Glucose activates mitogen-activated protein kinase (extracellular signal-regulated kinase) through proline-rich tyrosine kinase-2 and the Glut1 glucose transporter.
Glucose serves as both a nutrient and regulator of physiological and pathological processes. Presently, we found that glucose and certain sugars rapidly activated extracellular signal-regulated kinase (ERK) by a mechanism that was: (a) independent of glucose uptake/metabolism and protein kinase C but nevertheless cytochalasin B-inhibitable; (b) dependent upon proline-rich tyrosine kinase-2 (PYK2), GRB2, SOS, RAS, RAF, and MEK1; and (c) amplified by overexpression of the Glut1, but not Glut2, Glut3, or Glut4, glucose transporter. This amplifying effect was independent of glucose uptake but dependent on residues 463-468, IASGFR, in the Glut1 C terminus. Accordingly, glucose effects on ERK were amplified by expression of Glut4/Glut1 or Glut2/Glut1 chimeras containing IASGFR but not by Glut1/Glut4 or Glut1/Glut2 chimeras lacking these residues. Also, deletion of Glut1 residues 469-492 was without effect, but mutations involving serine 465 or arginine 468 yielded dominant-negative forms that inhibited glucose-dependent ERK activation. Glucose stimulated the phosphorylation of tyrosine residues 402 and 881 in PYK2 and binding of PYK2 to Myc-Glut1. Our findings suggest that: (a) glucose activates the GRB2/SOS/RAS/RAF/MEK1/ERK pathway by a mechanism that requires PYK2 and residues 463-468, IASGFR, in the Glut1 C terminus and (b) Glut1 serves as a sensor, transducer, and amplifier for glucose signaling to PYK2 and ERK.
Bandyopadhyay
G
G
J. A. Haley Veterans' Hospital Research Service, and Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida 33612, USA.
Sajan
M P
MP
Kanoh
Y
Y
Standaert
M L
ML
Burke
T R
TR
Quon
M J
MJ
Reed
B C
BC
Dikic
I
I
Noel
L E
LE
Newgard
C B
CB
Farese
R
R
D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D003847:Deoxyglucose / Q000378:metabolism; D004187:Disaccharides / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2; D005947:Glucose / Q000494:pharmacology*; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D051381:Rats
D004187:Disaccharides; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D009004:Monosaccharide Transport Proteins; C495678:Slc2a1 protein, mouse; C495679:Slc2a1 protein, rat; D003847:Deoxyglucose; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse; C496054:Ptk2b protein, rat; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose