Activation state-dependent interaction between G alpha(q) subunits and the Fhit tumor suppressor
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vor 11 Jahren
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.
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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