title: E-peptides control bioavailability of IGF-1.
abstract: Insulin-like growth factor 1 (IGF-1) is a potent cytoprotective growth factor that has attracted considerable attention as a promising therapeutic agent. Transgenic over-expression of IGF-1 propeptides facilitates protection and repair in a broad range of tissues, although transgenic mice over-expressing IGF-1 propeptides display little or no increase in IGF-1 serum levels, even with high levels of transgene expression. IGF-1 propeptides are encoded by multiple alternatively spliced transcripts including C-terminal extension (E) peptides, which are highly positively charged. In the present study, we use decellularized mouse tissue to show that the E-peptides facilitate in vitro binding of murine IGF-1 to the extracellular matrix (ECM) with varying affinities. This property is independent of IGF-1, since proteins consisting of the E-peptides fused to relaxin, a related member of the insulin superfamily, bound equally avidly to decellularized ECM. Thus, the E-peptides control IGF-1 bioavailability by preventing systemic circulation, offering a potentially powerful way to tether IGF-1 and other therapeutic proteins to the site of synthesis and/or administration.
authors.affiliation: European Molecular Biology Laboratory (EMBL)-Mouse Biology Unit, Monterotondo, Rome, Italy.
authors.forename: Marianne Smedegaard
authors.initials: MS
authors.lastname: Hede
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Salimova
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Piszczek
authors.forename: Emarald
authors.initials: E
authors.lastname: Perlas
authors.forename: Nadine
authors.initials: N
authors.lastname: Winn
authors.forename: Tommaso
authors.initials: T
authors.lastname: Nastasi
authors.forename: Nadia
authors.initials: N
authors.lastname: Rosenthal
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D001682:Biological Availability; D015152:Blotting, Northern; D017931:DNA Primers; D005109:Extracellular Matrix / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding
chemical_list: D017931:DNA Primers; D010455:Peptides; D007334:Insulin-Like Growth Factor I