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.
Webber
Elizabeth
E
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322-4218, USA.
Li
Lian
L
Chin
Lih-Shen
LS
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics*; D051379:Mice; D009122:Muscle Hypertonia / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C531552:TRAK1 protein, human; C509169:Trak1 protein, mouse; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D004815:Epidermal Growth Factor; D066246:ErbB Receptors