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2015 ; 14
(ä): 206
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A functional connectome: regulation of Wnt/TCF-dependent transcription by pairs
of pathway activators
#MMPMID26643252
Freeman J
; Smith D
; Latinkic B
; Ewan K
; Samuel L
; Zollo M
; Marino N
; Tyas L
; Jones N
; Dale TC
Mol Cancer
2015[Dec]; 14
(ä): 206
PMID26643252
show ga
BACKGROUND: Wnt/?-catenin signaling is often portrayed as a simple pathway that
is initiated by Wnt ligand at the cell surface leading, via linear series of
interactions between 'core pathway' members, to the induction of nuclear
transcription from genes flanked by ?-catenin/TCF transcription factor binding
sites. Wnt/?-catenin signaling is also regulated by a much larger set of
'non-core regulators'. However the relationship between 'non-core regulators' is
currently not well understood. Aberrant activation of the pathway has been shown
to drive tumorgenesis in a number of different tissues. METHODS: Mammalian cells
engineered to have a partially-active level of Wnt/?-catenin signaling were
screened by transfection for proteins that up or down-regulated a mid-level of
TCF-dependent transcription induced by transient expression of an activated LRP6
Wnt co-receptor (?NLRP). RESULTS: 141 novel regulators of TCF-dependent
transcription were identified. Surprisingly, when tested without ?NLRP
activation, most up-regulators failed to alter TCF-dependent transcription.
However, when expressed in pairs, 27 % (466/1170) functionally interacted to
alter levels of TCF-dependent transcription. When proteins were displayed as
nodes connected by their ability to co-operate in the regulation of TCF-dependent
transcription, a network of functional interactions was revealed. In this
network, 'core pathway' components (Eg. ?-catenin, GSK-3, Dsh) were found to be
the most highly connected nodes. Activation of different nodes in this network
impacted on the sensitivity to Wnt pathway small molecule antagonists.
CONCLUSIONS: The 'functional connectome' identified here strongly supports an
alternative model of the Wnt pathway as a complex context-dependent network. The
network further suggests that mutational activation of highly connected Wnt
signaling nodes predisposed cells to further context-dependent alterations in
levels of TCF-dependent transcription that may be important during tumor
progression and treatment.
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