STAM Proteins Bind Ubiquitinated Proteins on the Early Endosome via the VHS Domain and Ubiquitin-interacting Motif

Mizuno, Emi; Kawahata, Kensuke; Kato, Masaki; Kitamura, Naomi; Komada, Masayuki

doi:10.1091/mbc.e02-12-0823

Cited by 110 publications

(101 citation statements)

References 55 publications

(108 reference statements)

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“…Cooperativity of neighbor ubiquitin-binding domains has recently been observed in the signal transducing adaptor molecule 2 (STAM2), one of the ESCRT-0 subunits that coordinate the proper function of the ESCRT protein complex responsible for committing ubiquitinated cargo to the multivesicular body pathway (40). STAM2 possesses two ubiquitin-binding domains, the VHS domain and the ubiquitin-interacting motif, which are separated from each other by a linker of 20 amino acids (41). Also, we observed that the affinity of Tollip for PtdIns(3)P is about 10-fold higher than ubiquitin.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin Interacts with the Tollip C2 and CUE Domains and Inhibits Binding of Tollip to Phosphoinositides

Mitra¹,

Traughber²,

Brannon

et al. 2013

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Ubiquitin Interacts with the Tollip C2 and CUE Domains and Inhibits Binding of Tollip to Phosphoinositides

Mitra¹,

Traughber²,

Brannon

et al. 2013

Journal of Biological Chemistry

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“…Both Hrs and STAM bind ubiquitin via ubiquitin-interacting motifs (66 -68). STAM also contains a VHS domain reported to interact with ubiquitin (68). Ubiquitin binding by STAM and Hrs is thought to be essential for the efficient sorting of ubiquitinated membrane proteins (33,64,67,69).…”

Section: Discussionmentioning

confidence: 99%

AMSH Interacts with ESCRT-0 to Regulate the Stability and Trafficking of CXCR4

Sierra¹,

Wright

Nash

2010

Journal of Biological Chemistry

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Reversible ubiquitination is essential for the endocytic sorting and down-regulation of G protein-coupled receptors, such as the chemokine receptor CXCR4. The deubiquitinating enzyme AMSH has been implicated in the endocytic sorting of both G protein-coupled receptors and receptor-tyrosine kinases. Herein, we examine the role of AMSH in the regulation of CXCR4 stability and trafficking and characterize protein-protein interactions critical for this function. Loss of AMSH catalytic activity or depletion by RNAi results in increased steady-state levels of CXCR4 under basal conditions. Analysis of truncation and point mutation of AMSH reveal the importance of an RXXK motif for CXCR4 degradation. The RXXK motif of AMSH interacts with the SH3 domains of the STAM and Grb2 families of adaptor proteins with high affinity. Cells expressing a catalytically inactive mutant of AMSH show basal hyperubiquitination, but not increased degradation, of the ESCRT-0 components STAM1 and Hrs. This is dependent on the RXXK motif of AMSH. Ubiquitination of endocytic machinery modulates their activity, suggesting that AMSH may directly regulate endocytic adaptor protein function. This is reflected in CXCR4 trafficking and provides a mechanism by which AMSH specifies the fate of endocytosed receptors. Taken together, these studies implicate AMSH as a key modulator of receptor fate determination through its action on components of the endocytic machinery.The sorting and trafficking of cell surface receptors through endosomal compartments is a highly regulated process that is essential for maintaining cellular homeostasis and generating adaptive and coordinated responses to external stimuli. To avoid prolonged receptor activation and signaling, receptor-ligand complexes are endocytosed and either recycled back to the plasma membrane or sorted to lysosomes for degradation (1-4). This process is mediated by reversible ubiquitination. The modification of a target protein with ubiquitin moieties is extensively utilized to regulate the assembly of endosomal machinery as well as being a sorting signal for transmembrane proteins within the endosomal system (5-7). The crucial role for ubiquitination in the trafficking of endocytosed receptors has been documented for receptor-tyrosine kinases and a number of G protein-coupled receptors including the chemokine receptor CXCR4 (8 -10). CXCR4 has been extensively studied as a co-receptor for the entry of T-trophic human immunodeficiency virus into CD4ϩ T-cells (11,12). Along with its cognate ligand, Stromal cell-derived factor-1␣ (SDF-1/ CXCL12), CXCR4 plays important roles in hematopoiesis, development, and organization of the immune system and stem cell homing (13-15). CXCR4 deregulation is associated with various pathologies, including human immunodeficiency virus infection, cardiovascular disease, and neurodegenerative diseases and is associated with metastatic disease in a number of cancers (16 -20). Mutations that result in truncation of the C-terminal intracellular region of CXCR4 cause WHIM sy...

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“…Endosomal sorting of ubiquitinated RTKs is initiated by a complex of two Ub-binding proteins, hepatocyte growth factor-regulated substrate (Hrs) and signal-transducing adaptor molecule (STAM), which localizes on the cytoplasmic face of the early endosomal membrane (Komada et al, 1997;Bache et al, 2003b;Mizuno et al, 2003Mizuno et al, , 2004. Depletion of Hrs or STAM using RNA interference (RNAi) or gene disruption inhibits RTK down-regulation in mammalian cells (Bache et al, 2003b;Hammond et al, 2003;Kanazawa et al, 2003;Lu et al, 2003) and in Drosophila (Lloyd et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

Mizuno

Iura

Mukai

et al. 2005

MBoC

Self Cite

254

264

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Ligand-activated receptor tyrosine kinases undergo endocytosis and are transported via endosomes to lysosomes for degradation. This "receptor down-regulation" process is crucial to terminate the cell proliferation signals produced by activated receptors. During the process, ubiquitination of the receptors serves as a sorting signal for their trafficking from endosomes to lysosomes. Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells. Immunopurified UBPY deubiquitinated EGFR in vitro. In EGF-stimulated cells, UBPY underwent ubiquitination and bound to EGFR. Overexpression of Hrs or a dominant-negative mutant of SKD1, proteins that play roles in the endosomal sorting of ubiquitinated receptors, caused the accumulation of endogenous UBPY on exaggerated endosomes. A catalytically inactive UBPY mutant clearly localized on endosomes, where it overlapped with EGFR when cells were stimulated with EGF. Finally, depletion of endogenous UBPY by RNA interference resulted in elevated ubiquitination and accelerated degradation of EGF-activated EGFR. We conclude that UBPY negatively regulates the rate of EGFR down-regulation by deubiquitinating EGFR on endosomes.

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STAM Proteins Bind Ubiquitinated Proteins on the Early Endosome via the VHS Domain and Ubiquitin-interacting Motif

Cited by 110 publications

References 55 publications

Ubiquitin Interacts with the Tollip C2 and CUE Domains and Inhibits Binding of Tollip to Phosphoinositides

Ubiquitin Interacts with the Tollip C2 and CUE Domains and Inhibits Binding of Tollip to Phosphoinositides

AMSH Interacts with ESCRT-0 to Regulate the Stability and Trafficking of CXCR4

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

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