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

• Insulin controls glucose uptake by translocating GLUT4 and other glucose transporters to the plasma membrane in muscle and adipose tissues by a mechanism that appears to require protein kinase C (PKC)-zeta/lambda operating downstream of phosphatidylinositol 3-kinase. In diabetes mellitus, insulin-stimulated glucose uptake is diminished, but with hyperglycemia, uptake is maintained but by uncertain mechanisms. Presently, we found that glucose acutely activated PKC-zeta/lambda in rat adipocytes and rat skeletal muscle preparations by a mechanism that was independent of phosphatidylinositol 3-kinase but, interestingly, dependent on the apparently sequential activation of the dantrolene-sensitive, nonreceptor proline-rich tyrosine kinase-2; components of the extracellular signal-regulated kinase (ERK) pathway, including, GRB2, SOS, RAS, RAF, MEK1 and ERK1/2; and, most interestingly, phospholipase 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 glucose transport in adipocytes and muscle cells. Our findings suggest the operation of a novel pathway for activating PKC-zeta/lambda and glucose transport.

Nyckelord

Adipocytes/enzymology/metabolism

Androstadienes/pharmacology

Animals

Dantrolene/pharmacology

Enzyme Inhibitors/pharmacology

Flavonoids/pharmacology

Glucose/*pharmacology

Mitogen-Activated Protein Kinases/*metabolism

Monosaccharide Transport Proteins/metabolism

Muscle Proteins

Muscle; Skeletal/enzymology/metabolism

Phospholipase D/*metabolism

Protein Kinase C/*metabolism

Protein Transport

Protein-Tyrosine Kinase/*metabolism

Rats

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)