Regulation of the Duration and Intensity of Growth Factor Signaling in the Lens is Mediated by Suppressors of Cytokine Signaling

Abstract

Abstract: : Purpose: Suppressors of cytokine signaling (SOCS) are negative feedback regulators of growth factor and cytokine signaling. Although much is known about effects of growth factors such as IGF1, PDGF, FGF1 and FGF2 on lens cells and their roles in the growth and differentiation of the lens, very little is known about the mechanisms that attenuate or terminate their activities. In this study, we show that IGF1, PDGF, FGF1 or FGF2 activate STAT pathways in the lens and that these signaling pathways may be under feedback regulation by SOCS family of proteins. Methods: One day old lens organ or lens epithelial cell lines were treated with IGF1, PDGF, FGF1, FGF2 or combinations of these factors. Activation of STAT signaling pathways was assessed by Western blotting and electrophoretic mobility shift assays (EMSA). Induction of SOCS expression by growth factors was analyzed by Northern blotting or by quantitation of SOCS promoter activity in transient transfection and luciferase assays. Results: In freshly isolated mouse lens, STAT1 and STAT3 are constitutively activated in the lens epithelia, while in lens fibers only STAT3 activation is detectable. Stimulation of lens epithelial cell lines with IGF1, PDGF, FGF2 activates both STAT1 and STAT3 while FGF1 activates STAT3 but not STAT1. STAT activation by these factors is subsequently followed by upregulation of SOCS1 and SOCS3. IGF1 or PDGF synergizes with either FGFs to augment STAT activation and this is also followed by a corresponding synergistic induction of SOCS1 and SOCS3 Discussion: Our results suggest that IGF1, PDGF, FGF1 and FGF2 may mediate their effects in the lens by activating JAK/STAT pathways and these effects are under feedback regulation by SOCS proteins. Thus, whereas STAT1 and STAT3 may function to couple IGF1, PDGF, FGF1 or FGF2 signals to transcriptional activation of lens genes, cross-regulation and integration of these diverse pathways is mediated in part through SOCS. To our knowledge, this is the first report of the induction of SOCS expression in the lens by a growth factor or cytokine. It is also the first report that either FGF1 or FGF2 activates STAT pathways in the lens.

Keywords: growth factors/growth factor receptors • signal transduction • transcription factors