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J. Biol. Chem.-2018-Cai-jbc.RA118.001925.pdf (2.82 MB)

The kinase activity of the channel-kinase protein TRPM7 regulates stability and localization of the TRPM7 channel in polarized epithelial cells

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journal contribution
posted on 2019-03-03, 05:23 authored by Na Cai
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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.


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