%0 Journal Article %A Cai, Na %D 2019 %T The kinase activity of the channel-kinase protein TRPM7 regulates stability and localization of the TRPM7 channel in polarized epithelial cells %U https://hra.figshare.com/articles/journal_contribution/The_kinase_activity_of_the_channel-kinase_protein_TRPM7_regulates_stability_and_localization_of_the_TRPM7_channel_in_polarized_epithelial_cells/7796180 %R 10.25376/hra.7796180.v1 %2 https://hra.figshare.com/ndownloader/files/14509553 %K TRPM7 %K Kinase %K 14-3-3- binding %K Molecular Biology %X p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 11.0px Helvetica}
The channel-kinase transient receptor
potential melastatin 7 (TRPM7) is a bifunctional
protein with ion channel and kinase domains.
The kinase activity of TRPM7 has been linked
to the regulation of a broad range of cellular
activities, but little is understood as to how the
channel itself is regulated by its own kinase
activity. Here, using several mammalian cell
lines expressing wild-type TRPM7 or kinaseinactive
variants, we discovered that compared
with the cells expressing wildtype TRPM7, cells
in which TRPM7’s kinase activity was
inactivated had faster degradation, elevated
ubiquitination, and increased intracellular
retention of the channel. Mutational analysis of
TRPM7 autophosphorylation sites further
revealed a role for Ser-1360 of TRPM7 as a key
residue mediating both TRPM7 stability and
intracellular trafficking. Additional trafficking
roles were uncovered for Ser-1403 and Ser-1567,
whose phosphorylation by TRPM7’s kinase
activity mediated the interaction of the channel
with the signaling protein 14-3-3θ. In summary,
our results point to a critical role for TRPM7's
kinase activity in regulating proteasomemediated
turnover of the TRPM7 channel and
controlling its cellular localization in polarized
epithelial cells. Overall, these findings improve
our understanding of the significance of
TRPM7’s kinase activity for functional
regulation of its channel activity.
%I Health Research Alliance