Systematic proteomics of the VCP–UBXD adaptor network identifies a role for UBXN10 in regulating ciliogenesis

Raman, Malavika; Sergeev, Mikhail; Garnaas, Maija K.; Lydeard, John R.; Huttlin, Edward L.; Goessling, Wolfram; Shah, Jagesh V.; Harper, J. Wade

doi:10.1038/ncb3238

Cited by 88 publications

(111 citation statements)

References 54 publications

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“…6D). The recovery of increased UBXN7 and FAF2 in association with VCP upon NMS873 treatment is all the more remarkable given that NMS873 treatment reduces the steadystate level of these proteins (23). Inhibition of VCP by NMS873 could stabilize association of some adaptors by at least two conceivable mechanisms.…”

Section: Vcp-adaptor Interaction Is Largely Because Of Directmentioning

confidence: 95%

“…A Cautionary Note for Analysis of VCP-interacting Proteins-Because the interaction of VCP with its adaptors is so dynamic, lists of VCP-interacting proteins obtained through conventional immunoprecipitation protocols (21,23,28) are most likely dominated by proteins that formed interactions with VCP in cell lysate. Whereas many of these interactions are nonetheless likely to be physiological, some of them might not be, because of the loss of compartmentation and other forms of regulation that accompanies cell lysis.…”

Section: Discussionmentioning

confidence: 99%

“…New VCP functions and substrates have been sought through the application of affinity purification-mass spectrometry to identify proteins that bind to either VCP or its adaptors (21,23,28,39). These efforts have identified multiple new functions for VCP, linking it to cullin-RING ubiquitin ligases, endosomal sorting, and ciliary biogenesis.…”

Section: Protein Quality Control (Pqc)mentioning

confidence: 99%

“…The function of VCP is modulated by "primary" binding proteins, of which about two dozen well-validated partners are known (21)(22)(23). Of particular interest is a set of adaptors that are thought to serve as specificity factors that link substrates to VCP.…”

Section: Protein Quality Control (Pqc)mentioning

confidence: 99%

See 3 more Smart Citations

Valosin-containing protein (VCP)–Adaptor Interactions are Exceptionally Dynamic and Subject to Differential Modulation by a VCP Inhibitor

Xue

Blythe

Freiberger

et al. 2016

Molecular & Cellular Proteomics

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Protein quality control (PQC) plays an important role in stemming neurodegenerative diseases and is essential for the growth of some cancers. Valosin-containing protein (VCP)/p97 plays a pivotal role in multiple PQC pathways by interacting with numerous adaptors that link VCP to specific PQC pathways and substrates and influence the post-translational modification state of substrates. However, our poor understanding of the specificity and architecture of the adaptors, and the dynamic properties of their interactions with VCP hinders our understanding of fundamental features of PQC and how modulation of VCP activity can best be exploited therapeutically. In this study we use multiple mass spectrometry-based proteomic approaches combined with biophysical studies to characterize the interaction of adaptors with VCP. Our results reveal that most VCP-adaptor interactions are characterized by rapid dynamics that in some cases are modulated by the VCP inhibitor NMS873. These findings have significant implications for both the regulation of VCP function and the impact of VCP inhibition on different VCP-adaptor complexes.

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Section: Vcp-adaptor Interaction Is Largely Because Of Directmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Protein Quality Control (Pqc)mentioning

confidence: 99%

Section: Protein Quality Control (Pqc)mentioning

confidence: 99%

See 2 more Smart Citations

Valosin-containing protein (VCP)–Adaptor Interactions are Exceptionally Dynamic and Subject to Differential Modulation by a VCP Inhibitor

Xue

Blythe

Freiberger

et al. 2016

Molecular & Cellular Proteomics

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“…UBXN10 needs to bind p97 to localize within cilia, and loss of UBXN10 and p97 leads to a significant decrease in the number of cilia [40]. Further characterization of UBXN10’s functions in ciliogenesis may clarify the importance of UBXN10 in tumorigenesis initiated by dysregulated ciliogenesis.…”

Section: Ubxn10 Ciliogenesis and Human Cancer Cellsmentioning

confidence: 99%

UBXD Proteins: A Family of Proteins with Diverse Functions in Cancer

Rezvani

2016

IJMS

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The UBXD family is a diverse group of UBX (ubiquitin-regulatory X) domain-containing proteins in mammalian cells. Members of this family contain a UBX domain typically located at the carboxyl-terminal of the protein. In contrast to the UBX domain shared by all members of UBXD family, the amino-terminal domains are diverse and appear to carry out different roles in a subcellular localization-dependent manner. UBXD proteins are principally associated with the endoplasmic reticulum (ER), where they positively or negatively regulate the ER-associated degradation machinery (ERAD). The distinct protein interaction networks of UBXD proteins allow them to have specific functions independent of the ERAD pathway in a cell type- and tissue context-dependent manner. Recent reports have illustrated that a number of mammalian members of the UBXD family play critical roles in several proliferation and apoptosis pathways dysregulated in selected types of cancer. This review covers recent advances that elucidate the therapeutic potential of selected members of the UBXD family that can contribute to tumor growth.

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MammaPrint and BluePrint comprehensively capture the cancer hallmarks in early‐stage breast cancer patients

Haan

Bhaskaran

Ellappalayam

et al. 2021

Genes Chromosomes & Cancer

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MammaPrint ® (MP) is a 70-gene signature that stratifies early-stage breast cancer patients into low-and high risk of distant relapse. Further stratification of MP risk results identifies four risk subgroups, ultra-low (UL), low, high 1, and high 2, with specific prognostic and predictive outcomes. BluePrint ® (BP) is an 80-gene signature that classifies breast tumors as basal, luminal, or HER2 molecular subtype. To gain insight into their biological significance, we annotated the MP 70-and BP 80-genes with respect to the 10 hallmarks of cancer (HoC). Furthermore, we related gene expression profiles of the extreme ends of the MP low-and high-risk patients (here called, ultra-low (UL) and ultra-high (UH) or High2, respectively), to the 10 HoC per BP subtype by differential gene expression and pathway analysis. MP and BP gene functions reflected all 10 HoCs. Most MP and BP genes were associated with sustaining proliferative signaling, followed by genome instability and mutation categories. Based on the gene expression profiles, UL and UH subgroup pathways were down -or upregulated, respectively, reflecting proliferative and metastatic features, such as G2M checkpoint, DNA repair, oxidative phosphorylation, immune invasion, PI3K/AKT/mTOR signaling, and hypoxia pathways. Notably, the UH HER2-type was enriched in several immune signaling pathways, such as IL2/STAT5 signaling and TNFα signaling via NFκB. Our results show that MP and BP gene signatures represent and capture all 10 HoCs and highlight underlying biological processes of MP extreme samples, which might guide treatment decisions as the signature captures the full spectrum of early breast cancers.

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Systematic proteomics of the VCP–UBXD adaptor network identifies a role for UBXN10 in regulating ciliogenesis

Cited by 88 publications

References 54 publications

Valosin-containing protein (VCP)–Adaptor Interactions are Exceptionally Dynamic and Subject to Differential Modulation by a VCP Inhibitor

Valosin-containing protein (VCP)–Adaptor Interactions are Exceptionally Dynamic and Subject to Differential Modulation by a VCP Inhibitor

UBXD Proteins: A Family of Proteins with Diverse Functions in Cancer

MammaPrint and BluePrint comprehensively capture the cancer hallmarks in early‐stage breast cancer patients

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