Abstract
The ANKS1A gene product, also known as Odin, was first identified as a tyrosine-phosphorylated component of the epidermal growth factor receptor network. Here we show that Odin functions as an effector of EGFR recycling. In EGF-stimulated HEK293 cells tyrosine phosphorylation of Odin was induced prior to EGFR internalization and independent of EGFR-to-ERK signaling. Over-expression of Odin increased EGF-induced EGFR trafficking to recycling endosomes and recycling back to the cell surface, and decreased trafficking to lysosomes and degradation. Conversely, Odin knockdown in both HEK293 and the non-small cell lung carcinoma line RVH6849, which expresses roughly 10-fold more EGF receptors than HEK293, caused decreased EGFR recycling and accelerated trafficking to the lysosome and degradation. By governing the endocytic fate of internalized receptors, Odin may provide a layer of regulation that enables cells to contend with receptor cell densities and ligand concentration gradients that are physiologically and pathologically highly variable.
Highlights
The epidermal growth factor receptor (EGFR) is a prototypical receptor tyrosine kinase (RTK) and functions as part of a network of interacting proteins
The extent of Odin tyrosine phosphorylation was similar whether cells were stimulated at 37uC or held at ice-temperature (,4uC) in the presence of EGF, a temperature at which membrane dynamics and EGFR endocytosis are inhibited
We established that EGF-stimulated tyrosine phosphorylation of Odin occurs as an early event following ligand binding and independently of EGFR internalization or intracellular signaling to ERK (Fig. 1)
Summary
The epidermal growth factor receptor (EGFR) is a prototypical receptor tyrosine kinase (RTK) and functions as part of a network of interacting proteins. The EGFR is frequently activated by mutation and/or gene amplification in a variety of human cancers including lung, head and neck, breast, brain, and ovary, and EGFR-expressing tumours frequently evolve to express EGFR ligands (e.g. EGF; transforming growth factor alpha, TGFa) that further promotes their growth [2]. The latent oncogenicity of the EGFR is normally tempered because the activated receptor is subject to down-regulation by endocytosis, culminating with proteolytic destruction in the lysosome [3]. The EGFR network can drive the cancer cell phenotype subject to a variety of positive and negative regulatory mechanisms acting at the level of the receptor [1,6,7,8]
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