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J Biol Chem. 2018 Jul 20;293(29):11491-11504. doi: 10.1074/jbc.RA118.001925. Epub 2018 Jun 4.

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

Author information

1
From the Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854 and.
2
the University of Misan, Amarah 62001, Iraq.
3
From the Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854 and runnellw@rwjms.rutgers.edu.

Abstract

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 WT TRPM7 or kinase-inactive variants, we discovered that compared with the cells expressing WT 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 proteasome-mediated 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.

KEYWORDS:

14-3-3 protein; TRPM7; ion channel; phosphorylation; protein kinase; proteosome-mediated turnover; transient receptor potential cation channel subfamily M member 7; transient receptor potential channels (TRP channels)

PMID:
29866880
PMCID:
PMC6065181
[Available on 2019-07-20]
DOI:
10.1074/jbc.RA118.001925
[Indexed for MEDLINE]

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