β-arrestin and Mdm2 mediate IGF-1 receptor signalling Free

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IGF-1R plays several crucial roles in cancer cell growth. The accurate mechanisms involved in expression, down-regulation and activation of IGF-1R are still poorly understood. Phosphorylation is known as being the central process governing IGF-1R signaling. However, recently we described the involvement of ubiquitination on IGF-1R function. IGF-1R ubiquitination is dependent on the ubiquitin E3 ligase MDM2, and the adaptor protein β-arrestin1.

β-arrestin1 serves as adaptor which brings Mdm2, an E3 ubiquitin ligase to the insulin-like growth factor1 receptor (IGF-1R), leading to its proteasomal dependent destruction.

Our present work, aimed to investigate the role of ubiquitination on IGF-1R expression and function. We used a dominant negative MDM2 mutant to inhibit IGF-1R ubiquitination and the wild type MDM2 to enhance it. As alternative experimental model we used the mouse embryonic fibroblasts KO for MDM2. Increased IGF-1R ubiquitination in the presence of MDM2 and/or excess of β-arrestin1 accelerate IGF-1 induced ERK 1/2 activation and speed up the cell cycle progression. Transfection with MDM2 negative mutant and/or β-arrestin1 depletion, drastically decrease ERK1/2 phosphorylation in IGF-1 stimulated cells, and increase G1 accumulation in IGF-1R positive cells. IGF-1R stimulation also leads to monoubiquitination of β-arrestin1 which regulates vesicular trafficking and activation of ERK1/2.

Considered together, IGF-1R ubiquitination mediated by MDM2/ β-arrestin activates MAPK/ERK signaling pathway. In this context, IGF-1R ubiquitination represent a major event, controlling not only the receptor downregulation but also contributing to signal transduction.

β-arrestin-dependent ERK signalling by the IGF-1R regulates cell cycle progression and may thus be an important regulator of the growth of normal and malignant cells.