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.
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
Quon
M J
MJ
Reed
B C
BC
Dikic
I
I
Farese
R V
RV
D017667:Adipocytes / Q000201:enzymology / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D003620:Dantrolene / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2; D005947:Glucose / Q000494:pharmacology*; D051275:Glucose Transporter Type 4; D007527:Isoenzymes; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D000077191:Wortmannin; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
D000730:Androstadienes; D003620:Dantrolene; D004791:Enzyme Inhibitors; D005419:Flavonoids; D051418:Focal Adhesion Kinase 2; D005947:Glucose; D051275:Glucose Transporter Type 4; D007527:Isoenzymes; D020928:Mitogen-Activated Protein Kinases; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010739:Phospholipase D; D011493:Protein Kinase C; D011505:Protein-Tyrosine Kinases; D000077191:Wortmannin; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta; C495694:Slc2a4 protein, rat; C496054:Ptk2b protein, rat; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one