GLUT1 enhances mTOR activity independently of TSC2 and AMPK.
Authors Buller CL, Heilig CW, Brosius FC
Submitted By Frank Brosius on 2/22/2012
Status Published
Journal American journal of physiology. Renal physiology
Year 2011
Date Published 9/1/2011
Volume : Pages 301 : F588 - F596
PubMed Reference 21613414
Abstract Enhanced GLUT1 expression in mesangial cells plays an important role in the
development of diabetic nephropathy by stimulating signaling through several
pathways resulting in increased glomerular matrix accumulation. Similarly,
enhanced mammalian target of rapamycin (mTOR) activation has been implicated in
mesangial matrix expansion and glomerular hypertrophy in diabetes. We sought to
examine whether enhanced GLUT1 expression increased mTOR activity and, if so, to
identify the mechanism. We found that levels of GLUT1 expression and mTOR
activation, as evidenced by S6 kinase (S6K) and 4E-BP-1 phosphorylation, changed
in tandem in cell lines exposed to elevated levels of extracellular glucose. We
then showed that increased GLUT1 expression enhanced S6K phosphorylation by 1.7-
to 2.9-fold in cultured mesangial cells and in glomeruli from GLUT1 transgenic
mice. Treatment with the mTOR inhibitor, rapamycin, eliminated the GLUT1 effect
on S6K phosphorylation. In cells lacking functional tuberous sclerosis complex
(TSC) 2, GLUT1 effects on mTOR activity persisted, indicating that GLUT1 effects
were not mediated by TSC. Similarly, AMP kinase activity was not altered by
enhanced GLUT1 expression. Conversely, enhanced GLUT1 expression led to a
2.4-fold increase in binding of mTOR to its activator, Rheb, and a commensurate
2.1-fold decrease in binding of Rheb to glyceraldehyde 3-phosphate dehydrogenase
(GAPDH) consistent with mediation of GLUT1 effects by a metabolic effect on
GAPDH. Thus, GLUT1 expression appears to augment mesangial cell growth and
matrix protein accumulation via effects on glycolysis and decreased GAPDH
interaction with Rheb.

Investigators with authorship
Frank BrosiusUniversity of Arizona