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

2019-03-03T05:23:11Z (GMT) by Na Cai
p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 11.0px Helvetica} <p>The channel-kinase transient receptor</p> <p>potential melastatin 7 (TRPM7) is a bifunctional</p> <p>protein with ion channel and kinase domains.</p> <p>The kinase activity of TRPM7 has been linked</p> <p>to the regulation of a broad range of cellular</p> <p>activities, but little is understood as to how the</p> <p>channel itself is regulated by its own kinase</p> <p>activity. Here, using several mammalian cell</p> <p>lines expressing wild-type TRPM7 or kinaseinactive</p> <p>variants, we discovered that compared</p> <p>with the cells expressing wildtype TRPM7, cells</p> <p>in which TRPM7’s kinase activity was</p> <p>inactivated had faster degradation, elevated</p> <p>ubiquitination, and increased intracellular</p> <p>retention of the channel. Mutational analysis of</p> <p>TRPM7 autophosphorylation sites further</p> <p>revealed a role for Ser-1360 of TRPM7 as a key</p> <p>residue mediating both TRPM7 stability and</p> <p>intracellular trafficking. Additional trafficking</p> <p>roles were uncovered for Ser-1403 and Ser-1567,</p> <p>whose phosphorylation by TRPM7’s kinase</p> <p>activity mediated the interaction of the channel</p> <p>with the signaling protein 14-3-3θ. In summary,</p> <p>our results point to a critical role for TRPM7's</p> <p>kinase activity in regulating proteasomemediated</p> <p>turnover of the TRPM7 channel and</p> <p>controlling its cellular localization in polarized</p> <p>epithelial cells. Overall, these findings improve</p> <p>our understanding of the significance of</p> <p>TRPM7’s kinase activity for functional</p> <p>regulation of its channel activity.</p>



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