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First published online 15 January 2008
doi: 10.1242/jcs.017160

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STAT1 and STAT3 do not participate in FGF-mediated growth arrest in chondrocytes

¹ Institute of Experimental Biology, Masaryk University, 61137 Brno, Czech Republic
² Department of Cytokinetics, Institute of Biophysics ASCR, 61265 Brno, Czech Republic
³ Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA
⁴ Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
⁵ Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
⁶ Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
⁷ Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA

^* Author for correspondence (e-mail: krejcip{at}sci.muni.cz)

Accepted 30 October 2007

Activating mutations in fibroblast growth factor receptor 3 (FGFR3) cause several human skeletal dysplasias as a result of attenuation of cartilage growth. It is believed that FGFR3 inhibits chondrocyte proliferation via activation of signal transducers and activators of transcription (STAT) proteins, although the exact mechanism of both STAT activation and STAT-mediated inhibition of chondrocyte growth is unclear. We show that FGFR3 interacts with STAT1 in cells and is capable of activating phosphorylation of STAT1 in a kinase assay, thus potentially serving as a STAT1 kinase in chondrocytes. However, as demonstrated by western blotting with phosphorylation-specific antibodies, imaging of STAT nuclear translocation, STAT transcription factor assays and STAT luciferase reporter assays, FGF does not activate STAT1 or STAT3 in RCS chondrocytes, which nevertheless respond to a FGF stimulus with potent growth arrest. Moreover, addition of active STAT1 and STAT3 to the FGF signal, by means of cytokine treatment, SRC-mediated STAT activation or expression of constitutively active STAT mutants does not sensitize RCS chondrocytes to FGF-mediated growth arrest. Since FGF-mediated growth arrest is rescued by siRNA-mediated downregulation of the MAP kinase ERK1/2 but not STAT1 or STAT3, our data support a model whereby the ERK arm but not STAT arm of FGF signaling in chondrocytes accounts for the growth arrest phenotype.

Key words: FGFR3, STAT, Cartilage, Chondrocyte, Fibroblast growth factor, Growth arrest

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