Enhancement of AG1024-induced H9c2 cardiomyoblast cell apoptosis via the interaction of IGF2R with Galpha proteins and its downstream PKA and PLC-beta modulators by IGF-II.

Abstract

Our previous studies found that insulin-like growth factor-I receptor (IGF1R) signaling blockade caused cardiac hypertrophy, and that apoptosis is required for upregulating the IGF-II and the IGF-II/ mannose 6-phosphate receptor (IGF2R) gene. However, the role of IGF-II in the regulation of cell apoptosis through IGF2R is little known. In this study, we hypothesized that IGF-II may induce cell apoptosis through IGF2R but is dependent on IGF1R activity. Western blots and TUNEL assay revealed that in the presence of IGF1R, exogenous IGF-II acts, like IGF-I, would increase phospho-Akt through IGF1R, but does not affect the caspase 3 activation and apoptotic induction in H9c2 cardiomyoblast cells. Conversely, AG1024, an inhibitor of IGF1R activity, causes cell apoptosis, and the treatment with IGF-II further enhances this process, implying that it occurs through IGF2R. Moreover, immunoprecipitation assay revealed that treatment with IGF-II could enhance the interaction of IGF2R with Galphai and Galphaq but reduce its binding with Galphas, resulting in the reduction of phospho-PKA and the activation of PLC-beta. Taken together, these data provide new insight into the dual role of IGF-II in the control of IGF1R dependent cell apoptosis and involved activation of IGF2R signaling. Improving IGF1R activity and suppressing IGF2R may be a good strategy to prevent the progression of heart disease with cardiomyocyte apoptosis.

• Authors: Chun-Hsien Chu, Chih-Yang Huang, Ming-Chin Lu, James A Lin, Fuu-Jen Tsai, Chang-Hai Tsai, Chia-Yih Chu, Wu-Hsien Kuo, Li-Mien Chen, Ling-Yun Chen
• Journal: The Chinese journal of physiology (Chin J Physiol) Vol. 52 Issue 1 Pg. 31-7 (Feb 28 2009) ISSN: 0304-4920 [Print] India
• PMID: 19764351 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GTP-Binding Protein alpha Subunits
• Receptor, IGF Type 2
• Tyrphostins
• tyrphostin AG 1024
• Insulin-Like Growth Factor II
• Receptor, IGF Type 1
• Proto-Oncogene Proteins c-akt
• Cyclic AMP-Dependent Protein Kinases
• Protein Kinase C
• Protein Kinase C beta
• Casp3 protein, rat
• Caspase 3

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Caspase 3 (metabolism)
• Cell Line
• Cell Survival (drug effects, physiology)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Down-Regulation (drug effects, physiology)
• GTP-Binding Protein alpha Subunits (metabolism)
• Heart Diseases (metabolism, pathology)
• Humans
• Insulin-Like Growth Factor II (metabolism, pharmacology)
• Myoblasts, Cardiac (cytology, drug effects, metabolism)
• Phosphorylation (drug effects, physiology)
• Protein Kinase C (metabolism)
• Protein Kinase C beta
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Receptor, IGF Type 1 (metabolism)
• Receptor, IGF Type 2 (metabolism)
• Signal Transduction (drug effects, physiology)
• Tyrphostins (pharmacology)