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 pathol ogical processes. Presently, we found that glucose and certain sugars rapid ly activated extracellular signal-regulated kinase (ERK) by a mechanism tha t was: (a) independent of glucose uptake/metabolism and protein kinase C bu t nevertheless cytochalasin B-inhibitable; (b) dependent upon proline-rich tyrosine kinase-2 (PYK2), GRBB, SOS, RAS, RAF, and MEK1; and (c) amplified by overexpression of the Glut1, but not Glut2, Gluts, or Glut4, glucose tra nsporter. This amplifying effect was independent of glucose uptake but depe ndent on residues 463-468, IASGFR, in the Glut1 C terminus. Accordingly, gl ucose effects on ERK were amplified by expression of Glut 4/Glut1 or Glut2/ Glut1 chimeras containing IASGFR but not by Glut1/Glut4 or Glut1/Grlut4 chi meras 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. Gl ucose stimulated the phosphorylation of tyrosine residues 402 and 881 in PY K2 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 requi res PYK2 and residues 463-468, LASGFR, in the Glut1 C terminus and (b) Glut l serves as a sensor, transducer, and amplifier for glucose signaling to PY K2 and ERK.