14-3-3σ and Its Modulators in Cancer

Aljabal, Ghazi; Yap, Beow Keat

doi:10.3390/ph13120441

Cited by 23 publications

(20 citation statements)

References 111 publications

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“…Previous studies have identified 14-3-3σ as a tumor suppressor as it plays a pivotal role in controlling tumor metabolic reprogramming and thus cancer cell growth and metastasis [ 23 ]. For example, it has been reported that 14-3-3σ protects P53 against MDM2-mediated ubiquitination and degradation, resulting in direct control of the G2-M checkpoint of the cell cycle [ 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, to date, no ligand has been reported to target the central cavity of the dimer interface of the 14-3-3σ and stabilize its homodimeric form, as the reported modulators of 14-3-3σ (both stabilizers and inhibitors) generally target the amphipathic ligand-binding groove [ 23 , 51 ]. Nevertheless, one ligand (GCP-Lys-OMe) has been recently reported to bind to the dimer interface of the 14-3-3ζ isoform [ 47 ], though it is not known if the compound can stabilize the 14-3-3ζ dimer.…”

Section: Introductionmentioning

confidence: 99%

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In Silico Studies on GCP-Lys-OMe as a Potential 14-3-3σ Homodimer Stabilizer

Aljabal

Yap²

2022

Pharmaceuticals

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14-3-3 sigma is a vital negative cell cycle regulator. Its expression is consistently downregulated in many types of cancer through gene promoter hypermethylation or proteasomal degradation. 14-3-3 sigma needs to form a homodimer to be functional, while dimers are less prone to degradation than monomers. This suggests that a homodimer stabilizer may increase the tumor suppressive activities of 14-3-3 sigma. However, no known homodimer stabilizer of 14-3-3 sigma has been reported to date. Therefore, this study attempts to test the potential capability of GCP-Lys-OMe (previously reported to bind at the dimer interface of 14-3-3 zeta isoform), to bind and stabilize the 14-3-3 sigma homodimer. In silico docking of GCP-Lys-OMe on 14-3-3 sigma showed more favorable interaction energy (−9.63 kcal/mole) to the dimer interface than 14-3-3 zeta (−7.73 kcal/mole). Subsequent 100 ns molecular dynamics simulation of the GCP-Lys-OMe/14-3-3 sigma complex revealed a highly stable interaction with an average root-mean-square deviation of 0.39 nm (protein backbone) and 0.77 nm (ligand atoms). More contacts between residues at the homodimer interface and a smaller coverage of conformational space of protein atoms were detected for the bound form than for the apo form. These results suggest that GCP-Lys-OMe is a potential homodimer stabilizer of 14-3-3 sigma.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Silico Studies on GCP-Lys-OMe as a Potential 14-3-3σ Homodimer Stabilizer

Aljabal

Yap²

2022

Pharmaceuticals

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“…Based on the design and our results, it is presumed that TDPP could have great degradation efficiency for proteins with those three kinds of motifs. While 14-3-3 and P-14-3-3-BME proteins are involved in many cellular events, including neural development (Antunes et al, 2022), cancer proliferation and apoptosis (Aljabal and Yap, 2020; Huang et al, 2020; Yang et al, 2020), autoimmune disorder (McGowan et al, 2020), virus infection (Liu et al, 2021), etc., the TDPP-induced degradation could be significant in regulating the related downstream pathways and biological events.…”

Section: Discussionmentioning

confidence: 99%

A ubiquitination-mediated degradation system to target phospho-14-3-3-binding-motif embedded proteins

Huang

et al. 2022

Preprint

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The phosphorylation of 14-3-3 binding motif is involved in many cellular processes. A strategy that enables targeted degradation of phospho-14-3-3-binding-motif embedded (P-14-3-3-BME) proteins for studying their functions is highly desirable for basic research. Here, we report a phosphorylation-induced, ubiquitin-proteasome-system-mediated targeted protein degradation (TPD) strategy that allows specific degradation of P-14-3-3-BME proteins. Specifically, by ligating a modified von Hippel-Lindau E3-ligase with an engineered 14-3-3 bait, we generated a protein chimera referred to as Targeted Degradation of P-14-3-3-BME Protein (TDPP). TDPP can serve as a universal degrader for P-14-3-3-BME proteins based on the specific recognition of the phosphorylation in 14-3-3 binding motifs. TDPP shows high efficiency and specificity to a difopein-EGFP reporter, general and specific P-14-3-3-BME proteins. TDPP can also be applied for the validation of P-14-3-3-BME proteins. These results strongly support TDPP as a powerful tool for 14-3-3 related research.

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“…These results highlight a role for 14-3-3η binding to FOXO3 in invadosome formation and suggest that this event may become an attractive target for countering the ECM-degradative capacity of RA synoviocytes. In keeping with this possibility, various compounds targeting 14-3-3 protein interactions are in development, with potential therapeutic implications in other disorders such as cancer and neurological disorders [ 63 , 64 ].…”

Section: Discussionmentioning

confidence: 99%

14-3-3η Promotes Invadosome Formation via the FOXO3–Snail Axis in Rheumatoid Arthritis Fibroblast-like Synoviocytes

Kadiri

Charbonneau

Lalanne

et al. 2021

IJMS

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Erosive destruction of joint structures is a critical event in the progression of rheumatoid arthritis (RA), in which fibroblast-like synoviocytes (FLS) are the primary effectors. We previously reported that the ability of RA FLS to degrade extracellular matrix (ECM) components depends on the formation of actin-rich membrane protrusions, called invadosomes, through processes that remain elusive. 14-3-3η belongs to a family of scaffolding proteins involved in a wide range of cellular functions, and its expression is closely related to joint damage and disease activity in RA patients. In this study, we sought to assess the role of 14-3-3η in joint damage by examining its contribution to the invadosome formation phenotype of FLS. Using human primary FLS, we show that 14-3-3η expression is closely associated with their ability to form invadosomes. Furthermore, knockdown of 14-3-3η using shRNAs decreases the level of invadosome formation in RA FLS, whereas addition of the recombinant protein to FLS from healthy individuals promotes their formation. Mechanistic studies suggest that 14-3-3η regulates invadosome formation by increasing Snail expression, a mechanism that involves nuclear exclusion of the transcription repressor FOXO3. Our results implicate the 14-3-3η–FOXO3–Snail axis in promoting the aggressive ECM-degrading phenotype of RA FLS, and suggest a role for this scaffolding protein in cartilage degradation.

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14-3-3σ and Its Modulators in Cancer

Cited by 23 publications

References 111 publications

In Silico Studies on GCP-Lys-OMe as a Potential 14-3-3σ Homodimer Stabilizer

In Silico Studies on GCP-Lys-OMe as a Potential 14-3-3σ Homodimer Stabilizer

A ubiquitination-mediated degradation system to target phospho-14-3-3-binding-motif embedded proteins

14-3-3η Promotes Invadosome Formation via the FOXO3–Snail Axis in Rheumatoid Arthritis Fibroblast-like Synoviocytes

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