Cbl, IRS-1, and IRS-2 mediate effects of rosiglitazone on PI3K, PKC-lambda, and glucose transport in 3T3/L1 adipocytes.
The thiazolidenedione, rosiglitazone, increases basal and/or insulin-stimulated glucose transport in various cell types by diverse but uncertain mechanisms that may involve insulin receptor substrate (IRS)-1-dependent PI3K. Presently, in 3T3/L1 adipocytes, rosiglitazone induced sizable increases in basal glucose transport that were: dependent on PI3K, 3-phosphoinositide-dependent protein kinase-1 (PDK-1), and PKC-lambda; accompanied by increases in tyrosine phosphorylation of Cbl and Cbl-dependent increases in PI3K and PKC-lambda activity; but not accompanied by increases in IRS-1/2-dependent PI3K or protein kinase B activity. Additionally, rosiglitazone increased IRS-1 and IRS-2 levels, thereby enhancing insulin effects on IRS-1- and IRS-2-dependent PI3K and downstream signaling factors PKC-lambda and protein kinase B. Our findings suggest that Cbl participates in mediating effects of rosiglitazone on PI3K, PDK-1, and PKC-lambda and the glucose transport system and that this Cbl-dependent pathway complements the IRS-1 and IRS-2 pathways for activating PI3K, PDK-1, and PKC-lambda during combined actions of rosiglitazone and insulin in 3T3/L1 cells.
Standaert
Mary L
ML
Research Service, J. A. Haley Veterans' Hospital, 13000 Bruce B. Downs Boulevard, Tampa, Florida 33612, USA.
Kanoh
Yoshinori
Y
Sajan
Mini P
MP
Bandyopadhyay
Gautam
G
Farese
Robert V
RV
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D000963:Antimetabolites; D001693:Biological Transport, Active / Q000187:drug effects; D015153:Blotting, Western; D003847:Deoxyglucose; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects*; D010750:Phosphoproteins / Q000187:drug effects* / Q000235:genetics; D011493:Protein Kinase C / Q000096:biosynthesis / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000099293:Protein Kinase C-lambda
D000963:Antimetabolites; D003847:Deoxyglucose; D005947:Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077154:Rosiglitazone; D013844:Thiazoles; D045162:Thiazolidinediones; D000099293:Protein Kinase C-lambda; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse