Distinct Interactions of EBP1 Isoforms with FBXW7 Elicits Different Functions in Cancer

Wang, Yuli; Zhang, Pengju; Wang, Yunshan; Zhan, Panpan; Liu, Chunyan; Mao, Jian‐Hua; Wei, Guangwei

doi:10.1158/0008-5472.can-16-2246

Cited by 28 publications

(44 citation statements)

References 51 publications

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“…PKC may facilitate cellular transformation by inactivating FBXW7α through cytoplasmic sequestration. Finally, the EBP1 (ErbB3 receptor-binding protein) gene encodes two alternatively spliced isoforms: P48 and P42 [ 86 ]. P48 forms a negative feedback loop with FBXW7α, whereby FBXW7α degrades P48 in a GSK3-dependent manner, and P48 is able to bind FBXW7α and sequester it in the cytosol.…”

Section: Inactivation Of Fbxw7 Functionsmentioning

confidence: 99%

“…P48 forms a negative feedback loop with FBXW7α, whereby FBXW7α degrades P48 in a GSK3-dependent manner, and P48 is able to bind FBXW7α and sequester it in the cytosol. This prevents FBXW7α from degrading its substrates [ 86 ]. In contrast, P42 acts as an adaptor to stabilize the interaction between FBXW7 and its substrates, which enhances FBXW7-mediated degradation [ 86 ].…”

Section: Inactivation Of Fbxw7 Functionsmentioning

confidence: 99%

“…This prevents FBXW7α from degrading its substrates [ 86 ]. In contrast, P42 acts as an adaptor to stabilize the interaction between FBXW7 and its substrates, which enhances FBXW7-mediated degradation [ 86 ]. The EBP2 (EBNA1-binding protein 2) protein also facilitates different isoforms of FBXW7 nucleolar distribution [ 87 ].…”

Section: Inactivation Of Fbxw7 Functionsmentioning

confidence: 99%

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FBXW7: a critical tumor suppressor of human cancers

2018

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The ubiquitin-proteasome system (UPS) is involved in multiple aspects of cellular processes, such as cell cycle progression, cellular differentiation, and survival (Davis RJ et al., Cancer Cell 26:455-64, 2014; Skaar JR et al., Nat Rev Drug Discov 13:889-903, 2014; Nakayama KI and Nakayama K, Nat Rev Cancer 6:369-81, 2006). F-box and WD repeat domain containing 7 (FBXW7), also known as Sel10, hCDC4 or hAgo, is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a critical tumor suppressor and one of the most commonly deregulated ubiquitin-proteasome system proteins in human cancer. FBXW7 controls proteasome-mediated degradation of oncoproteins such as cyclin E, c-Myc, Mcl-1, mTOR, Jun, Notch and AURKA. Consistent with the tumor suppressor role of FBXW7, it is located at chromosome 4q32, a genomic region deleted in more than 30% of all human cancers (Spruck CH et al., Cancer Res 62:4535-9, 2002). Genetic profiles of human cancers based on high-throughput sequencing have revealed that FBXW7 is frequently mutated in human cancers. In addition to genetic mutations, other mechanisms involving microRNA, long non-coding RNA, and specific oncogenic signaling pathways can inactivate FBXW7 functions in cancer cells. In the following sections, we will discuss the regulation of FBXW7, its role in oncogenesis, and the clinical implications and prognostic value of loss of function of FBXW7 in human cancers.

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Section: Inactivation Of Fbxw7 Functionsmentioning

confidence: 99%

Section: Inactivation Of Fbxw7 Functionsmentioning

confidence: 99%

Section: Inactivation Of Fbxw7 Functionsmentioning

confidence: 99%

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FBXW7: a critical tumor suppressor of human cancers

2018

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“…Repression of PA2G4 expression was associated with an increase in MYCN ubiquitination. Studies in colorectal cancer cells suggested PA2G4 could bind directly to, and sequester Fbxw7 in the cytoplasm, thus indirectly increasing nuclear MYC protein stability (12). We investigated this potential mechanism of PA2G4 influencing MYCN protein stability indirectly by shifting the location of Fbxw7 toward the cytoplasm and possibly protecting nuclear proteins including MYCN.…”

