Glucose activates protein kinase C-zeta/lambda through proline-rich tyrosine kinase-2, extracellular signal-regulated kinase, and phospholipase D - Anovel mechanism for activating glucose transporter translocation

Insulin controls glucose uptake by translocating GLUT4 and other glucose tr ansporters to the plasma membrane in muscle and adipose tissues by a mechan ism that appears to require protein kinase C (PKC)-zeta/lambda operating do wnstream of phosphatidylinositol 3-kinase. In diabetes mellitus, insulin-st imulated glucose uptake is diminished, but with hyperglycemia, uptake is ma intained but by uncertain mechanisms. Presently, we found that glucose acut ely activated PKC-zeta/lambda in rat adipocytes and rat skeletal muscle pre parations by a mechanism that was independent of phosphatidylinositol 3-kin ase but, interestingly, dependent on the apparently sequential activation o f the dantrolene-sensitive, nonreceptor proline-rich tyrosine kinase-2; com ponents of the extracellular signal-regulated kinase (ERK) pathway, includi ng, GRB2, SOS, RAS, RAN, MEK1 and ERK1/2; and, most interestingly, phosphol ipase D, thus yielding increases in phosphatidic acid, a known activator of PKC-zeta/lambda. This activation of PKC-zeta/lambda, moreover, appeared to be required for glucose-induced increases in GLUT4 translocation and gluco se transport in adipocytes and muscle cells. Our findings suggest the opera tion of a novel pathway for activating PKC-zeta/lambda and glucose transpor t.