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Altered Met receptor phosphorylation and LRP1-mediated uptake in cells lacking carbohydrate-dependent lysosomal targeting.
Aarnio-Peterson, Megan; Zhao, Peng; Yu, Seok-Ho; Christian, Courtney; Flanagan-Steet, Heather; Wells, Lance; Steet, Richard.
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  • Aarnio-Peterson M; From the Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602.
  • Zhao P; From the Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602.
  • Yu SH; From the Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602.
  • Christian C; From the Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602.
  • Flanagan-Steet H; From the Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602.
  • Wells L; From the Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602.
  • Steet R; From the Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602 rsteet@ccrc.uga.edu.
J Biol Chem ; 292(36): 15094-15104, 2017 09 08.
Article en En | MEDLINE | ID: mdl-28724630
Acid hydrolases utilize a carbohydrate-dependent mechanism for lysosomal targeting. These hydrolases acquire a mannose 6-phosphate tag by the action of the GlcNAc-1-phosphotransferase enzyme, allowing them to bind receptors and traffic to endosomes. Loss of GlcNAc-1-phosphotransferase results in hydrolase hypersecretion and profound lysosomal storage. Little, however, is known about how these cellular phenotypes affect the trafficking, activity, and localization of surface glycoproteins. To address this question, we profiled the abundance of surface glycoproteins in WT and CRISPR-mediated GNPTAB-/- HeLa cells and identified changes in numerous glycoproteins, including the uptake receptor LRP1 and multiple receptor tyrosine kinases. Decreased cell surface LRP1 in GNPTAB-/- cells corresponded with a reduction in its steady-state level and less amyloid-ß-40 (Aß40) peptide uptake. GNPTAB-/- cells displayed elevated activation of several kinases including Met receptor. We found increased Met phosphorylation within both the kinase and the docking domains and observed that lower concentrations of pervanadate were needed to cause an increase in phospho-Met in GNPTAB-/- cells. Together, these data suggested a decrease in the activity of the receptor and non-receptor protein-tyrosine phosphatases that down-regulate Met phosphorylation. GNPTAB-/- cells exhibited elevated levels of reactive oxygen species, known to inactivate cell surface and cytosolic phosphatases by oxidation of active site cysteine residues. Consistent with this mode of action, peroxide treatment of parental HeLa cells elevated phospho-Met levels whereas antioxidant treatment of GNPTAB-/- cells reduced phospho-Met levels. Collectively, these findings identify new mechanisms whereby impaired lysosomal targeting can impact the activity and recycling of receptors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carbohidratos / Transferasas (Grupos de Otros Fosfatos Sustitutos) / Proteínas Proto-Oncogénicas c-met / Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad / Lisosomas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Biol Chem Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carbohidratos / Transferasas (Grupos de Otros Fosfatos Sustitutos) / Proteínas Proto-Oncogénicas c-met / Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad / Lisosomas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Biol Chem Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos