Hypertonia-associated protein Trak1 is a novel regulator of endosome-to-lysosome trafficking.

Hypertonia, which is characterized by stiff gait, abnormal posture, jerky movements, and tremor, is associated with a number of neurological disorders, including cerebral palsy, dystonia, Parkinson's disease, stroke, and spinal cord injury. Recently, a spontaneous mutation in the gene encoding trafficking protein, kinesin-binding 1 (Trak1), was identified as the genetic ...
defect that causes hypertonia in mice. The subcellular localization and biological function of Trak1 remain unclear. Here we report that Trak1 interacts with hepatocyte-growth-factor-regulated tyrosine kinase substrate (Hrs), an essential component of the endosomal sorting and trafficking machinery. Double-label immunofluorescence confocal studies show that the endogenous Trak1 protein partially colocalizes with Hrs on early endosomes. Like Hrs, both overexpression and small-interfering-RNA-mediated knockdown of Trak1 inhibit degradation of internalized epidermal growth factor receptors through a block in endosome-to-lysosome trafficking. Our findings support a role for Trak1 in the regulation of Hrs-mediated endosomal sorting and have important implications for understanding hypertonia associated with neurological disorders.
Mesh Terms:
Adaptor Proteins, Vesicular Transport, Animals, Binding Sites, Carrier Proteins, Endocytosis, Endosomal Sorting Complexes Required for Transport, Endosomes, Epidermal Growth Factor, HeLa Cells, Humans, Lysosomes, Mice, Muscle Hypertonia, Phosphoproteins, Protein Binding, Protein Structure, Tertiary, Protein Transport, RNA, Small Interfering, Receptor, Epidermal Growth Factor, Recombinant Fusion Proteins
J. Mol. Biol.
Date: Oct. 10, 2008
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