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Zuo, Hao; Chan, Grace P. W.; Zhu, Jing; Yeung, Wendy W. S.; Chan, Anthony S. L.; Ammer, Hermann and Wong, Yung H. (2013): Activation state-dependent interaction between G alpha(q) subunits and the Fhit tumor suppressor. In: Cell Communication and Signaling 11:59 [PDF, 2MB]

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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 G alpha subunits and Fhit. Results: Several members of the G alpha(q) subfamily (G alpha(16), G alpha(14), and G alpha(q)) were found to co-immunoprecipitate with Fhit in their GTP-bound active state in HEK293 cells. The binding of activated G alpha(q) members to Fhit appeared to be direct and was detectable in native DLD-1 colon carcinoma cells. The use of G alpha(16/z) chimeras further enabled the mapping of the Fhit-interacting domain to the alpha 2-beta 4 region of G alpha(16). However, G alpha(q)/Fhit did not affect either Ap(3)A binding and hydrolysis by Fhit, or the ability of G alpha(q/16) to regulate downstream effectors including phospholipase C beta, Ras, ERK, STAT3, and IKK. Functional mutants of Fhit including the H96D, Y114F, L25W and L25W/I10W showed comparable abilities to associate with G alpha(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 G alpha(q) members interact with Fhit through their alpha 2-beta 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.

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