The TBC (Tre-2/Bub2/Cdc16) Domain Protein TRE17 Regulates Plasma Membrane-Endosomal Trafficking through Activation of Arf6

Martinu, Lenka; Robens, Jeffrey; Robertson, Sarah E.; Santy, Lorraine C.; Casanova, James E.; Chou, Margaret M.

doi:10.1128/mcb.24.22.9752-9762.2004

Cited by 65 publications

(87 citation statements)

References 67 publications

(99 reference statements)

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“…However, USP6 also contains a TBC domain, which binds to the ADP ribosylation 6 (ARF6) GTPase and promotes its activation in vivo independent of its USP domain (37). Recent studies have shown that ARF6 can activate Wnt signaling by stimulating MAPK1/ERK activation and phosphatidylinositide production to promote LRP6 phosphorylation (38,39).…”

Section: Discussionmentioning

confidence: 99%

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

Madan

Walker

Young

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The Wnt signaling pathways play pivotal roles in carcinogenesis. Modulation of the cell-surface abundance of Wnt receptors is emerging as an important mechanism for regulating sensitivity to Wnt ligands. Endocytosis and degradation of the Wnt receptors Frizzled (Fzd) and lipoprotein-related protein 6 (LRP6) are regulated by the E3 ubiquitin ligases zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43), which are disrupted in cancer. In a genome-wide small interfering RNA screen, we identified the deubiquitylase ubiquitin-specific protease 6 (USP6) as a potent activator of Wnt signaling. USP6 enhances Wnt signaling by deubiquitylating Fzds, thereby increasing their cell-surface abundance. Chromosomal translocations in nodular fasciitis result in USP6 overexpression, leading to transcriptional activation of the Wnt/β-catenin pathway. Inhibition of Wnt signaling using Dickkopf-1 (DKK1) or a Porcupine (PORCN) inhibitor significantly decreased the growth of USP6-driven xenograft tumors, indicating that Wnt signaling is a key target of USP6 during tumorigenesis. Our study defines an additional route to ectopic Wnt pathway activation in human disease, and identifies a potential approach to modulate Wnt signaling for therapeutic benefit.

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Section: Discussionmentioning

confidence: 99%

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

Madan

Walker

Young

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…One obvious, possible mechanism of action for TBC1D3 would be to induce ARF6 activation, similarly to what has been reported for USP6 (Martinu et al, 2004). Thus, we analyzed ARF6-GTP levels in cells overexpressing TBC1D3, or EFA6 or ARF6-Q67L as controls.…”

Section: Tbc1d3 Interacts and Colocalize With Gga3 At The Plasma Membmentioning

confidence: 99%

“…RNTRE regulates clathrin-dependent endocytosis and macropinocytosis by acting as a GAP on RAB5 (Lanzetti et al, 2000(Lanzetti et al, , 2004, and possibly on other RABs (Haas et al, 2005). Conversely, USP6, whose TBC domain is apparently devoid of GAP activity, is involved in the control of plasma membrane-endosomal trafficking in an ARF6-dependent manner (Martinu et al, 2004). Little is known, instead, about TBC1D3.…”

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confidence: 99%

“…Thus, we analyzed ARF6-GTP levels in cells overexpressing TBC1D3, or EFA6 or ARF6-Q67L as controls. We used an assay based on the ability of a ␥-ear-containing fragment of GGA3, an ARF-binding protein, to bind to ARF6 in a GTP-dependent manner (Dell'Angelica et al, 2000;Martinu et al, 2004). No significant activation of ARF6 in TBC1D3-overexpressing cells could be detected, under conditions in which expression of EFA6 induced a significant increase in ARF6-GTP levels ( Figure 5A).…”

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confidence: 99%

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The Primate-specific Protein TBC1D3 Is Required for Optimal Macropinocytosis in a Novel ARF6-dependent Pathway

