The Ion Transporter NKCC1 Links Cell Volume to Cell Mass Regulation by Suppressing mTORC1
Wael L. Demian,
Avinash Persaud,
Chong Jiang,
Étienne Coyaud,
Shixuan Liu,
Andras Kapus,
Ran Kafri,
Brian Raught,
Daniela Rotin
Affiliations
Wael L. Demian
Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Biochemistry Department, University of Toronto, Toronto, ON M5S 1A8, Canada
Avinash Persaud
Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Biochemistry Department, University of Toronto, Toronto, ON M5S 1A8, Canada
Chong Jiang
Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
Étienne Coyaud
Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2C1, Canada
Shixuan Liu
Biochemistry Department, University of Toronto, Toronto, ON M5S 1A8, Canada
Andras Kapus
Biochemistry Department, University of Toronto, Toronto, ON M5S 1A8, Canada; St. Michael Hospital Research Institute, Toronto, ON M5B 1W8, Canada
Ran Kafri
Biochemistry Department, University of Toronto, Toronto, ON M5S 1A8, Canada
Brian Raught
Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2C1, Canada
Daniela Rotin
Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Biochemistry Department, University of Toronto, Toronto, ON M5S 1A8, Canada; Corresponding author
Summary: mTORC1 regulates cellular growth and is activated by growth factors and by essential amino acids such as Leu. Leu enters cells via the Leu transporter LAT1-4F2hc (LAT1). Here we show that the Na+/K+/2Cl− cotransporter NKCC1 (SLC12A2), a known regulator of cell volume, is present in complex with LAT1. We further show that NKCC1 depletion or deletion enhances LAT1 activity, as well as activation of Akt and Erk, leading to activation of mTORC1 in cells, colonic organoids, and mouse colon. Moreover, NKCC1 depletion reduces intracellular Na+ concentration and cell volume (size) and mass and stimulates cell proliferation. NKCC1, therefore, suppresses mTORC1 by inhibiting its key activating signaling pathways. Importantly, by linking ion transport and cell volume regulation to mTORC1 function, NKCC1 provides a long-sought link connecting cell volume (size) to cell mass regulation. : Demian et al. show that the Na/K/2Cl ion transporter NKCC1, a known regulator of cell volume, inhibits the Leu transporter LAT1 and the Akt/Erk pathways, thus inhibiting mTORC1 activation and providing a link between cell volume (size) and cell mass regulation. Keywords: Leu transporter, LAT1-4F2hc, SLC7A5-SLC3A2, SLC12A2, Gln transporter, mTORC1, cell volume, cell mass
