SIK2: A Novel Negative Feedback Regulator of FGF2 Signaling

Abstract

A wide range of cells respond to fibroblast growth factor 2 (FGF2) by proliferation via activation of the Ras/ERK1/2 pathway. In this study, the potential involvement of salt inducible kinase SIK2) in this cascade within retinal M & uuml;ller glia is explored. It is found that SIK2 phosphorylation status and activity are modulated in an FGF2-dependent manner, possibly via ERK1/2. With SIK2 downregulation, enhanced ERK1/2 activation with delayed attenuation and increased cell proliferation is observed, while SIK2 overexpression hampers FGF2-dependent ERK1/2 activation. In vitro kinase and site-directed mutagenesis studies indicate that SIK2 targets the pathway element GRB2-associated-binding protein 1 (Gab1) on Ser266. This phosphorylation event weakens Gab1 interactions with its partners growth factor receptor-bound protein 2 (Grb2) and Src homology region 2 domain containing phosphatase 2 (Shp2). Collectively, these results suggest that during FGF2-dependent proliferation process ERK1/2-mediated activation of SIK2 targets Gab1, resulting in downregulation of the Ras/ERK1/2 cascade in a feedback loop. The potential involvement of SIK2 in FGF2-dependent Ras/ERK1/2 pathway within retinal M & uuml;ller glia is investigated in this study. It is found that upon FGF2 stimulation, activated ERK1/2 targets SIK2, SIK2 phosphorylates GAB1 and reduces its association with Grb2 and Shp2 resulting in downregulation of the Ras/ERK1/2 pathway. A novel negative feedback loop controlling FGF2-dependent cell proliferation is proposed. image