title: Phosphoproteomics of Fibroblast Growth Factor 1 (FGF1) Signaling in Chondrocytes: Identifying the Signature of Inhibitory Response.
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.
authors.affiliation: From the ‡Proteomics Laboratory.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Chapman
authors.affiliation: Departments of §Microbiology.
authors.forename: Olga
authors.initials: O
authors.lastname: Katsara
authors.affiliation: Departments of §Microbiology.
authors.forename: Rachel
authors.initials: R
authors.lastname: Ruoff
authors.affiliation: From the ‡Proteomics Laboratory.
authors.forename: David
authors.initials: D
authors.lastname: Morgenstern
authors.affiliation: From the ‡Proteomics Laboratory.
authors.forename: Shruti
authors.initials: S
authors.lastname: Nayak
authors.affiliation: Departments of §Microbiology.
authors.forename: Claudio
authors.initials: C
authors.lastname: Basilico
authors.affiliation: From the ‡Proteomics Laboratory.|¶Biochemistry and Molecular Pharmacology, NYU Langone Medical Center, 550 First Avenue, New York, New York 10016.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Ueberheide
authors.affiliation: Departments of §Microbiology; kolupv01@nyumc.org.
authors.forename: Victoria
authors.initials: V
authors.lastname: Kolupaeva
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019902:Chondrocytes / Q000378:metabolism*; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D010766:Phosphorylation; D040901:Proteomics; D051381:Rats; D015398:Signal Transduction
chemical_list: D016220:Fibroblast Growth Factor 1; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat