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)

UBPY is a ubiquitin-specific protease that can deubiquitinate monoubiquitinated receptor tyrosine kinases, as well as process Lys-48- and Lys-63-linked polyubiquitin to lower denomination forms in vitro. Catalytically inactive UBPY localizes to endosomes, which accumulate ubiquitinated proteins. We have explored the sequelae of short interfering RNA-mediated knockdown of UBPY. Global levels of ubiquitinated protein increase and ubiquitin accumulates on endosomes, although free ubiquitin levels are unchanged. UBPY-depleted cells have more and larger multivesicular endosomal structures that are frequently associated through extended contact areas, characterized by regularly spaced, electron-dense, bridging profiles. Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation. In contrast, stability of the UBPY binding partner STAM is dramatically compromised in UBPY knockdown cells. The cellular functions of UBPY are complex but clearly distinct from those of the Lys-63-ubiquitin-specific protease, AMSH, with which it shares a binding site on the SH3 domain of STAM.
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PMID:The ubiquitin isopeptidase UBPY regulates endosomal ubiquitin dynamics and is essential for receptor down-regulation. 1652 Mar 78

Dynamic modification of endosomal cargo proteins, such as the epidermal growth factor receptor, by ubiquitin can regulate their sorting into the lumen of multivesicular bodies through interactions with a complex protein network incorporating the endosomal sorting complexes required for transport (ESCRTs). Two deubiquitinating enzymes, AMSH and UBPY, interact with ESCRT protein components but exert opposite effects upon the rate of epidermal growth factor receptor downregulation. This might reflect their distinct specificities for different types of polyubiquitin chain linkage. We propose that AMSH might rescue ubiquitinated cargo from lysosomal degradation through disassembly of K63-linked polyubiquitin chains. UBPY function is essential for effective downregulation but is likely to be multifaceted, encompassing activity against both K63-linked and K48-linked polyubiquitin chains and including regulation of the stability of ESCRT-associated proteins such as STAM, by reversing their ubiquitination.
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PMID:Endocytosis: the DUB version. 1699 68

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