Resveratrol inhibits PDGF receptor mitogenic signaling in mesangial cells: role of PTP1B.
Mesangioproliferative glomerulonephritis is associated with overactive PDGF receptor signal transduction. We show that the phytoalexin resveratrol dose dependently inhibits PDGF-induced DNA synthesis in mesangial cells with an IC(50) of 10 microM without inducing apoptosis. Remarkably, the increased SIRT1 deacetylase activity induced by resveratrol was not necessary for this inhibitory effect. Resveratrol significantly blocked PDGF-stimulated c-Src and Akt kinase activation, resulting in reduced cyclin D1 expression and attenuated pRb phosphorylation and cyclin-dependent kinase-2 (CDK2) activity. Furthermore, resveratrol inhibited PDGFR phosphorylation at the PI 3 kinase and Grb-2 binding sites tyrosine-751 and tyrosine-716, respectively. This deficiency in PDGFR phosphorylation resulted in significant inhibition of PI 3 kinase and Erk1/2 MAPK activity. Interestingly, resveratrol increased the activity of protein tyrosine phosphatase PTP1B, which dephosphorylates PDGF-stimulated phosphorylation at tyrosine-751 and tyrosine-716 on PDGFR with concomitant reduction in Akt and Erk1/2 kinase activity. PTP1B significantly inhibited PDGF-induced DNA synthesis without inducing apoptosis. These results for the first time provide evidence that the stilbene resveratrol targets PTP1B to inhibit PDGFR mitogenic signaling.
Venkatesan
Balachandar
B
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
Ghosh-Choudhury
Nandini
N
Das
Falguni
F
Mahimainathan
Lenin
L
Kamat
Amrita
A
Kasinath
Balakuntalam S
BS
Abboud
Hanna E
HE
Choudhury
Goutam Ghosh
GG
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D019938:Cyclin D1 / Q000037:antagonists & inhibitors; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D004261:DNA Replication / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D050527:Mesangial Cells / Q000187:drug effects* / Q000201:enzymology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D019061:src-Family Kinases
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016160:Retinoblastoma Protein; D013267:Stilbenes; D019938:Cyclin D1; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D051057:Proto-Oncogene Proteins c-akt; D051357:Cyclin-Dependent Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol