Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth factor-activated receptor tyrosine kinases (RTKs) undergo rapid endocytosis and degradation in lysosomes. This process, known as receptor downregulation, is essential to prevent the overgrowth of cells by terminating signal transduction from activated RTKs. Thus, defects in RTK downergulation lead to cell proliferative disorders such as cancer. Upon endocytosis, RTKs are delivered to endosomes, from where they are further transported to lysosomes. Ubiquitin serves as a sorting signal that is tagged on activated RTKs and directs their trafficking from endosomes to lysosomes. On the endosomal membrane, ubiquitinated RTKs are sorted by coordinated actions of the class E vacuolar protein sorting (Vps) proteins some of which form complexes that directly recognize the ubiquitin moieties of RTKs. UBPY and AMSH in mammals, as well as Doa4 in yeast, are deubiquitinating enzymes (DUBs) that associate with class E Vps proteins on endosomes. Here I review the recently unveiled roles and regulatory mechanisms of these DUBs in the endosomal sorting of ubiquitinated cargo proteins. These findings suggest that RTK downregulation is controlled not only by ubiquitination but also by deubiquitination of RTKs as well as other endosomal proteins. Therefore, elucidating the entire functions and regulation of the endosomal DUBs potentially provides novel molecular targets for the treatment of cancer accompanied by overexpression or constitutive activation of RTKs.
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PMID:Controlling receptor downregulation by ubiquitination and deubiquitination. 1853 71

Biochemistry and structural biology are undergoing a dramatic revolution. Until now, mostly in vitro techniques have been used to study subtle and complex biological processes under conditions usually remote from those existing in the cell. We developed a novel in-cell methodology to post-translationally modify interactor proteins and identify the amino acids that comprise the interaction surface of a target protein when bound to the post-translationally modified interactors. Modifying the interactor proteins causes structural changes that manifest themselves on the interacting surface of the target protein and these changes are monitored using in-cell NMR. We show how Ubiquitin interacts with phosphorylated and non-phosphorylated components of the receptor tyrosine kinase (RTK) endocytic sorting machinery: STAM2 (Signal-transducing adaptor molecule), Hrs (Hepatocyte growth factor regulated substrate) and the STAM2-Hrs heterodimer. Ubiquitin binding mediates the processivity of a large network of interactions required for proper functioning of the RTK sorting machinery. The results are consistent with a weakening of the network of interactions when the interactor proteins are phosphorylated. The methodology can be applied to any stable target molecule and may be extended to include other post-translational modifications such as ubiquitination or sumoylation, thus providing a long-awaited leap to high resolution in cell biochemistry.
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PMID:In-cell biochemistry using NMR spectroscopy. 1862 16