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S116R Phosphorylation Site Mutation in Human FGF-1 Differentially Affects Mitogenic and Glucose Lowering Activities

Title: An S116R Phosphorylation Site Mutation in Human FGF-1 Differentially Affects Mitogenic and Glucose Lowering Activities .
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Name(s): Xia, Xue, author
Kumru, Ozan, author
Blaber, Sachiko, author
Middaugh, Russell, author
Li, Ling, author
Ornitz, David, author
Suh, Jae Myoung, author
Atkins, Annette, author
Downes, Michael, author
Evans, Ronald, author
Tenorio, Connie, author
Bienkiewicz, Ewa, author
Blaber, Michael, author
Type of Resource: text
Genre: Text
Date Issued: 2016-09-07
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Fibroblast growth factor-1 (FGF-1), a potent human mitogen and insulin sensitizer, signals through both tyrosine kinase receptor mediated autocrine/paracrine pathways as well as a nuclear intracrine pathway. Phosphorylation of FGF-1 at serine 116 (S116) has been proposed to regulate intracrine signalling. Position S116 is located within a ~17 amino acid C-terminal loop that contains a rich set of functional determinants including heparin\heparan sulfate (HS) affinity, thiol reactivity, nuclear localization, pharmacokinetics, functional half-life, nuclear ligand affinity, stability, and structural dynamics. Mutational targeting of specific functionality in this region without perturbing other functional determinants is a design challenge. S116R is a non-phosphorylatable variant present in bovine FGF-1 and other members of the human FGF family. We show that the S116R mutation in human FGF-1 is accommodated with no perturbation of biophysical or structural properties, and is therefore an attractive mutation with which to elucidate the functional role of phosphorylation. Characterization of S116R shows reduction of NIH 3T3 fibroblast mitogenic stimulation, increase in FGFR-1c activation, and prolonged duration of glucose lowering in ob/ob hyperglycemic mice. A novel FGF-1/FGFR-1c dimerization interaction combined with non-phosphorylatable intracrine signaling is hypothesized to be responsible for these observed functional effects.
Identifier: FSU_libsubv1_scholarship_submission_1473276315 (IID)
Keywords: blood glucose, FGF-1, protein stabilty, protein design, mitogenicity
Publication Note: in press
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_libsubv1_scholarship_submission_1473276315
Owner Institution: FSU
Is Part Of: Journal of Pharmaceutical Sciences.

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Xia, X., Kumru, O., Blaber, S., Middaugh, R., Li, L., Ornitz, D., … Blaber, M. (2016). An S116R Phosphorylation Site Mutation in Human FGF-1 Differentially Affects Mitogenic and Glucose Lowering Activities . Journal Of Pharmaceutical Sciences. Retrieved from http://purl.flvc.org/fsu/fd/FSU_libsubv1_scholarship_submission_1473276315