Something old, something new and something borrowed: emerging paradigm of insulin-like growth factor type 1 receptor (IGF-1R) signaling regulation.

Abstract

The insulin-like growth factor type 1 receptor (IGF-1R) plays a key role in the development and progression of cancer; however, therapeutics targeting it have had disappointing results in the clinic. As a receptor tyrosine kinase (RTK), IGF-1R is traditionally described as an ON/OFF system, with ligand stabilizing the ON state and exclusive kinase-dependent signaling activation. Newly added to the traditional model, ubiquitin-mediated receptor downregulation and degradation was originally described as a response to ligand/receptor interaction and thus inseparable from kinase signaling activation. Yet, the classical model has proven over-simplified and insufficient to explain experimental evidence accumulated over the last decade, including kinase-independent signaling, unbalanced signaling, or dissociation between signaling and receptor downregulation. Based on the recent findings that IGF-1R "borrows" components of G-protein coupled receptor (GPCR) signaling, including β-arrestins and G-protein-related kinases, we discuss the emerging paradigm for the IGF-1R as a functional RTK/GPCR hybrid, which integrates the kinase signaling with the IGF-1R canonical GPCR characteristics. The contradictions to the classical IGF-1R signaling concept as well as the design of anti-IGF-1R therapeutics treatment are considered in the light of this paradigm shift and we advocate recognition of IGF-1R as a valid target for cancer treatment.

• Authors: Leonard Girnita, Claire Worrall, Shin-Ichiro Takahashi, Stefan Seregard, Ada Girnita
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 71 Issue 13 Pg. 2403-27 (Jul 2014) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 24276851 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Arrestins
• Receptors, G-Protein-Coupled
• Ubiquitin
• beta-Arrestins
• Phosphatidylinositol 3-Kinases
• Receptor, IGF Type 1

Topics

• Arrestins (genetics, metabolism)
• Humans
• Molecular Targeted Therapy
• Neoplasms (genetics, pathology, therapy)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphorylation
• Receptor, IGF Type 1 (genetics, metabolism)
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Signal Transduction
• Ubiquitin (genetics)
• beta-Arrestins