pr5006372_si_005.xlsx (115.75 kB)
Quantitative Phosphoproteomics of Murine Fmr1-KO Cell Lines Provides New Insights into FMRP-Dependent Signal Transduction Mechanisms
dataset
posted on 2014-10-03, 00:00 authored by Katarina Matic, Timo Eninger, Barbara Bardoni, Laetitia Davidovic, Boris MacekFragile X mental retardation protein
(FMRP) is an RNA-binding protein
that has a major effect on neuronal protein synthesis. Transcriptional
silencing of the FMR1 gene leads to loss of FMRP
and development of Fragile X syndrome (FXS), the most common known
hereditary cause of intellectual impairment and autism. Here we utilize
SILAC-based quantitative phosphoproteomics to analyze murine FMR1– and FMR1+ fibroblastic cell lines derived from FMR1-KO embryos
to identify proteins and phosphorylation sites dysregulated as a consequence
of FMRP loss. We quantify FMRP-related changes in the levels of 5,023
proteins and 6,133 phosphorylation events and map them onto major
signal transduction pathways. Our study confirms global downregulation
of the MAPK/ERK pathway and decrease in phosphorylation level of ERK1/2
in the absence of FMRP, which is connected to attenuation of long-term
potentiation. We detect differential expression of several key proteins
from the p53 pathway, pointing to the involvement of p53 signaling
in dysregulated cell cycle control in FXS. Finally, we detect differential
expression and phosphorylation of proteins involved in pre-mRNA processing
and nuclear transport, as well as Wnt and calcium signaling, such
as PLC, PKC, NFAT, and cPLA2. We postulate that calcium homeostasis
is likely affected in molecular pathogenesis of FXS.