguably the most commonly altered gene in cancer since it is inactivated in about 60% of human tumors. The Fhit protein is a member of the ubiquitous histidine triad proteins which hydrolyze dinucleoside polyphosphates such as Ap 3 A. 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, we explored the relationship between Gα subunits and Fhit.    Results  Several members of the Gα q  subfamily (Gα 16 , Gα 14 , and Gα q ) were 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 and was detectable in native DLD-1 colon carcinoma cells. The use of Gα 16/z  chimeras further enabled the mapping of the Fhit-interacting domain to the α2-β4 region of Gα 16 . However, Gα q /Fhit did not affect either Ap 3 A binding and hydrolysis by Fhit, or the ability of Gα q/16  to regulate downstream effectors including phospholipase Cβ, Ras, ERK, STAT3, and IKK. Functional mutants of Fhit including the H96D, Y114F, L25W and L25W/I10W showed comparable abilities to associate with Gα q . Despite the lack of functional regulation of G q  signaling by Fhit, 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.    Conclusions  Activated Gα q  members interact with Fhit through their α2-β4 region which may result in enhancement of the growth inhibitory effect of Fhit, thus providing a possible avenue for G protein-coupled receptors to modulate tumor suppression.

Activation state-dependent interaction between Gαq subunits and the Fhit tumor suppressor