Cell cycle control by the insulin-like growth factor signal: at the crossroad between cell growth and mitotic regulation

Abstract

In proliferating cells and tissues a number of checkpoints (G1/S and G2/M) preceding cell division (M-phase) require the signal provided by growth factors present in serum. IGFs (I and II) have been demonstrated to constitute key intrinsic components of the peptidic active fraction of mammalian serum. In vivo genetic ablation studies have shown that the cellular signal triggered by the IGFs through their cellular receptors represents a non-replaceable requirement for cell growth and cell cycle progression. Retroactive and current evaluation of published literature sheds light on the intracellular circuitry activated by these factors providing us with a better picture of the pleiotropic mechanistic actions by which IGFs regulate both cell size and mitogenesis under developmental growth as well as in malignant proliferation. The present work aims to summarize the cumulative knowledge learned from the IGF ligands/receptors and their intracellular signaling transducers towards control of cell size and cell-cycle with particular focus to their actionable circuits in human cancer. Furthermore, we bring novel perspectives on key functional discriminants of the IGF growth-mitogenic pathway allowing re-evaluation on some of its signal components based upon established evidences.

Keywords: (scavenger protein for IGF2 & mannose-6-phosphate); GF; GH; HybR; HybR-A; IGF-I/II: insulin like growth factor peptides; IGF-Type I receptor gene; IGF1R; IGF1R/IR hybrid receptor; IGF1R/IR-A; IR (also InsR); IR isoform A (exon 11-); IR-A; IRS; Insulin-like growth factor receptor; RTK; growth factor; growth hormone; igf1/2; igf1r; igf2r/m6pr/SpI2-6; insr; insulin like growth factor genes; insulin receptor gene; insulin receptor protein; insulin receptor substrate; mTOR; mTOR complex. additional acronyms are clarified in the text; mTORC; mammalian target of rapamycin; property of a GF to increase growth (hypertrophy) and number (hyperplasia) of a target cell or tissue; receptor tyrosine kinase; trans-membrane high affinity IGF2 scavenger protein; trophic (effect); type I (protein).

Figure 1.

Growth/proliferative-related effects of the Insulin/IGF ligands/receptor system in mammalians*. *ased on predominant effects observed in isolated/optimized ex-vivo models or net clinical study end-point.

Figure 2.

The essential circuitry for the Insulin/IGFs system involved in growth and proliferation signal (refer to text and Table IV).

Figure 3.

Essential IGF ligands/receptor signal determinants for cell size net effect (refer to text for further explanation).

Figure 4.

Proposed relationship between cellular growth, cell division and relative Polymerases activities in response to the Insulin/IGF proliferative signal. Refer to text for further explanation. [337](renumber to 336).