Plotting the placental protein NRK: Understanding the molecular
evolution processes underlying placenta acquisition in eutherian ancestors


Date:
March 2, 2022
Source:
Tokyo Institute of Technology
Summary:
The molecular evolution of placental protein NRK and its function
in regulating placental growth has finally been clarified. They
elucidated that eutherian NRK regulates placental development by
a novel mechanism, modulating the CK2-PTEN-AKT pathway. They also
determined that this new function was acquired due to the amazingly
rapid molecular evolution of NRK in eutherian ancestors.



FULL STORY ==========================================================================
The molecular evolution of placental protein NRK and its function in
regulating placental growth has finally been clarified by researchers
from Tokyo Tech.

They elucidated that eutherian NRK regulates placental development by a
novel mechanism, modulating the CK2-PTEN-AKT pathway. They also determined
that this new function was acquired due to the amazingly rapid molecular evolution of NRK in eutherian ancestors.


========================================================================== Viviparity is a reproductive strategy in which the mother provides
the embryo with a continuous supply of nutrients in her body to
grow sufficiently before giving birth. Compared with oviparity, it
can increase the survival rate of fetuses and newborns. The mammalian
placenta is a representative tissue for supplying nutrients to the fetus
and is evolutionarily novel. NIK-related kinase (NRK) is a key protein discovered to play an important role in placental development. Previous research showed that mouse NRK is specifically expressed in the placenta,
and "knocking out" this protein resulted in placental hyperplasia and
difficult delivery. However, the specifics on how this was achieved
were unclear.

This is soon to be an issue of the past, with a team of researchers
from Tokyo Institute of Technology(Tokyo Tech) in Japan, publishing a
study in Molecular Biology and Evolution, elucidating the evolutionary
factors and molecular mechanisms involved in the observed functions of
NRK. Elucidating these issues behind NRK function is of great importance, according to the author Assistant Professor Toshiaki Fukushima, who
says, "It will not only lead to understanding some of the mechanisms
of placental evolution but provide a basis for developing diagnostic
and therapeutic methods for pregnancy complications, including fetal
growth retardation." To understand the evolutionary patterns involved,
the team carried out synteny and phylogenetic studies on the Nrk gene in different species as it was detected across vertebrates. Interestingly,
the Nrk gene sequence of eutherians was found to significantly differ from other groups, and phylogenetic analysis showed that NRK protein underwent
rapid molecular evolution including amino acid insertions/substitutions
in the process of evolving into eutherians at an unparalleled rate.

These evolutionary patterns gave insight into the molecular mechanisms
of NRK function in eutherians. Previous studies had already confirmed
that the ability to impede cell proliferation was restricted only to
this form of NRK, with other members of the family proteins lacking this suppressive function. On closer examination of the protein structure, scientists were able to identify specific regions of interest. One such
section identified was situated in the middle region of this protein,
spanning from amino acid 565-868. Functional assays revealed that it
was bound to casein kinase-2 (CK2), an inactivator of PTEN, which is
a regulator of the AKT signaling pathway. Another important region
identified was the citron homology domain located at the end of the
protein. Through fluorescent imaging, it was discovered that this domain
is crucial for the localization of NRK to the plasma membrane.

Based on the subsequent experiments, this research team revealed detailed molecular mechanism of NRK function. This protein is localized to the
plasma membrane by means of the citron homology domain, where the middle
region binds to CK2, thus preventing it from phosphorylating PTEN. This activated PTEN downregulates phosphatidylinositol (3,4,5)-trisphosphate,
an important driving factor of AKT signaling. Reduced AKT signaling
leads to attenuation of cell proliferation. CK2, PTEN, and AKT have been reported to regulate placental growth, respectively, and now it has been revealed that the placenta-specific protein NRK regulates this pathway
as an upstream factor.

Importantly, the functional regions in NRK were gained in the process
of evolving into eutherians. This study is the first to suggest that
placental protein NRK is now control of cell proliferation signaling by
getting functional sequences in the eutherian ancestors. As the author concludes, "NRK evolution facilitated the proper control of placental development in placenta mammals." This research opens up new avenues
for investigating molecular evolutions for mammals to acquire the unique developmental tissue, the placenta.

========================================================================== Story Source: Materials provided by Tokyo_Institute_of_Technology. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Beni Lestari, Satomi Naito, Akinori Endo, Hidenori Nishihara,
Akira Kato,
Erika Watanabe, Kimitoshi Denda, Masayuki Komada, Toshiaki
Fukushima.

Placental Mammals Acquired Functional Sequences in NRK
for Regulating the CK2-PTEN-AKT Pathway and Placental Cell
Proliferation. Molecular Biology and Evolution, 2022; 39 (2) DOI:
10.1093/molbev/msab371 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220302092717.htm

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