Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 71, Issue 13, Pages 2403-2427Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-013-1514-y
Keywords
IGF-1R; GRKs; IRS; Beta-arrestins; Serine phosphorylation; Cancer; Ubiquitination; GPCR; RTK
Categories
Funding
- Swedish Cancer Society
- Swedish Research Council
- Swedish Childhood Cancer Foundation
- Crown Princess Margareta's Foundation for the Visually Impaired
- Welander Finsen Foundation
- King Gustaf V Jubilee Foundation
- Vinnova
- Stockholm Cancer Society
- Stockholm County
- Karolinska Institute
- Japan Society for the Promotion of Science [25221204]
- Grants-in-Aid for Scientific Research [22248030] Funding Source: KAKEN
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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 beta-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.
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