Section: Pa2g4 and Mycn Exhibit Functionally Interdependent Expressionmentioning

confidence: 99%

“…The proliferation-associated 2AG4 protein (PA2G4), or ErbB3 binding protein (EBP1), binds Fbxw7, sequestering it in the cytoplasm, hence stabilizing MYC in colorectal cancer cells (12). PA2G4 is a ubiquitously expressed DNA and RNA binding protein with roles in normal embryonal muscle and neural crest cell growth (13,14).…”

Section: Introductionmentioning

confidence: 99%

Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

et al. 2019

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MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferationassociated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCNdependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN-PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN-PA2G4 protein-protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease.Significance: Competitive chemical inhibition of the PA2G4-MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCNbinding partners in malignancies driven by MYC family oncoproteins. Characterization of the PA2G4-MYCN protein-protein interface. A, GST pulldown of overexpressed GST-MYCN deletion mutant proteins and a PA2G4-3xFlag expression vector for 24 hours in HEK-293T cells, which were then immunoblotted with an anti-Flag antibody. B, Overlay of the independent representation of the docking solutions of WS6 (green carbons) and the MYCN oligopeptide DHKALST (white carbons) to PA2G4. Both were predicted to bind to the same surface pocket of PA2G4 (gray-filled space). C, A representative SPR (Biacore T200) experiment demonstrating a direct dose-response binding interaction between the bound PA2G4 exposed to increasing concentrations of the MYCN oligopeptide, DHKALST. Each experiment was run in duplicate. Overall this interaction had a calculated K d of 28.3 AE 0.73 mmol/L (n ¼ 5). D, A molecular model of the PA2G4-MYCN protein interface. The addition of two MYCN amino acids at the C-terminus and five at the N-terminus of the DHKALST MYCN oligopeptide resulted in an oligopeptide, GGDHKALSTGEDTL (cyan carbons), which interacted with PA2G4 (white carbons) in this molecular model. A visual analysis of this static dock predicted putative hydrogen bonds (yellow dashes) with residues Ser47, Arg271, and Arg272, which were subsequently targeted for mutagenesis. E, Representative SPR curves showing the concentration-response binding of DHKALST to PA2G4 (solid lines). The addition of 10 mmol/L WS6 resulted in a repression of this binding (dotted lines). This experiment was conducted in duplicate, three times. F, HEK293 cells were transiently transfecte...

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USP35 mitigates endoplasmic reticulum stress‐induced apoptosis by stabilizing RRBP1 in non‐small cell lung cancer

Wang

Wang²,

Xiao

et al. 2021

Molecular Oncology

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Deubiquitinating enzymes (DUBs) serve to maintain cellular homeostasis via protein ubiquitination and exert diverse regulatory functions in cancers and other diseases. Much progress has been made in characterizing biological roles of DUBs over the decades, yet the specific functions of many subclass members remain largely unexplored. It was not until recent years that the role of ubiquitin-specific-processing protease 35 (USP35) in cancers began to be understood. Here, we focus on delineating the roles and underlying mechanisms of USP35 in non-small cell lung cancer (NSCLC). The isobaric tags for relative and absolute quantitation (iTRAQ) comparative proteomic approach were employed to identify differentially expressed proteins (DEPs) in H1299 cells induced by USP35 overexpression or silencing. Among the potential interactome of USP35, ribosome-binding protein 1 (RRBP1), a membrane-bound protein in endoplasmic reticulum (ER), captured our attentions. RRBP1 expression was found to positively correlate with USP35 levels in both genetically modified cells and human NSCLC tissues. Concordantly, both RRBP1 expression and USP35 expression were found to positively correlate with poor prognoses in lung adenocarcinoma patients. At the molecular level, USP35 was verified to directly interact with RRBP1 to prevent it from proteasomal-dependent degradation. Functionally, USP35 alleviated ER stress-induced cell apoptosis by stabilizing RRBP1 in NSCLC cells. Collectively, these findings indicate that USP35 plays a critical role in resisting ER stress-induced cell death through deubiquitinating RRBP1, hence providing a rationale to target the USP35-RRBP1 axis as an alternative therapeutic option for NSCLC.

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Distinct Interactions of EBP1 Isoforms with FBXW7 Elicits Different Functions in Cancer

Cited by 28 publications

References 51 publications

FBXW7: a critical tumor suppressor of human cancers

FBXW7: a critical tumor suppressor of human cancers

Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

USP35 mitigates endoplasmic reticulum stress‐induced apoptosis by stabilizing RRBP1 in non‐small cell lung cancer

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