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PPARγ‐independent activation of Src by Thiazolidinediones involves intracellular calcium and phosphatases
Author(s) -
Dewar Brian James,
Gardner Olivia S,
Graves Lee M
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1121-d
Subject(s) - proto oncogene tyrosine protein kinase src , chemistry , phosphorylation , microbiology and biotechnology , tyrosine phosphorylation , troglitazone , tyrosine kinase , kinase , signal transduction , biology , biochemistry , peroxisome proliferator activated receptor , receptor
Thiazolidinediones (TZDs) are synthetic ligands for the peroxisome proliferator‐activated receptorγ (PPARγ), but also elicit PPARγ‐independent effects, most notably activation of MAPKs. Src, a non‐receptor tyrosine kinase was recently shown to play a role in EGFR‐dependent activation of MAPK following ciglitazone treatment; however, mechanisms involved in Src activation by TZDs are not completely understood. In this study the TZDs, ciglitazone and troglitazone, induced rapid activation of Src in rat liver epithelial cells, GN4. We observed an increase in Src Tyr416 phosphorylation that was accompanied by loss of Tyr527 phosphorylation. Additionally, we observed that derivatives of each TZD, which lack the ability to activate PPARγ, produced similar changes in Src phosphorylation, suggesting a mechanism independent of PPARγ. Pre‐treatment of cells with the intracellular calcium chelator, BAPTA‐AM prevented Src Tyr416 phosphorylation, whereas removal of extracellular calcium had no effect. Interestingly, inhibition of Pyk2, a calcium‐dependent kinase known to associate with activated Src, did not affect TZD‐induced changes in Src phosphorylation. However, PP 2 , a Src inhibitor, prevented Pyk2 phosphorylation following TZD exposure, suggesting that Pyk2 activation is mediated by Src. Pervanadate, a tyrosine phosphatase inhibitor, prevented loss of Tyr527 phosphorylation, suggesting that phosphatases play a role in mediating activation of Src by TZDs. Our data demonstrate that dephosphorylation of Src may involve a calcium‐responsive phosphatase, leading to subsequent activation Src by TZDs.