Differential signaling activation by insulin and insulin-like growth factors I and II upon binding to insulin receptor isoform A.

Abstract

A variety of human malignancies overexpresses isoform A of the insulin receptor (IR-A) and produces IGFs (IGF-I and/or IGF-II). IR-A binds IGF-II with high affinity (although 4-fold lower than that for insulin), whereas it binds IGF-I with low affinity (approximately 30-fold lower than that for insulin). However, in engineered cells expressing only the IR-A, but not IGF-I receptor (R(-)/IR-A cells), IGF-II is a more potent mitogen than insulin. Herein, we investigated downstream signaling of IGF-II, IGF-I, and insulin in R(-)/IR-A cells to better understand their role in cell growth. We found that despite inducing a lower IR-A autophosphorylation than insulin, IGF-II was more potent than insulin for activating p70S6 kinase (p70S6K) and approximately equally potent in activating the early peaks of ERK1/2 and Akt. However, ERK1/2 activation persisted longer after IGF-II, whereas Akt activation persisted longer after insulin. Therefore, cells stimulated with IGF-II had a higher p70S6K/Akt activation ratio than cells stimulated with insulin. Remarkably, IGF-I also elicited a similar signaling pattern as IGF-II, despite inducing minimal IR-A autophosphorylation. ERK1/2 and protein kinase C seem to be involved in the preferential stimulation of p70S6K by IGFs. In conclusion, our study has identified a novel complex role of IR-A, which not only elicits a unique signaling pattern after IGF-II binding but also induces substantial downstream signaling upon binding to the low-affinity ligand IGF-I. These results underline the role of IR-A in physiology and disease.

• Authors: Antonella Sacco, Alaide Morcavallo, Giuseppe Pandini, Riccardo Vigneri, Antonino Belfiore
• Journal: Endocrinology (Endocrinology) Vol. 150 Issue 8 Pg. 3594-602 (Aug 2009) ISSN: 1945-7170 [Electronic] United States
• PMID: 19443570 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• Cell Cycle Proteins
• Eif4ebp1 protein, mouse
• Eukaryotic Initiation Factors
• Hypoglycemic Agents
• Insulin
• Phosphoproteins
• Protein Isoforms
• Insulin-Like Growth Factor I
• Insulin-Like Growth Factor II
• Receptor, Insulin
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa
• Protein Kinase C
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• p38 Mitogen-Activated Protein Kinases

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Blotting, Western
• Carrier Proteins (metabolism)
• Cell Cycle Proteins
• Cell Line
• Eukaryotic Initiation Factors
• Hypoglycemic Agents (pharmacology)
• Insulin (metabolism, pharmacology)
• Insulin-Like Growth Factor I (metabolism, pharmacology)
• Insulin-Like Growth Factor II (metabolism, pharmacology)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Mice
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Phosphoproteins (metabolism)
• Phosphorylation (drug effects)
• Protein Isoforms (metabolism)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, Insulin (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• Signal Transduction (drug effects)
• p38 Mitogen-Activated Protein Kinases (metabolism)