Anxious moments for the protein tyrosine phosphatase PTP1B

Krishnan, Navasona; Tonks, Nicholas K.

doi:10.1016/j.tins.2015.06.006

Cited by 10 publications

(5 citation statements)

References 15 publications

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“…3 A ). PTP1B is a clinically relevant treatment target for cancer and diabetes with roles in insulin and EGF signaling and anxiety (48–51). In GeneMANIA, 21 genes in the BioID of RHBDL4 in HEK293 cells had predicted direct connections with PTP1B.…”

Section: Resultsmentioning

confidence: 99%

Spatial proteomics reveal that the protein phosphatase PTP1B interacts with and may modify tyrosine phosphorylation of the rhomboid protease RHBDL4

Ikeda

Freeman

2019

Journal of Biological Chemistry

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Rhomboid-like proteins are evolutionarily conserved, ubiquitous polytopic membrane proteins, including the canonical rhomboid intramembrane serine proteases and also others that have lost protease activity during evolution. We still have much to learn about their cellular roles, and evidence suggests that some may have more than one function. For example, RHBDL4 (rhomboid-like protein 4) is an endoplasmic reticulum (ER)–resident protease that forms a ternary complex with ubiquitinated substrates and p97/VCP (valosin-containing protein), a major driver of ER-associated degradation (ERAD). RHBDL4 is required for ERAD of some substrates, such as the pre–T-cell receptor α chain (pTα) and has also been shown to cleave amyloid precursor protein to trigger its secretion. In another case, RHBDL4 enables the release of full-length transforming growth factor α in exosomes. Using the proximity proteomic method BioID, here we screened for proteins that interact with or are in close proximity to RHBDL4. Bioinformatics analyses revealed that BioID hits of RHBDL4 overlap with factors related to protein stress at the ER, including proteins that interact with p97/VCP. PTP1B (protein-tyrosine phosphatase nonreceptor type 1, also called PTPN1) was also identified as a potential proximity factor and interactor of RHBDL4. Analysis of RHBDL4 peptides highlighted the presence of tyrosine phosphorylation at the cytoplasmic RHBDL4 C terminus. Site-directed mutagenesis targeting these tyrosine residues revealed that their phosphorylation modifies binding of RHBDL4 to p97/VCP and Lys 63 -linked ubiquitinated proteins. Our work lays a critical foundation for future mechanistic studies of the roles of RHBDL4 in ERAD and other important cellular pathways.

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Section: Resultsmentioning

confidence: 99%

Spatial proteomics reveal that the protein phosphatase PTP1B interacts with and may modify tyrosine phosphorylation of the rhomboid protease RHBDL4

Ikeda

Freeman

2019

Journal of Biological Chemistry

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“…So far, vanadium compounds join the failures of finding specific drugs that target PTP1B, which after enormous efforts were deemed “undruggable” by the pharmaceutical industry. However, PTP1B has received additional attention because it is a validated therapeutic target in Her2-positive breast cancer and inhibitors are discussed as a therapeutic approach to Rett syndrome and anxiety disorders [94], [95].…”

Section: Significance Of Ptp1b Inhibitionmentioning

confidence: 99%

The metal face of protein tyrosine phosphatase 1B

Bellomo

Singh

Massarotti

et al. 2016

Coordination Chemistry Reviews

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“…We have previously reported that the small molecule trodusquemine, an aminosterol first discovered in dogfish sharks and initially investigated for its therapeutic potential against bacterial infection, obesity, cancer, and anxiety disorders 23 – 26 , and as a stimulant of tissue regeneration 27 , acts as a potent inhibitor of αS aggregation by reducing the rates associated with the lipid-induced nucleation and fibril amplification steps in the aggregation process 20 . In a surprising contrast, we also found that trodusquemine enhances the aggregation of Aβ 42 by increasing the rate of monomer-dependent secondary nucleation and, to a lower extent, fibril elongation, while maintaining the rate of primary nucleation almost unaffected 28 .…”

Section: Introductionmentioning

confidence: 99%

Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism

et al. 2020

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The onset and progression of numerous protein misfolding diseases are associated with the presence of oligomers formed during the aberrant aggregation of several different proteins, including amyloid-β (Aβ) in Alzheimer's disease and α-synuclein (αS) in Parkinson's disease. These small, soluble aggregates are currently major targets for drug discovery. In this study, we show that trodusquemine, a naturally-occurring aminosterol, markedly reduces the cytotoxicity of αS, Aβ and HypF-N oligomers to human neuroblastoma cells by displacing the oligomers from cell membranes in the absence of any substantial morphological and structural changes to the oligomers. These results indicate that the reduced toxicity results from a mechanism that is common to oligomers from different proteins, shed light on the origin of the toxicity of the most deleterious species associated with protein aggregation and suggest that aminosterols have the therapeutically-relevant potential to protect cells from the oligomer-induced cytotoxicity associated with numerous protein misfolding diseases.

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Anxious moments for the protein tyrosine phosphatase PTP1B

Cited by 10 publications

References 15 publications

Spatial proteomics reveal that the protein phosphatase PTP1B interacts with and may modify tyrosine phosphorylation of the rhomboid protease RHBDL4

Spatial proteomics reveal that the protein phosphatase PTP1B interacts with and may modify tyrosine phosphorylation of the rhomboid protease RHBDL4

The metal face of protein tyrosine phosphatase 1B

Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism

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