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Phosphorylation of insulin-like growth factor binding protein-3 by deoxyribonucleic acid-dependent protein kinase reduces ligand binding and enhances nuclear accumulation

Schedlich, Lynette; Nilsen, Trine; John, Anna; Jans, David A; Baxter, Rohan

Description

The IGF binding proteins (IGFBPs) regulate the mitogenic effects of IGFs in the extracellular environment. Several members of this family, including IGFBP-3, also appear to have IGF-independent effects on cell function. For IGFBP-3 and IGFBP-5, both of which are translocated to the cell nuclei, these effects may be related to their putative nuclear actions. Because reversible phosphorylation is an important mechanism for controlling nuclear protein import, we have examined the effect of...[Show more]

dc.contributor.authorSchedlich, Lynette
dc.contributor.authorNilsen, Trine
dc.contributor.authorJohn, Anna
dc.contributor.authorJans, David A
dc.contributor.authorBaxter, Rohan
dc.date.accessioned2015-12-13T22:31:45Z
dc.date.available2015-12-13T22:31:45Z
dc.identifier.issn0013-7227
dc.identifier.urihttp://hdl.handle.net/1885/75402
dc.description.abstractThe IGF binding proteins (IGFBPs) regulate the mitogenic effects of IGFs in the extracellular environment. Several members of this family, including IGFBP-3, also appear to have IGF-independent effects on cell function. For IGFBP-3 and IGFBP-5, both of which are translocated to the cell nuclei, these effects may be related to their putative nuclear actions. Because reversible phosphorylation is an important mechanism for controlling nuclear protein import, we have examined the effect of phosphorylating IGFBP-3 with a number of serine/threonine protein kinases on its nuclear import. Phosphorylation of IGFBP-3 by the double-stranded DNA-dependent protein kinase (DNA-PK) increased both the nuclear import of IGFBP-3 and the binding of IGFBP-3 to components within the nucleus compared with nonphosphorylated IGFBP-3. However, there was no difference in the binding of the nuclear transport factor, importin β, to nonphosphorylated and phosphorylated IGFBP-3. The ability of the DNA-PK phosphoform of IGFBP-3 to bind IGFs was severely attenuated, and in contrast to nonphosphorylated IGFBP-3, the DNA-PK phosphoform was unable to transport IGF-I to the nucleus. Furthermore, IGFBP-3 was phosphorylated by DNA-PK when complexed to IGF-I causing the phosphoform to release IGF-I. Together, these results suggest that when IGF-I is cotransported into the nucleus by IGFBP-3, phosphorylation of IGFBP-3 by nuclear DNA-PK provides a means for releasing bound IGF-I and creating a phosphoform of IGFBP-3 with increased affinity for nuclear components.
dc.publisherEndocrine Society (USA)
dc.sourceEndocrinology
dc.subjectKeywords: DNA dependent protein kinase; double stranded DNA; karyopherin beta; protein serine threonine kinase; somatomedin binding protein 3; somatomedin C; animal cell; article; cell function; cell nucleus; controlled study; gene control; human; human cell; ligan
dc.titlePhosphorylation of insulin-like growth factor binding protein-3 by deoxyribonucleic acid-dependent protein kinase reduces ligand binding and enhances nuclear accumulation
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume144
dc.date.issued2003
local.identifier.absfor111499 - Paediatrics and Reproductive Medicine not elsewhere classified
local.identifier.ariespublicationMigratedxPub4603
local.type.statusPublished Version
local.contributor.affiliationSchedlich, Lynette, University of Sydney
local.contributor.affiliationNilsen, Trine, University of Sydney
local.contributor.affiliationJohn, Anna, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationJans, David A, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationBaxter, Rohan, CSIRO
local.bibliographicCitation.issue5
local.bibliographicCitation.startpage1984
local.bibliographicCitation.lastpage1993
local.identifier.doi10.1210/en.2002-220798
dc.date.updated2015-12-11T09:02:34Z
local.identifier.scopusID2-s2.0-0037733063
CollectionsANU Research Publications

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