Resveratrol inhibits PDGF receptor mitogenic signaling in mesangial cells: Role of PTP1B

Balachandar Venkatesan, Nandini Ghosh-Choudhury, Falguni Das, Lenin Mahimainathan, Amrita Kamat, Balakuntalam S. Kasinath, Hanna E. Abboud, Goutam Ghosh Choudhury

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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 IC50 of 10 μM 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.

Original languageEnglish (US)
Pages (from-to)3469-3482
Number of pages14
JournalFASEB Journal
Volume22
Issue number10
DOIs
StatePublished - Oct 2008

Keywords

  • Akt kinase
  • CDK2
  • SIRT1

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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