Molecular Medicine

, Volume 20, Issue 1, pp 202–214 | Cite as

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

  • Anastassios Philippou
  • Maria Maridaki
  • Spiros Pneumaticos
  • Michael Koutsilieris
Review Article


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.


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Authors and Affiliations

  • Anastassios Philippou
    • 1
  • Maria Maridaki
    • 2
  • Spiros Pneumaticos
    • 3
  • Michael Koutsilieris
    • 1
  1. 1.Department of Experimental Physiology, Medical SchoolNational and Kapodistrian University of AthensAthensGreece
  2. 2.Department of Sports Medicine and Biology of Physical Activity, Faculty of Physical Education and Sport ScienceNational and Kapodistrian University of AthensAthensGreece
  3. 3.Third Department of Orthopaedic Surgery, Medical SchoolNational and Kapodistrian University of AthensAthensGreece

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