Abstract
Fibroblast growth factor (FGF) signaling is vital for many biological processes, beginning with development. The importance of FGF signaling for skeleton formation was first discovered by the analysis of genetic FGFR mutations which cause several bone morphogenetic disorders, including achondroplasia, the most common form of human dwarfism. The formation of the long bones is mediated through proliferation and differentiation of highly specialized cells-chondrocytes. Chondrocytes respond to FGF with growth inhibition, a unique response which differs from the proliferative response of the majority of cell types; however, its molecular determinants are still unclear. Quantitative phosphoproteomic analysis was utilized to catalogue the proteins whose phosphorylation status is changed upon FGF1 treatment. The generated dataset consists of 756 proteins. We could localize the divergence between proliferative (canonical) and inhibitory (chondrocyte specific) FGF transduction pathways immediately upstream of AKT kinase. Gene Ontology (GO) analysis of the FGF1 regulated peptides revealed that many of the identified phosphorylated proteins are assigned to negative regulation clusters, in accordance with the observed inhibitory growth response. This is the first time a comprehensive subset of proteins involved in FGF inhibitory response is defined. We were able to identify a number of targets and specifically discover glycogen synthase kinase3β (GSK3β) as a novel key mediator of FGF inhibitory response in chondrocytes.
| Original language | English |
|---|---|
| Pages (from-to) | 1126-1137 |
| Number of pages | 12 |
| Journal | Molecular & Cellular Proteomics |
| Volume | 16 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 2017 |
Funding
NIH [AR063128]; NIH/ORIP [S10OD010582]This work was supported by NIH grant AR063128 (to V.K.) and with a Shared Instrumentation Grant from the NIH/ORIP S10OD010582 for the purchase of an Orbitrap Fusion mass spectrometer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported by NIH grant AR063128 (to V.K.) and with a Shared Instrumentation Grant from the NIH/ORIP S10OD010582 for the purchase of an Orbitrap Fusion mass spectrometer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
All Science Journal Classification (ASJC) codes
- Analytical Chemistry
- Biochemistry
- Molecular Biology