A Connection between the Microtubule System and ERK activation;Picropodophyllin, an Inhibitor of the IGF-1 receptor, and IGF-1 Destabilize Microtubules and Activate ERK

• Insulin-like growth factor-1 receptor (IGF-1R) is important for growth and survival of cancer cells, but is not obligatory for growth of normal cells. This has led to attempts to target this receptor to terminate growth of malignant cells. The cyclolignan, picropodophyllin (PPP), has proven useful in inhibiting signalling through the IGF-1R. PPP inhibits IGF-1R autophosphorylation and activation of PI3-kinase/Akt, but it activates ERK in an IGF-1R dependent manner, and causes IGF-1R downregulation. Interestingly, ERK activation and IGF-1R downregulation by IGF-1 and PPP both require ubiquitination of IGF-1R by the E3-ligase Mdm2. In this context, beta-arrestin1 acts as an adapter protein bringing Mdm2 to IGF-1R. How beta-arrestin is recruited to the receptor is unknown. It was recently reported, however, that beta-arrestins bind to microtubules (MT), and that this interaction likely influences signaling via G-protein coupled receptors (GPCRs). This paper reports that the ligand IGF-1 and PPP both have distinct effects on the organization of MT in cultured cells as seen by indirect immunofluorescence, and corroborated by biochemical analysis, demonstrating that IGF-1, as well as PPP, induce MT reorganization and depolymerization. Likely, subsequent association of beta-arrestin1:Mdm2 to the IGF-1R is required for ERK activation, receptor ubiquitination and internalization/downregulation.

Nyckelord

PPP

tubulin

betA-arrestin

cell cycle regulation

PI3-Kinase

Akt

microfilament system

cellbiologi

Cellbiology

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