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Proinsulin Binds with High Affinity the Insulin Receptor Isoform A and Predominantly Activates the Mitogenic Pathway.
MedLine Citation:
PMID:  22355074     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Proinsulin is generally regarded as an inactive prohormone because of its low metabolic activity. However, proinsulin appears to regulate embryo development in animal models. In this study, we evaluated whether proinsulin may differentially bind to and activate the two insulin receptor (IR) isoforms (IR-A and IR-B), because IR-A is a relatively low-specificity receptor that is prevalent in fetal and cancer cells and is able to mediate the growth effects of IGF-II. Mouse R(-) fibroblasts devoid of IGF-I receptor (IGF-IR) and stably transfected with cDNA encoding either human IR-A or IR-B (R(-) /IR-A and R(-) /IR-B cells) were used. Three human cancer cell lines were also studied. We found that proinsulin stimulated phosphorylation of IR-A with an EC(50) of 4.5 ± 0.6 nm and displaced [(125)I]insulin from IR-A with a similar EC(50). In contrast, proinsulin EC(50) values for stimulation of IR-B phosphorylation and for [(125)I]insulin displacement from IR-B were approximately 7-fold higher. Proinsulin did not bind or activate IGF-IR or IR/IGF-IR hybrids. Via IR-A, proinsulin activated the ERK/p70S6K pathway to a similar degree as insulin but elicited a weaker Akt response. Despite its low metabolic activity, proinsulin was almost equipotent as insulin in inducing cell proliferation and migration in cells expressing various IR-A levels. In conclusion, proinsulin is a selective IR-A ligand and may induce biological effects through this IR isoform.
Authors:
Roberta Malaguarnera; Antonella Sacco; Concetta Voci; Giuseppe Pandini; Riccardo Vigneri; Antonino Belfiore
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-2-21
Journal Detail:
Title:  Endocrinology     Volume:  -     ISSN:  1945-7170     ISO Abbreviation:  -     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-2-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0375040     Medline TA:  Endocrinology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Endocrinology (R.M., A.S., C.V., A.B.), Department of Health, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; and Endocrinology (G.P., R.V.), Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi-Nesima Hospital, 95123 Catania, Italy.
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