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2015 ; 10
(6
): e0130818
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Endocytic Adaptor Protein Tollip Inhibits Canonical Wnt Signaling
#MMPMID26110841
Toru? A
; Szyma?ska E
; Castanon I
; Woli?ska-Nizio? L
; Bartosik A
; Jastrz?bski K
; Mi?tkowska M
; González-Gaitán M
; Miaczynska M
PLoS One
2015[]; 10
(6
): e0130818
PMID26110841
show ga
Many adaptor proteins involved in endocytic cargo transport exhibit additional
functions in other cellular processes which may be either related to or
independent from their trafficking roles. The endosomal adaptor protein Tollip is
an example of such a multitasking regulator, as it participates in trafficking
and endosomal sorting of receptors, but also in interleukin/Toll/NF-?B signaling,
bacterial entry, autophagic clearance of protein aggregates and regulation of
sumoylation. Here we describe another role of Tollip in intracellular signaling.
By performing a targeted RNAi screen of soluble endocytic proteins for their
additional functions in canonical Wnt signaling, we identified Tollip as a
potential negative regulator of this pathway in human cells. Depletion of Tollip
potentiates the activity of ?-catenin/TCF-dependent transcriptional reporter,
while its overproduction inhibits the reporter activity and expression of Wnt
target genes. These effects are independent of dynamin-mediated endocytosis, but
require the ubiquitin-binding CUE domain of Tollip. In Wnt-stimulated cells,
Tollip counteracts the activation of ?-catenin and its nuclear accumulation,
without affecting its total levels. Additionally, under conditions of
ligand-independent signaling, Tollip inhibits the pathway after the stage of
?-catenin stabilization, as observed in human cancer cell lines, characterized by
constitutive ?-catenin activity. Finally, the regulation of Wnt signaling by
Tollip occurs also during early embryonic development of zebrafish. In summary,
our data identify a novel function of Tollip in regulating the canonical Wnt
pathway which is evolutionarily conserved between fish and humans.
Tollip-mediated inhibition of Wnt signaling may contribute not only to embryonic
development, but also to carcinogenesis. Mechanistically, Tollip can potentially
coordinate multiple cellular pathways of trafficking and signaling, possibly by
exploiting its ability to interact with ubiquitin and the sumoylation machinery.
|Animals
[MESH]
|Carcinogenesis/genetics
[MESH]
|Embryonic Development/genetics
[MESH]
|HEK293 Cells
[MESH]
|Humans
[MESH]
|Intracellular Signaling Peptides and Proteins/genetics/*metabolism
[MESH]
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