The <i>TRE17</i> Oncogene Encodes a Component of a Novel Effector Pathway for Rho GTPases Cdc42 and Rac1 and Stimulates Actin Remodeling

Robens, Jeffrey; Kutney, Sara N.; Qi, Hongwei; Chou, Margaret M.

doi:10.1128/mcb.23.6.2151-2161.2003

Cited by 52 publications

(53 citation statements)

References 55 publications

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“…As reported previously (Masuda-Robens et al, 2003;Martinu et al, 2004), TRE17 localized at the plasma membrane and tubular endosomes (Fig. 4).…”

Section: Compartmentalization Of Dubs Contributes To Recognition Of Csupporting

confidence: 54%

“…Interestingly, TRE17 is known to bind Arf6, a key regulatory factor for the CIE trafficking pathway. It has been shown that Arf6 and TRE17 colocalize at the plasma membrane and tubular recycling endosomes (Masuda-Robens et al, 2003;Martinu et al, 2004). In addition, Rueckert and Haucke (Rueckert and Haucke, 2012) have shown that subcellular localization of TRE17 depends on Arf6.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…As reported previously (Masuda-Robens et al, 2003;Martinu et al, 2004), TRE17 localized at the plasma membrane and tubular endosomes (Fig. 4).…”

Section: Compartmentalization Of Dubs Contributes To Recognition Of Csupporting

confidence: 54%

Section: Discussionmentioning

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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“…Immunofluorescence was performed as previously described, except that saponin (0.1%) was used in lieu of Triton X-100 (Masuda-Robens et al, 2003). Briefly, cells were fixed with formaldehyde, permeabilized, incubated with primary antibodies for 2-3 hours, then washed.…”

Section: Immunofluorescence Confocal Microscopymentioning

confidence: 99%

The adaptor complex AP-2 regulates post-endocytic trafficking through the non-clathrin Arf6-dependent endocytic pathway

Lau

Chou

2008

Journal of Cell Science

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The ADP-ribosylation factor 6 (Arf6) GTPase functions as a key regulator of endocytic trafficking, participating in clathrin-independent endocytosis in most cell types. Unexpectedly, we found that siRNA-mediated depletion of clathrin or of adaptor protein 2 (AP-2)-complex subunits alters trafficking of Arf6 pathway cargo proteins, such as major histocompatibility complex class I (MHCI) and β1 integrin. Internalization of these cargoes from the plasma membrane was not affected in cells depleted of clathrin, but was modestly delayed in cells lacking AP-2. Furthermore, depletion of clathrin or AP-2 altered the intracellular distribution of MHCI and β1 integrin, inducing clustering in a perinuclear region. Despite this altered localization in both depleted populations, enhanced lysosomal targeting of MHCI was observed uniquely in cells that lack AP-2. Total levels of MHCI were modestly but consistently reduced in AP-2-depleted cells, and restored by the lysosomal inhibitor bafilomycin A. Furthermore, the half-life of surface-derived MHCI was reduced in AP-2-depleted cells. Consistent with enhanced degradative sorting, colocalization of Arf6 cargo with the late endosome and lysosome markers CD63 and Lamp1 was increased in cells depleted of AP-2 but not clathrin. These studies indicate a role for AP-2 in maintaining normal post-endocytic trafficking through the Arf6-regulated, non-clathrin pathway, and reveal pervasive effects of clathrin and AP-2 depletion on the endosomal and lysosomal system.

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“…Anti-GST has been described previously (19). Anti-ubiquitin (Ub) antibody (FK2) was purchased from Affiniti Research Products, and antimaltose-binding protein (MBP) from New England Biolabs.…”

Section: Methodsmentioning

confidence: 99%

“…The entire open reading frame was subcloned into the mammalian expression vector pEBG to generate a GST-tagged fusion protein (CaM⅐pEBG). Hemagglutinin (HA)-TRE17(long), HA-TRE17(onco), and T17(447)/pcDNA3 have been described previously (18,19). Point mutants HA-T17(447)/ F328E/pcDNA3, T17(447)/L319D, W320D/pcDNA3, HA-T17(447)/ V306D,L311D)/pcDNA3, and HA-T17(447)/R15A/pcDNA3 were generated by overlap extension PCR.…”

Section: Methodsmentioning

confidence: 99%

Calcium/Calmodulin Regulates Ubiquitination of the Ubiquitin-specific Protease TRE17/USP6

Shen

Robertson

et al. 2005

Journal of Biological Chemistry

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The TRE17 (USP6/TRE-2) oncogene induces tumorigenesis in both humans and mice. However, little is known regarding its regulation or mechanism of transformation. TRE17 encodes a TBC (Tre-2/Bub2/Cdc16)/Rab GTPase-activating protein homology domain at its N terminus and a ubiquitin-specific protease at its C terminus. In the current study, we identified the ubiquitous calcium (Ca 2؉ )-binding protein calmodulin (CaM) as a novel binding partner for TRE17. CaM bound directly to TRE17 in a Ca 2؉ -dependent manner both in vitro and in vivo. The CaM-binding site was mapped to two hydrophobic motifs near the C terminus of the TBC domain. Point mutations within these motifs significantly reduced the interaction of TRE17 with CaM. We further found that TRE17 is monoubiquitinated and promotes its own deubiquitination in vivo. CaM binding-deficient mutants of TRE17 exhibited significantly reduced monoubiquitination, suggesting that binding of Ca 2؉ /CaM to TRE17 promotes this modification. Consistent with this notion, treatment of cells with the CaM inhibitor W7 reduced levels of TRE17 monoubiquitination. Interestingly, the calcium ionophore A23187 induced accumulation of a polyubiquitinated TRE17 species. The effect of A23187 was attenuated in CaM binding-deficient mutants of TRE17. Taken together, these studies indicate a role for Ca 2؉ /CaM in regulating ubiquitination through direct interaction with TRE17.

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The TRE17 Oncogene Encodes a Component of a Novel Effector Pathway for Rho GTPases Cdc42 and Rac1 and Stimulates Actin Remodeling

Cited by 52 publications

References 55 publications

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

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

The adaptor complex AP-2 regulates post-endocytic trafficking through the non-clathrin Arf6-dependent endocytic pathway

Calcium/Calmodulin Regulates Ubiquitination of the Ubiquitin-specific Protease TRE17/USP6

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