UBE3A is a HECT domain E3 ubiquitin ligase whose dysfunction is linked to autism, Angelman syndrome, and cancer. Recently, we characterized a de novo autism-linked UBE3A mutant (UBE3AT485A) that disrupts phosphorylation control of UBE3A activity. Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A. We also found that UBE3AT485A activates Wnt signaling to a greater extent in cells with low levels of ongoing Wnt signaling, suggesting that cells with low basal Wnt activity are particularly vulnerable to UBE3AT485A mutation. Ligase-dead UBE3A did not stimulate Wnt pathway activation. Overexpression of several proteasome subunits reversed the effect of UBE3AT485A on Wnt signaling. We also observed that subunits that interact with UBE3A and affect Wnt signaling are located along one side of the 19S regulatory particle, indicating a previously unrecognized spatial organization to the proteasome. Altogether, our findings indicate that UBE3A regulates Wnt signaling in a cell context-dependent manner and that an autism-linked mutation exacerbates these signaling effects. Our study has broad implications for human disorders associated with UBE3A gain or loss-of-function, and suggest that dysfunctional UBE3A might affect additional proteins and pathways that are sensitive to proteasome activity.
from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2skqFKE
via IFTTT
Εγγραφή σε:
Σχόλια ανάρτησης (Atom)
Δημοφιλείς αναρτήσεις
-
Objective Outpatient parenteral antimicrobial therapy (OPAT) provides opportunities for improved cost savings, but in the UK, implementation...
-
Abstract Purpose Overcoming the flaws of current data management conditions in head and neck oncology could enable integrated informatio...
-
CBN News Cancer Took Most of His Tongue, but This Pastor Is Still Singing ... CBN News A youth pastor in San Diego, California is not ...
-
Related Articles Audiologic and radiologic findings in cochlear hypoplasia. Auris Nasus Larynx. 2017 Jan 10;: Authors: Cinar BC, Bat...
-
Universal newborn hearing screening (UNHS) has become the standard of care in many countries. The aim of this study was to evaluate the resu...
-
Abstract The head-mounted display (HMD) has the potential to improve the quality of ultrasound-guided procedures. The aim of this non-clin...
-
http://ift.tt/2pnwWaQ
-
IJMS, Vol. 19, Pages 38: Recombinant Zika NS1 Protein Secreted from Vero Cells Is Efficient for Inducing Production of Immune Serum Directed...
-
Background. Globally 3 to 8% of reproductive age women are suffering from premenstrual dysphoric disorder (PMDD). Several mental and reprodu...
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου