Characterization of PXK as a protein involved in epidermal growth factor receptor trafficking.
The phox homology (PX) domain is a phosphoinositide-binding module that typically binds phosphatidylinositol 3-phosphate. Out of 47 mammalian proteins containing PX domains, more than 30 are denoted sorting nexins and several of these have been implicated in internalization of cell surface proteins to the endosome, where phosphatidylinositol-3-phosphate is concentrated. Here ... we investigated a multimodular protein termed PXK, composed of a PX domain, a protein kinase-like domain, and a WASP homology 2 domain. We show that the PX domain of PXK localizes this protein to the endosomal membrane via binding to phosphatidylinositol 3-phosphate. PXK expression in COS7 cells accelerated the ligand-induced internalization and degradation of epidermal growth factor receptors by a mechanism requiring phosphatidylinositol 3-phosphate binding but not involving the WASP homology 2 domain. Conversely, depletion of PXK using RNA interference decreased the rate of epidermal growth factor receptor internalization and degradation. Ubiquitination of epidermal growth factor receptor by the ligand stimulation was enhanced in PXK-expressing cells. These results indicate that PXK plays a critical role in epidermal growth factor receptor trafficking through modulating ligand-induced ubiquitination of the receptor.
Mesh Terms:
Amino Acid Sequence, Animals, Cell Line, Cysteine Proteinase Inhibitors, Female, Humans, Intracellular Membranes, Intracellular Signaling Peptides and Proteins, Leupeptins, Macrolides, Molecular Sequence Data, Mutagenesis, Site-Directed, Nerve Tissue Proteins, Phosphatidylinositol Phosphates, Proteasome Endopeptidase Complex, Protein Structure, Tertiary, Protein Transport, Protein-Serine-Threonine Kinases, RNA Interference, Rats, Receptor, Epidermal Growth Factor, Recombinant Fusion Proteins, Sequence Alignment, Tissue Distribution
Amino Acid Sequence, Animals, Cell Line, Cysteine Proteinase Inhibitors, Female, Humans, Intracellular Membranes, Intracellular Signaling Peptides and Proteins, Leupeptins, Macrolides, Molecular Sequence Data, Mutagenesis, Site-Directed, Nerve Tissue Proteins, Phosphatidylinositol Phosphates, Proteasome Endopeptidase Complex, Protein Structure, Tertiary, Protein Transport, Protein-Serine-Threonine Kinases, RNA Interference, Rats, Receptor, Epidermal Growth Factor, Recombinant Fusion Proteins, Sequence Alignment, Tissue Distribution
Mol. Cell. Biol.
Date: Apr. 01, 2010
PubMed ID: 20086096
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