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Novel Shuttling Domain in a Regulator ( RSC1A1 ) of Transporter SGLT1 Steers Cell Cycle‐Dependent Nuclear Location
Author(s) -
Filatova Alina,
Leyerer Marina,
Gorboulev Valentin,
Chintalapati Chakravarthi,
Reinders Yvonne,
Müller Thomas D.,
Srinivasan Aruna,
Hübner Stefan,
Koepsell Hermann
Publication year - 2009
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2009.00982.x
Subject(s) - nuclear transport , biology , microbiology and biotechnology , phosphorylation , nuclear localization sequence , nuclear export signal , cell cycle , nuclear protein , importin , calmodulin , protein kinase c , cell nucleus , transcription factor , biochemistry , cell , nucleus , gene , enzyme
The gene product of RSC1A1 , RS1, participates in the regulation of the Na + ‐ d ‐glucose cotransporter SGLT1. RS1 inhibits release of SGLT1 from the trans Golgi network. In subconfluent LLC‐PK 1 cells, RS1 migrates into the nucleus and modulates transcription of SGLT1, whereas most confluent cells do not contain RS1 in the nuclei. We showed that confluence‐dependent nuclear location of RS1 is because of different phases of the cell cycle and identified a RS1 nuclear shuttling domain (RNS) with an associated protein kinase C (PKC) phosphorylation site (RNS‐PKC) that mediates cell cycle‐dependent nuclear location. RNS‐PKC contains a novel non‐conventional nuclear localization signal interacting with importin β1, a nuclear export signal mediating export via protein CRM1 and a Ca 2+ ‐dependent calmodulin binding site. PKC and calmodulin compete for binding to RNS‐PKC. Mutagenesis experiments and analyses of the phosphorylation status suggest the following sequences of events. Subconfluent cells without and with synchronization to the G2/M phase contain non‐phosphorylated RNS‐PKC that mediates nuclear import of RS1 but not its export. During confluence or synchronization of subconfluent cells to the G2/M phase, phosphorylation of RNS‐PKC mediates rapid nuclear export of RS1.