scholarly journals Comprehensive Profiling of Mammalian Tribbles Interactomes Implicates TRIB3 in Gene Repression

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6318
Author(s):  
Miguel Hernández-Quiles ◽  
Rosalie Baak ◽  
Anouska Borgman ◽  
Suzanne den Haan ◽  
Paula Sobrevals Alcaraz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Interactions ◽  
Breast Cancer Cells ◽  
Transcriptional Regulators ◽  
Gene Repression ◽  
Specific Interactions ◽  
Protein Protein Interactions ◽  
Domain Specific ◽  
Proteomics Approach ◽  
Cancer Initiation

The three human Tribbles (TRIB) pseudokinases have been implicated in a plethora of signaling and metabolic processes linked to cancer initiation and progression and can potentially be used as biomarkers of disease and prognosis. While their modes of action reported so far center around protein–protein interactions, the comprehensive profiling of TRIB interactomes has not been reported yet. Here, we have developed a robust mass spectrometry (MS)-based proteomics approach to characterize Tribbles’ interactomes and report a comprehensive assessment and comparison of the TRIB1, -2 and -3 interactomes, as well as domain-specific interactions for TRIB3. Interestingly, TRIB3, which is predominantly localized in the nucleus, interacts with multiple transcriptional regulators, including proteins involved in gene repression. Indeed, we found that TRIB3 repressed gene transcription when tethered to DNA in breast cancer cells. Taken together, our comprehensive proteomic assessment reveals previously unknown interacting partners and functions of Tribbles proteins that expand our understanding of this family of proteins. In addition, our findings show that MS-based proteomics provides a powerful tool to unravel novel pseudokinase biology.

scholarly journals Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells

2020 ◽  
Vol 117 (47) ◽  
pp. 29684-29690
Author(s):  
Matthias Barone ◽  
Matthias Müller ◽  
Slim Chiha ◽  
Jiang Ren ◽  
Dominik Albat ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Protein Interactions ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Cancer Therapies ◽  
Protein Protein Interactions ◽  
Zebrafish Model ◽  
Therapeutic Concept ◽  
Protein Protein Interaction

Battling metastasis through inhibition of cell motility is considered a promising approach to support cancer therapies. In this context, Ena/VASP-depending signaling pathways, in particular interactions with their EVH1 domains, are promising targets for pharmaceutical intervention. However, protein–protein interactions involving proline-rich segments are notoriously difficult to address by small molecules. Hence, structure-based design efforts in combination with the chemical synthesis of additional molecular entities are required. Building on a previously developed nonpeptidic micromolar inhibitor, we determined 22 crystal structures of ENAH EVH1 in complex with inhibitors and rationally extended our library of conformationally defined proline-derived modules (ProMs) to succeed in developing a nanomolar inhibitor (Kd=120 nM,MW=734Da). In contrast to the previous inhibitor, the optimized compounds reduced extravasation of invasive breast cancer cells in a zebrafish model. This study represents an example of successful, structure-guided development of low molecular weight inhibitors specifically and selectively addressing a proline-rich sequence-recognizing domain that is characterized by a shallow epitope lacking defined binding pockets. The evolved high-affinity inhibitor may now serve as a tool in validating the basic therapeutic concept, i.e., the suppression of cancer metastasis by inhibiting a crucial protein–protein interaction involved in actin filament processing and cell migration.

scholarly journals Investigation into the molecular mechanism of the antiapoptotic functions of CTCF in breast cancer cells using a proteomics approach

2008 ◽  
Vol 10 (S2) ◽  
Author(s):  
CF Méndez-Catalá ◽  
I Cherhukhin ◽  
F Docquier ◽  
D Farrar ◽  
E Pugacheva ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Molecular Mechanism ◽  
Breast Cancer Cells ◽  
Proteomics Approach

scholarly journals Engineering selective competitors for the discrimination of highly conserved protein-protein interaction modules

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Charlotte Rimbault ◽  
Kashyap Maruthi ◽  
Christelle Breillat ◽  
Camille Genuer ◽  
Sara Crespillo ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Pdz Domain ◽  
Specific Inhibitor ◽  
Rational Approach ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Domain Specific ◽  
Postsynaptic Protein ◽  
Protein Interfaces ◽  
Direct Generation

Abstract Designing highly specific modulators of protein-protein interactions (PPIs) is especially challenging in the context of multiple paralogs and conserved interaction surfaces. In this case, direct generation of selective and competitive inhibitors is hindered by high similarity within the evolutionary-related protein interfaces. We report here a strategy that uses a semi-rational approach to separate the modulator design into two functional parts. We first achieve specificity toward a region outside of the interface by using phage display selection coupled with molecular and cellular validation. Highly selective competition is then generated by appending the more degenerate interaction peptide to contact the target interface. We apply this approach to specifically bind a single PDZ domain within the postsynaptic protein PSD-95 over highly similar PDZ domains in PSD-93, SAP-97 and SAP-102. Our work provides a paralog-selective and domain specific inhibitor of PSD-95, and describes a method to efficiently target other conserved PPI modules.

Underexpression of transcriptional regulators is common in metastatic breast cancer cells overexpressing Bcl-x L

2006 ◽  
Vol 27 (6) ◽  
pp. 1169-1179 ◽  
Author(s):  
Olga Méndez ◽  
Berta Martín ◽  
Rebeca Sanz ◽  
Ramón Aragüés ◽  
Victor Moreno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Metastatic Breast ◽  
Transcriptional Regulators

FGFR4 GLY388 isotype suppresses motility of MDA-MB-231 breast cancer cells by EDG-2 gene repression

2006 ◽  
Vol 18 (6) ◽  
pp. 783-794 ◽  
Author(s):  
Christiane Regina Stadler ◽  
Pjotr Knyazev ◽  
Johannes Bange ◽  
Axel Ullrich
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Gene Repression
Sign in / Sign up

Export Citation Format

Share Document