Abstract
BackgroundInsulin-like growth factor-I receptor (IGF-IR) is a tyrosine kinase receptor (RTK) associated with caveolae, invaginations of the plasma membrane that regulate vesicular transport, endocytosis and intracellular signaling. IGF-IR internalization represents a key mechanism of down-modulation of receptors number on plasma membrane. IGF-IR interacts directly with Caveolin-1 (Cav-1), the most relevant protein of caveolae. Recently it has been demonstrated that the Polymerase I and Transcript Release Factor I (PTRF/Cavin) is required for caveolae biogenesis and function. The role of Cav-1 and PTRF/Cavin in IGF-IR internalization is still to be clarified.Methodology/Principal FindingsWe have investigated the interaction of IGF-IR with Cav-1 and PTRF/Cavin in the presence of IGF1in human Hacat cells. We show that IGF-IR internalization triggers Cav-1 and PTRF/Cavin translocation from plasma membrane to cytosol and increases IGF-IR interaction with these proteins. In fact, Cav-1 and PTRF/Cavin co-immunoprecipitate with IGF-IR during receptor internalization. We found a different time course of co-immunoprecipitation between IGF-IR and Cav-1 compared to IGF-IR and PTRF/Cavin. Cav-1 and PTRF/Cavin silencing by siRNA differently affect surface IGF-IR levels following IGF1 treatment: Cav-1 and PTRF/Cavin silencing significantly affect IGF-IR rate of internalization, while PTRF/Cavin silencing also decreases IGF-IR plasma membrane recovery. Since Cav-1 phosphorylation could have a role in IGF-IR internalization, the mutant Cav-1Y14F lacking Tyr14 was transfected. Cav-1Y14F transfected cells showed a reduced internalization of IGF-IR compared with cells expressing wild type Cav-1. Receptor internalization was not impaired by Clathrin silencing. These findings support a critical role of caveolae in IGF-IR intracellular traveling.Conclusions/SignificanceThese data indicate that Caveolae play a role in IGF-IR internalization. Based on these findings, Cav-1 and PTRF/Cavin could represent two relevant and distinct targets to modulate IGF-IR function.
Highlights
Insulin like growth factor I receptor (IGF-IR) is a tyrosine kinase receptor (RTK) that regulates cell proliferation and survival both in normal and malignant phenotypes [1]
Since Cav-1 and PTRF/Cavin are important components of caveolae [15,22,23] we tested the hypothesis that Cav-1 and PTRF/Cavin could affect Insulin-like growth factor-I receptor (IGF-IR) intracellular traveling in HaCaT keratinocytes, a cell line that constitutively expresses Cav-1 [24], PTRF/Cavin and IGF-IR
We investigated whether PTRF/Cavin, could physically interact with IGF-IR during IGF-IR activation
Summary
Insulin like growth factor I receptor (IGF-IR) is a tyrosine kinase receptor (RTK) that regulates cell proliferation and survival both in normal and malignant phenotypes [1]. IGF-IR plasma membrane compartmentalization could affect its downstream signaling and activation [2,3]. Clathrin-coated pits take part to IGF-IR internalization [5,6] but recently it has been demonstrated that different plasma membrane micro-domains such as caveolae could regulate the biological actions of many plasma membrane receptors [7,8]. Insulin-like growth factor-I receptor (IGF-IR) is a tyrosine kinase receptor (RTK) associated with caveolae, invaginations of the plasma membrane that regulate vesicular transport, endocytosis and intracellular signaling. IGF-IR internalization represents a key mechanism of down-modulation of receptors number on plasma membrane. The role of Cav-1 and PTRF/Cavin in IGF-IR internalization is still to be clarified
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