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S116R Phosphorylation Site Mutation in Human Fibroblast Growth Factor-1 Differentially Affects Mitogenic and Glucose-Lowering Activities.

Title: An S116R Phosphorylation Site Mutation in Human Fibroblast Growth Factor-1 Differentially Affects Mitogenic and Glucose-Lowering Activities.
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Name(s): Xia, Xue, author
Kumru, Ozan S, author
Blaber, Sachiko I, author
Middaugh, C Russell, author
Li, Ling, author
Ornitz, David M, author
Suh, Jae Myoung, author
Atkins, Annette R, author
Downes, Michael, author
Evans, Ronald M, author
Tenorio, Connie A, author
Bienkiewicz, Ewa, author
Blaber, Michael, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2016-12-01
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 signaling. Position S116 is located within a ∼17 amino acid C-terminal loop that contains a rich set of functional determinants including heparin∖heparan sulfate 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 in NIH 3T3 fibroblast mitogenic stimulation, increase in fibroblast growth factor receptor-1c activation, and prolonged duration of glucose lowering in ob/ob hyperglycemic mice. A novel FGF-1/fibroblast growth factor receptor-1c dimerization interaction combined with non-phosphorylatable intracrine signaling is hypothesized to be responsible for these observed functional effects.
Identifier: FSU_pmch_27773526 (IID), 10.1016/j.xphs.2016.09.005 (DOI), PMC5310217 (PMCID), 27773526 (RID), 27773526 (EID), S0022-3549(16)41698-9 (PII)
Keywords: X-ray crystallography, Fibroblast growth factor receptor, Heparan sulfate proteoglycan, Human fibroblast growth factor-1, Protein engineering, Protein stability, Thermodynamics
Grant Number: R15 NS057771, R37 DK057978
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310217.
Subject(s): Amino Acid Sequence
Animals
Cattle
Cell Survival/physiology
Crystallography, X-Ray
Dose-Response Relationship, Drug
Fibroblast Growth Factor 1/chemistry
Fibroblast Growth Factor 1/genetics
Fibroblast Growth Factor 1/metabolism
Glucose/metabolism
Humans
Mice
Mitogens/metabolism
Mutation/physiology
NIH 3T3 Cells
Phosphorylation/physiology
Protein Structure, Secondary
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_27773526
Owner Institution: FSU
Is Part Of: Journal of pharmaceutical sciences.
1520-6017
Issue: iss. 12, vol. 105

Choose the citation style.
Xia, X., Kumru, O. S., Blaber, S. I., Middaugh, C. R., Li, L., Ornitz, D. M., … Blaber, M. (2016). An S116R Phosphorylation Site Mutation in Human Fibroblast Growth Factor-1 Differentially Affects Mitogenic and Glucose-Lowering Activities. Journal Of Pharmaceutical Sciences. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_27773526