The Wnt pathway gets even more complicated

Date:
September 15, 2020
Source:
IMBA- Institute of Molecular Biotechnology of the Austrian Academy
of Sciences
Summary:
A new role for Casein Kinase-1 on RNF43 is identified.



FULL STORY ==========================================================================
The Wnt signalling pathway has been studied for decades, still it holds surprises in store. Bon-Kyoung Koo, group leader at IMBA -- Institute
of Molecular Biotechnology of the Austrian Academy of Sciences and
Tadasuke Tsukiyama at the Hokkaido University have now uncovered a
new and unexpected role for a key component of the Wnt pathway, Casein Kinase-1, in regulating the pathway at the plasma membrane. This is the
result of a study published today in Nature Communications,and broadens
our understanding of the regulatory loops controlling the Wnt pathway,
a pathway associated with stem cell maintenance, cell proliferation
and cancer.


==========================================================================
In the Wnt pathway, Casein Kinase-1 is well-known as a part of the
destruction complex. In the steady-state, when no Wnt signal is present,
this complex destines the downstream mediator b-catenin for constant degradation. When a Wnt signal reaches the cell, the Wnt receptor
Frizzled inhibits the destruction complex. This allows b-catenin to
enter the nucleus, where it sets downstream responses in motion.

Casein Kinase-1 responsible for phosphoswitch of RNF43 In the newly
published study, Tadasuke Tsukiyama and Bon-Kyoung Koo find that Casein Kinase-1 also regulates Wnt signalling at the plasma membrane. At the
plasma membrane, the ubiquitin ligase RNF43 marks the Wnt receptor
Frizzled for degradation, effectively shutting off the Wnt signalling
pathway. The researchers discovered that Casein Kinase-1 triggers the
switch for RNF43: When Casein Kinase-1 phosphorylates RNF43, RNF43
is activated and marks Frizzled with ubiquitin for degradation. When
Casein Kinase-1 does not phosphorylate RNF43, RNF43 is inactive and
signalling via Frizzled can continue. "We find that Casein Kinase-1
has an essential function in activating RNF43. With our work, we are effectively reintroducing Casein Kinase-1 to the field, defining a new
role for this well-known regulator," Bon-Kyoung Koo explains.

This new understanding could lead to a novel approach for reining the
Wnt pathway in cancer cells. Tsukiyama and Koo found that a mutation
in RNF43's extracellular domain interrupts its function in negative
feedback regulation, the tumour suppressor function of RNF43. This
mutation changes RNF43 into an oncogenic form that abnormally enhances
Wnt signalling. The researchers found that mimicking the phosphorylation,
by adding negatively charged residues to the mutant RNF43, can revert it
back to a functional tumour suppressor. With this mimicked phosphoswitch,
the mutant RNF43 was again able to inhibit Frizzled. "Some patients carry
a mutation in RNF43's extracellular domain. We hope that, once we know how
to mimic phosphorylation in cells, this phosphorylation would revive the
RNF43 tumour suppressor, enabling it to again control the Wnt pathway," Bon-Kyoung Koo adds.


========================================================================== Story Source: Materials provided by IMBA-_Institute_of_Molecular_Biotechnology_of_the
Austrian_Academy_of_Sciences. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Tadasuke Tsukiyama, Juqi Zou, Jihoon Kim, Shohei Ogamino, Yuki
Shino,
Takamasa Masuda, Alessandra Merenda, Masaki Matsumoto, Yoichiro
Fujioka, Tomonori Hirose, Sayuri Terai, Hidehisa Takahashi,
Tohru Ishitani, Keiichi I. Nakayama, Yusuke Ohba, Bon-Kyoung Koo,
Shigetsugu Hatakeyama.

A phospho-switch controls RNF43-mediated degradation of Wnt
receptors to suppress tumorigenesis. Nature Communications, 2020;
11 (1) DOI: 10.1038/ s41467-020-18257-3 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200915105957.htm

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