Activation state-dependent interaction between G?q subunits and the Fhit tumor suppressor.

ABSTRACT: 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 Ap3A. 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 G? subunits and Fhit. RESULTS: Several members of the G?q subfamily (G?16, G?14, and G?q) were found to co-immunoprecipitate with Fhit in their GTP-bound active state in HEK293 cells. The binding of activated G?q members to Fhit appeared to be direct and was detectable in native DLD-1 colon carcinoma cells. The use of G?16/z chimeras further enabled the mapping of the Fhit-interacting domain to the ?2-?4 region of G?16. However, G?q/Fhit did not affect either Ap3A binding and hydrolysis by Fhit, or the ability of G?q/16 to regulate downstream effectors including phospholipase C?, Ras, ERK, STAT3, and IKK. Functional mutants of Fhit including the H96D, Y114F, L25W and L25W/I10W showed comparable abilities to associate with G?q. Despite the lack of functional regulation of Gq signaling by Fhit, stimulation of Gq-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 G?q members interact with Fhit through their ?2-?4 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.

SUBMITTER: Zuo H 

PROVIDER: S-EPMC3751744 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature