GSK3 β phosphorylates Six1 transcription factor and regulates its APC/C < sup > Cdh1 < /sup > mediated proteosomal degradation

Cell Signal. 2023 Dec 30:111030. doi: 10.1016/j.cellsig.2023.111030. Online ahead of print.ABSTRACTSine oculis homeobox homolog 1 (Six1) is a developmentally important transcription factor that regulates cellular proliferation, apoptosis, and dissemination during embryogenesis. Six1 overexpression as reported in multiple cancers modulates expression of a repertoire of its target genes causing an increase in proliferation, metastasis and survival of cancer cells. Six1 exists as a cell cycle regulated nuclear phosphoprotein and its cellular turnover is regulated by APC/C (Anaphase promoting complex / Cyclosome) complex mediated proteolysis. However, the kinases that regulate Six1 proteolysis have not been identified and the mechanistic details that cause its overproduction in various cancers are lacking. Here, we report that Six1 is a physiological GSK3β substrate. GSK3β interacts with Six1 and phosphorylates it at Ser221 within the conserved consensus sequence in its carboxy terminus. Using pharmacological inhibition, siRNA mediated knockdown and protein overexpression of GSK3β; we show that GSK3β regulates Six1 protein stability. Pulse chase analysis of Six1 revealed that GSK3β regulates its ubiquitin proteolysis such that Six1 phosphomimicking mutant (Six1S221E) for Ser221 site had dramatically increased half-life than its phosphodeficient (Six1S221A) and wild type variants. Furthermore, we demonstrate that GSK3β rescues Six1 from APC dependent proteolysis by regulatin...
Source: Cellular Signalling - Category: Cytology Authors: Source Type: research