Kuser-Abali, G.Ugurlu-Bayarslan, A.Yilmaz, Y.Ozcan, F.Karaer, F.Bugra, K.2024-09-252024-09-252024.01.012701-0198https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=dspace_ku&SrcAuth=WosAPI&KeyUT=WOS:001310339100001&DestLinkType=FullRecord&DestApp=WOS_CPLhttps://hdl.handle.net/20.500.12597/33574A 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. imageeninfo:eu-repo/semantics/openAccesscontrol of cell proliferationFGF2 signalingRas/ERK1/2 pathwaySIK2Article10.1002/adbi.202400032001310339100001