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First published on September 13, 2006; DOI: 10.1124/mol.106.026534

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Received for publication May 24, 2006.
Revised September 4, 2006.
Accepted for publication September 6, 2006.

2,3,7,8-tetrachlorodibenzo-p-dioxin and EGF cooperatively suppress PPAR{gamma}1 stimulation and restore focal adhesion complexes during adipogenesis: Selective contributions of Src, Rho and Erk distinguish these overlapping processes in C3H10T1/2 cells

Xueqing Liu 1 Colin Jefcoate 1*

1 Department of Pharmacology, University of Wisconsin-Madison Medical School

* Address correspondence to: E-mail: liu1{at}wisc.edu

Abstract

Stimulation of PPAR{gamma}1 and adipogenesis in multipotential C3H10T1/2 cells by dexamethasone and methylisobutylxanthine (DM) is suppressed by 2,3,7,8 tetrachlorodibenzodioxin (TCDD) (10nM). This suppression requires sustained activation of Erk1/2. We show that it arises from an effect of TCDD on EGF signaling. DM initiates an early loss of cell adhesion which is reversed by this TCDD/EGF synergy. Src kinase activity was completely essential for adhesion restoration, sustained Erk activation and suppression of PPAR{gamma}1. MEK/Erk activity did not however contribute to TCDD-induced adhesion. Stimulation of adhesion may therefore precede elevation of Erk. Adhesion is produced by interaction of {alpha}{beta} integrins with extracellular matrix proteins with subsequent Src-mediated phosphorylation of focal adhesion kinase (FAK, Y576/577) and paxillin (Y118). TCDD enhanced the steady state Src-mediated phosphorylation of FAK but not of paxillin. PTPase inhibition by orthovanadate (OVA) showed that this Src activity is highly restricted by PTPases. Partial inhibition of PTPases by OVA mimicked TCDD in producing EGF and Src-dependent effects on cell adhesion and PPAR{gamma}1 suppression. TCDD may therefore induce a protein that enhances Src effectiveness at adhesion sites. Rho kinase (ROCK) inhibition blocked TCDD/EGF stimulation of clustered focal adhesion complexes without affecting either sustained Erk activation or suppression of PPAR{gamma}1. Thus, this ROCK-mediated clustering of integrin complexes is not needed for the effects of TCDD on Erk and PPAR{gamma}1. A minimal cholesterol depletion with {beta}-methylcyclodextrin attenuated TCDD effects on PPAR{gamma}1 and Erk activation. TCDD intervention is therefore linked to extracellular proteins. It indicates that TCDD-enhanced stimulation of EGF signaling to Erk may derive from the initial {alpha}{beta} integrin complexes.


Key words: NGF/EGF, PPARs, Src and other nonreceptor tyrosine kinases, MAP Kinase, Fluorescence techniques, Ah receptor




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