The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

Anastassios Philippou,Maria Maridaki,Michael Koutsilieris,Spiros Pneumaticos

doi:10.2119/molmed.2014.00011

Anastassios Philippou, Maria Maridaki + Show 2 more

Open Access

https://doi.org/10.2119/molmed.2014.00011

Copy DOI

Abstract

The insulinlike growth factor-I (IGF-I) is an important factor which regulates a variety of cellular responses in multiple biological systems. The IGF1 gene comprises a highly conserved sequence and contains six exons, which give rise to heterogeneous mRNA transcripts by a combination of multiple transcription initiation sites and alternative splicing. These multiple transcripts code for different precursor IGF-I polypeptides, namely the IGF-IEa, IGF-IEb and IGF-IEc isoforms in humans, which also undergo posttranslational modifications, such as proteolytic processing and glycosylation. IGF-I actions are mediated through its binding to several cell-membrane receptors and the IGF-I domain responsible for the receptor binding is the bioactive mature IGF-I peptide, which is derived after the posttranslational cleavage of the pro-IGF-I isoforms and the removal of their carboxy-terminal E-peptides (that is, the Ea, Eb and Ec). Interestingly, differential biological activities have been reported for the different IGF-I isoforms, or for their E-peptides, implying that IGF-I peptides other than the IGF-I ligand also possess bioactivity and, thus, both common and unique or complementary pathways exist for the IGF-I isoforms to promote biological effects. The multiple peptides derived from IGF-I and the differential expression of its various transcripts in different conditions and pathologies appear to be compatible with the distinct cellular responses observed to the different IGF-I peptides and with the concept of a complex and possibly isoform-specific IGF-I bioactivity. This concept is discussed in the present review, in the context of the broad range of modifications that this growth factor undergoes which might regulate its mechanism(s) of action.

Highlights

The insulinlike growth factor-I (IGF-I), called somatomedin C, is a cellular and secreted growth factor which is critical for normal body growth, development and maintenance, and has important roles in multiple biological systems [1,2,3]
IGF-I is produced by many tissues, indicating that a significant component of IGF-I action is due to its autocrine and paracrine mode of function, it acts as a classical circulating hormone
Circulating IGF-I is mainly derived from the liver, and from skeletal muscle [3,16,17,18], and is mostly bound to high affinity IGF-binding proteins, which protect it from proteolytic degradation and modulate its bioavailability to the IGF-I receptors [2,19]

Summary

INTRODUCTION

The insulinlike growth factor-I (IGF-I), called somatomedin C, is a cellular and secreted growth factor which is critical for normal body growth, development and maintenance, and has important roles in multiple biological systems [1,2,3]. Its cDNA differs from the IGF-IEa variant by the presence of the first 49 base pairs from exon 5 (52 bp in rodents), It results from a splice acceptor site in the intron preceding exon 6 and, due to a reading frame shift, it gives rise to a different carboxy-terminal peptide sequence and a premature stop codon in exon 6 This transcript was named mechanogrowth factor (MGF) since it was found to be upregulated in response to muscle stretch and/or damage [71]; for review see [72]. The sequences of the signal peptides and the E-peptides are less strongly conserved compared with mature IGF-I peptide, though to a variable extent [23]

NCBI reference sequence

CONCLUSION