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

Funakoshi, Yuji; Chou, Margaret M.; Kanaho, Yasunori; Donaldson, Julie G.

doi:10.1242/jcs.156786

Cited by 19 publications

(30 citation statements)

References 40 publications

(70 reference statements)

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“…However, a vital question that remained unanswered was the identity of USP6’s relevant substrates. Previous studies indicate that USP6 promotes both de-ubiquitination of itself and of clathrin-independent endocytic pathway cargoes in vivo (21), (22). However, it remained unknown whether any of these proteins are direct substrates of USP6, and what their relevance is to transformation.…”

Section: Introductionmentioning

confidence: 99%

Jak1–STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis

et al. 2016

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Bone and soft tissue tumors are relatively poorly understood, hampering the development of effective therapies. Here we report a critical effector pathway for the ubiquitin-specific protease 6(USP6)/TRE17, which is overexpressed upon chromosome translation in various human tumors, including aneurysmal bone cyst and the related benign lesion nodular fasciitis. Ectopic expression of USP6 is known to drive formation of tumors which recapitulate key features of ABC and NF, however, the identity of USP6's relevant substrates has been obscure. Here we report that the Jak1-STAT3 signaling pathway serves as an essential effector of USP6 in BSTT formation. We found that USP6 directly de-ubiquitinated Jak1, leading to its stabilization and activation of STAT3. The tumorigenic potential of USP6 was attenuated significantly by CRISPR-mediated deletion of Jak1 or STAT3, or by administration of a Jak family inhibitor. Analysis of primary clinical samples of NF confirmed the activation of a Jak1-STAT3 gene signature in vivo. Together, our studies highlight Jak1 as the first identified substrate for USP6, and they offer a mechanistic rationale for the clinical investigation of Jak and STAT3 inhibitors as therapeutics for the treatment of bone and soft tissue tumors along with other neoplasms driven by USP6 overexpression.

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Section: Introductionmentioning

confidence: 99%

Jak1–STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis

et al. 2016

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“…USP6NL , ubiquitin specific peptidase 6 N-terminal like, has a role in the EGF receptor (EGFR) signaling pathway by acting as a GTPase-activating protein and inhibiting internalization of EGFR [27]. Insight for a role of USP6NL may be gained from information about USP6 which regulates ubiquitylation and trafficking of cargo protein by clathrin-independent endocytosis [28]. There is a growing body of evidence from studies in humans and mice supporting a role for clathrin-mediated endocytosis in AD [29-31] In addition, the association of the phosphatidylinositol binding clathrin assembly protein ( PICALM ) gene to AD is well established [12].…”

Section: Discussionmentioning

confidence: 99%

Transethnic genome‐wide scan identifies novel Alzheimer's disease loci

Jun¹,

Chung²,

Mez³

et al. 2017

Alzheimer's & Dementia

175

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BACKGROUND Genetic loci for Alzheimer disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. METHODS We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer’s Disease Genetics Consortium (ADGC). Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer’s Project (IGAP) GWAS dataset. RESULTS Genome-wide significant (GWS) associations in SNP-based tests (P<5×10−8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1, and for the interaction of the APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P<2.7×10−6) for gene-based association in the total sample with a novel locus, TPBG (P=1.8×10−6). DISCUSSION Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

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“…In all cases, the entire coding sequence of USP6 is retained. USP6 functions in remodeling of the cytoskeleton and extracellular matrix, inflammatory response, cell signaling, cellular trafficking, and protein turnover, 23,27,[36][37][38][39][40][41][42][43][44] but its specific role in tumorigenesis is not entirely clear. More recently, Quick et al 45 reported that Jak1-STAT3 signaling has an essential role in USP6-related tumorigenesis, while Madan et al 46 suggested a role for Wnt signaling.…”

Section: Discussionmentioning

confidence: 99%

USP6 activation in nodular fasciitis by promoter-swapping gene fusions

et al. 2017

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Nodular fasciitis is a self-limited myofibroblastic lesion that can be misdiagnosed as a sarcoma as a result of its rapid growth, cellularity, and sometimes prominent mitotic activity. A recurrent translocation t(17;22) has been identified in nodular fasciitis, fusing the coding region of USP6 to the promoter region of MYH9, and resulting in increased USP6 expression. A subset of cases show USP6 rearrangement without the typical fusion variants by RT-PCR, or any MYH9 rearrangement by FISH. We sought to further characterize such tumors using molecular diagnostic assays. A novel RT-PCR assay was designed to detect the two known MYH9-USP6 fusion types in formalin-fixed paraffin-embedded and frozen tissue, and a break-apart FISH assay was designed to detect USP6 rearrangement. Twenty-six cases of nodular fasciitis diagnosed between 2002 and 2013 were retrieved from the pathology files of our institutions and were confirmed to be positive by FISH and/or RT-PCR. Seven samples showed USP6 rearrangement by FISH but were negative for MYH9-USP6 fusion by RT-PCR; these cases were subjected to a next-generation sequencing assay utilizing anchored multiplex PCR technology. This assay targets a single partner gene associated with fusions in bone and soft tissue tumors for agnostic detection of gene fusion partners. Novel fusion partners were identified in all seven cases and confirmed by RT-PCR. Structurally, all fusions consisted of the juxtaposition of the entire coding region of USP6 with the promoter of the partner gene, driving increased USP6 expression. This study confirms the neoplastic nature of nodular fasciitis, defines additional pathogenic fusion partners, and adds to the growing body of literature on USP6-associated neoplasia. Given the diagnostic challenges of these tumors, molecular assays can be useful ancillary tools; however, the prevalence of promoter swapping must be recognized when interpreting results.

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

Cited by 19 publications

References 40 publications

Jak1–STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis

Jak1–STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis

Transethnic genome‐wide scan identifies novel Alzheimer's disease loci

USP6 activation in nodular fasciitis by promoter-swapping gene fusions

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