Human Molecular Genetics Advance Access originally published online on April 20, 2005
Human Molecular Genetics 2005 14(11):1529-1538; doi:10.1093/hmg/ddi161
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Sustained ERK1/2 but not STAT1 or 3 activation is required for thanatophoric dysplasia phenotypes in PC12 cells
1Department of Psychiatry and Human Behavior, 2121 Gillespie, 2Department of Physiology and Biophysics, 346-D Medical Sciences I and 3Department of Biological Chemistry, D240 Medical Sciences I, University of California at Irvine, Irvine, CA 92697, USA
* To whom correspondence should be addressed at: Department of Psychiatry and Human Behavior, 2121 Gillespie, University of California at Irvine, Irvine, CA 92697-4260, USA. Tel: +1 9498246756; Fax: +1 9498242577; Email: lmthomps{at}uci.edu
Received February 1, 2005; Revised April 5, 2005; Accepted April 11, 2005
Mutations in fibroblast growth factor receptor 3 (FGFR3) cause the most common genetic form of short-limbed dwarfism, achondroplasia (ACH), as well as neonatal lethal forms, thanatophoric dysplasia (TD) I and II. The causative mutations induce graded levels of constitutive activation of the receptor that correspond to the severity of the disorder, resulting in premature entry into hypertrophic differentiation and reduced proliferation of chondrocytes in developing cartilage. Although FGFR3 promotes growth in most tissues, it is a negative regulator of endochondral bone growth. Several signaling pathways have been implicated in these skeletal disorders including the Ras/MEK/ERK pathway and the JAK/STAT, the latter in the most severe phenotypes, however their functional relevance remains incompletely understood. Using PC12 cell lines stably expressing inducible mutant receptors containing the TDII mutation, K650E, sustained activation of ERK1/2 and activation of STAT1 and STAT3, but not STAT5, is observed in the absence of ligand. This activation leads to neurite outgrowth, a phenotypic readout of constitutive receptor activity, and sustained ERK1/2 activity is required for this ligand-independent differentiation. To assess the functional relevance of STAT activation induced by the mutant receptor, STATs were specifically downregulated using RNA-interference. Silencing of STAT1 or 3 independently or in combination had no significant effect on ligand-independent neurite outgrowth, ERK1/2 activation or p21WAF1/CIP1 protein levels. These results support a model in which sustained activation of ERK1/2 is a key regulator of the increased transition to hypertrophic differentiation of the growth plate, whereas activation of STATs 1 and 3 is not required.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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