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1.
J Histochem Cytochem ; 70(1): 9-16, 2022 01.
Article in English | MEDLINE | ID: mdl-34165350

ABSTRACT

Glioma stem cells (GSCs) live in a continuous process of stemness reprogramming to achieve specific cell commitment within the so-called GSC niches, specifically located in periarteriolar regions. In this review, we analyze the expression levels, cellular and subcellular location, and role of three scaffold proteins (IQGAP1, FKBP51, and AmotL2) in GSC niches. Scaffold proteins contribute to cell differentiation, migration, and angiogenesis in glioblastoma. It could be of diagnostic interest for establishing stages, for therapeutic targets, and for improving glioblastoma prognosis, which is still at the experimental level.


Subject(s)
Angiomotins/genetics , Glioblastoma/genetics , Tacrolimus Binding Proteins/genetics , ras GTPase-Activating Proteins/genetics , Cell Differentiation , Glioblastoma/diagnosis , Glioblastoma/drug therapy , Humans , Neoplastic Stem Cells
2.
Life Sci Alliance ; 4(10)2021 10.
Article in English | MEDLINE | ID: mdl-34404733

ABSTRACT

Contact inhibition is a key cellular phenomenon that prevents cells from hyper-proliferating upon reaching confluence. Although not fully characterized, a critical driver of this process is the Hippo signaling pathway, whose downstream effector yes-associated protein plays pivotal roles in cell growth and differentiation. Here, we provide evidence that the E3 ligase WWP1 (WW-domain containing protein 1) mono-ubiquitinates AMOTL2 (angiomotin-like 2) at K347 and K408. Mono-ubiquitinated AMOTL2, in turn, interacts with the kinase LATS2, which facilitates recruitment of the upstream Hippo pathway component SAV1 and ultimately promotes yes-associated protein phosphorylation and subsequent cytoplasmic sequestration and/or degradation. Furthermore, contact inhibition induced by high cell density promoted the localization and stabilization of WWP1 at cell junctions, where it interacted with Crumbs polarity proteins. Notably, the Crumbs complex was functionally important for AMOTL2 mono-ubiquitination and LATS activation under high cell density conditions. These findings delineate a functionally important molecular mechanism in which AMOTL2 mono-ubiquitination by WWP1 at cell junctions and LATS activation are tightly coupled to upstream cell density cues.


Subject(s)
Angiomotins/metabolism , Contact Inhibition , Protein Serine-Threonine Kinases/metabolism , Ubiquitin-Protein Ligases/metabolism , Angiomotins/genetics , Contact Inhibition/genetics , Enzyme Activation , Humans , Phosphorylation , Protein Binding , Protein Serine-Threonine Kinases/genetics , Protein Transport , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitination
3.
Stem Cells ; 39(2): 210-226, 2021 02.
Article in English | MEDLINE | ID: mdl-33237582

ABSTRACT

Enrichment of angiomotin (AMOT) in the ectoplacental cone of E7.5 murine placenta prompted our investigation on the role of AMOT in trophoblast differentiation. We show here that AMOT levels increased in mouse placenta during gestation and also upon induction of differentiation in trophoblast stem cell ex vivo. Proteomic data unravelling AMOT-interactome in trophoblast cells indicated a majority of AMOT interactors to be involved in protein translation. In-depth analysis of AMOT-interactome led to identification of eukaryotic translation initiation factor 4A (eIF4A) as the most plausible AMOT interactor. Loss of function of AMOT enhanced, whereas, gain in function resulted in decline of global protein synthesis in trophoblast cells. Bioinformatics analysis evaluating the potential energy of AMOT-eIF4A binding suggested a strong AMOT-eIF4A interaction using a distinct groove encompassing amino acid residue positions 238 to 255 of AMOT. Co-immunoprecipitation of AMOT with eIF4A reaffirmed AMOT-eIF4A association in trophoblast cells. Deletion of 238 to 255 amino acids of AMOT resulted in abrogation of AMOT-eIF4A interaction. In addition, 238 to 255 amino acid deletion of AMOT was ineffective in eliciting AMOT's function in reducing global protein synthesis. Interestingly, AMOT-dependent sequestration of eIF4A dampened its loading to the m7 -GTP cap and hindered its interaction with eIF4G. Furthermore, enhanced AMOT expression in placenta was associated with intrauterine growth restriction in both rats and humans. These results not only highlight a hitherto unknown novel function of AMOT in trophoblast cells but also have broad biological implications as AMOT might be an inbuilt switch to check protein synthesis in developmentally indispensable trophoblast cells.


Subject(s)
Angiomotins/biosynthesis , Eukaryotic Initiation Factor-4A/biosynthesis , Protein Biosynthesis/physiology , Trophoblasts/metabolism , Angiomotins/chemistry , Angiomotins/genetics , Animals , Cells, Cultured , Eukaryotic Initiation Factor-4A/chemistry , Eukaryotic Initiation Factor-4A/genetics , Female , Hep G2 Cells , Humans , Mice , Placenta/cytology , Placenta/metabolism , Pregnancy , Protein Structure, Tertiary , Rats , Rats, Sprague-Dawley
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