Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling

Abstract

Fibroblast growth factor receptor (FGFR) signaling is transduced by the mitogen-activated protein kinase (MAPK) cascade and the signal transducers and activators of transcription (STATs). Suppressors of cytokine signaling (SOCS) proteins are expressed in response to cytokine-inducible stimulation of STAT phosphorylation, acting in a negative-feedback mechanism to hinder the activities of these receptors. However, there are no data concerning the role of SOCS proteins in the regulation of fibroblast growth factor receptor (FGFR) signaling. In the present study, we show that activation of FGFR in chondrocytes induces the expression of SOCS1 and SOCS3 mRNA, and that these proteins are constitutively associated with FGFR3, as demonstrated by co-immunoprecipitation studies. Transfection of cells with FGFR3-GFP and SOCS1-CFP revealed their colocalization, clustered prominently in the perinuclear cytosolic part of the cell. The effect of the interaction between FGFR3 and SOCS1 on receptor activity was investigated in a chondrocytic cell line overexpressing SOCS1. In these cells, STAT1 phosphorylation is repressed, MAPK phosphorylation is elevated and prolonged, and FGFR3 downregulation is attenuated. Expression of osteopontin (OPN), which is directly upregulated by FGF in chondrocytes, was stimulated by lower levels of FGF in cells expressing SOCS1 compared with parental cells. Blocking of MAPK phosphorylation by PD98059 decreased OPN expression in both cell types, but this decrease was more marked in cells expressing SOCS1. The presented results suggest a novel interaction between the SOCS1 and SOCS3 proteins and the FGFR3 signaling pathway.