Frittoli

Palamidessi

Pizzigoni

et al. 2008

MBoC

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The generation of novel genes and proteins throughout evolution has been proposed to occur as a result of whole genome and gene duplications, exon shuffling, and retrotransposition events. The analysis of such genes might thus shed light into the functional complexity associated with highly evolved species. One such case is represented by TBC1D3, a primatespecific gene, harboring a TBC domain. Because TBC domains encode Rab-specific GAP activities, TBC-containing proteins are predicted to play a major role in endocytosis and intracellular traffic. Here, we show that the TBC1D3 gene originated late in evolution, likely through a duplication of the RNTRE locus, and underwent gene amplification during primate speciation. Despite possessing a TBC domain, TBC1D3 is apparently devoid of Rab-GAP activity. However, TBC1D3 regulates the optimal rate of epidermal growth factor-mediated macropinocytosis by participating in a novel pathway involving ARF6 and RAB5. In addition, TBC1D3 binds and colocalize to GGA3, an ARF6-effector, in an ARF6-dependent manner, and synergize with it in promoting macropinocytosis, suggesting that the two proteins act together in this process. Accordingly, GGA3 siRNA-mediated ablation impaired TBC1D3-induced macropinocytosis. We thus uncover a novel signaling pathway that appeared after primate speciation. Within this pathway, a TBC1D3:GGA3 complex contributes to optimal propagation of signals, ultimately facilitating the macropinocytic process. INTRODUCTIONGene duplication, exon shuffling, and retrotransposition events played crucial roles during vertebrate evolution (Long, 2001;McLysaght et al., 2002;Brosius, 2003). About 5% of the human genome is composed of duplicated segments that emerged during the past 35 million years of primate evolution, resulting in the generation of novel protein functions (Courseaux and Nahon, 2001;Taylor and Raes, 2004).One of the cellular processes, whose regulation has became more and more complex and tightly regulated during evolution is endocytosis. Endocytosis serves to maintain cellular and organismal homeostasis by mediating the uptake of fluids, solutes, and signaling molecules and their receptors. Multiple mechanisms of endocytosis operate within a single cell (Conner and Schmid, 2003). Among them, two major categories are phagocytosis and pinocytosis, which mediate the uptake of particles or of fluid, respectively (Conner and Schmid, 2003).Pinocytosis encompasses a variety of different membraneentry routes and is invariably characterized by the relatively small size (50 -150 nm) of the internalized particles. Large volumes of fluid are, instead, engulfed by extension, folding, and closure of plasma membranes (PM) through a process termed macropinocytosis (Swanson and Watts, 1995). Macropinocytosis displays many similarities to phagocytosis; the biochemical and cellular components of these endocytic mechanisms have been best characterized in hematopoietic cells, in processes such as phagocytosis by macrophages in response to Fc receptor stimulation, or ma...

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“…However, relevant substrates have not been identified to date. TRE17 has another characteristic domain, the TBC (Tre-2, Bub2, Cdc16) domain, through which it binds to Arf6, a G protein associated with the CIE endosomal membrane system (Martinu et al, 2004). TRE17 colocalizes with Arf6 and CIE cargo proteins.…”

Section: Introductionmentioning

confidence: 99%

TRE17/USP6 regulates ubiquitination and trafficking of cargo proteins that enter cells by clathrin-independent endocytosis

Funakoshi¹,

Chou²,

Kanaho³

et al. 2014

Journal of Cell Science

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Plasma membrane proteins that enter cells by clathrin-independent endocytosis (CIE) are sorted either to lysosomes for degradation or recycled back to the plasma membrane. Expression of some MARCH E3 ubiquitin ligases promotes trafficking of CIE cargo proteins to lysosomes by ubiquitylating the proteins. Here, we show that co-expression of the ubiquitin-specific protease TRE17/USP6 counteracts the MARCH-dependent targeting of CIE cargo proteins, but not that of transferrin receptor, to lysosomes, leading to recovery of the stability and cell surface level of the proteins. The ubiquitylation of CIE cargo proteins by MARCH8 was reversed by TRE17, suggesting that TRE17 leads to deubiquitylation of CIE cargo proteins. The effects of TRE17 were dependent on its deubiquitylating activity and expression of TRE17 alone led to a stabilization of surface major histocompatibility complex class I (MHCI) molecules, a CIE cargo, suggesting that deubiquitylation of endogenous CIE cargo proteins promotes their stability. This study demonstrates that cycles of ubiquitylation and deubiquitylation can determine whether CIE cargo proteins are degraded or recycled.

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The TBC (Tre-2/Bub2/Cdc16) Domain Protein TRE17 Regulates Plasma Membrane-Endosomal Trafficking through Activation of Arf6

Cited by 65 publications

References 67 publications

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

The Primate-specific Protein TBC1D3 Is Required for Optimal Macropinocytosis in a Novel ARF6-dependent Pathway

TRE17/USP6 regulates ubiquitination and trafficking of cargo proteins that enter cells by clathrin-independent endocytosis

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