Jade-1S phosphorylation induced by CK1α contributes to cell cycle progression

Abstract

The PHD zinc finger protein Jade-1S is a component of the HBO1 histone acetyltransferase complex and binds chromatin in a cell cycle-dependent manner. Jade-1S also acts as an E3 ubiquitin ligase for the canonical Wnt effector protein b-catenin and is influenced by CK1a-mediated phosphorylation. To further elucidate the functional impact of this phosphorylation, we used a stable, low-level expression system to express either wild-type or mutant Jade-1S lacking the N-terminal CK1a phosphorylation motif. Interactome analyses revealed that the Jade-1S mutant unable to be phosphorylated by CK1a has an increased binding affinity to proteins involved in chromatin remodelling, histone deacetylation, transcriptional repression, and ribosome biogenesis. Interestingly, cells expressing the mutant displayed an elongated cell shape and a delay in cell cycle progression. Finally, phosphoproteomic analyses allowed identification of a Jade-1S site phosphorylated in the presence of CK1a but closely resembling a PLK1 phosphorylation motif. Our data suggest that Jade-1S phosphorylation at an N-terminal CK1a motif creates a PLK1 phospho-binding domain. We propose CK1a phosphorylation of Jade 1S to serve as a molecular switch, turning off chromatin remodelling functions of Jade-1S and allowing timely cell cycle progression. As Jade-1S protein expression in the kidney is altered upon renal injury, this could contribute to understanding mechanisms underlying epithelial injury repair.

Casein kinase 1α: biological mechanisms and theranostic potential

“…Low-density lipoprotein receptor-related protein 6 (LRP6) is a single-pass transmembrane receptor that cooperates with Frizzled proteins for Wnt ligand binding and can be phosphorylated by CK1α and CK1δ at Thr1493, which activates and promotes recruitment of Axin to the membrane in response to the Wnt signal, leading to Wnt pathway activation [ 34 ]. The plant homeodomain zinc finger protein Jade-1 functions as an E3 ubiquitin ligase that ubiquitinates both phosphorylated and non-phosphorylated forms of β-catenin [ 35 ] and is a substrate of CK1α; it is phosphorylated at Ser18 and Ser20, which reduces its ability to inhibit Wnt/β-catenin signaling [ 36 , 37 ]. Thus, CK1α can act as a positive regulator of Wnt/β-catenin signaling (Fig.…”

Predict the role of lncRNA in kidney aging based on RNA sequencing

“…In this study, there was a transregulatory relationship between lncRNA Gm43360 and Csnk1a1 . Csnk1a1 is a tumor suppressor gene [ 26 ] that encodes a protein that participates in the cell cycle and the cell division process [ 27 ]. Csnk1a1 downregulation induces a senescence-associated inflammatory response with growth arrest in colorectal tumors [ 26 ].…”

JADE family proteins regulate proteasome abundance and activity

“…JADE1 and in parts the other members of the JADE protein family have been previously described as components of several protein complexes and their potential cell biological functions have been mainly deduced by JADE interacting or associated proteins. Based on this, JADE proteins were found to be part of the HBO1/HAT complex (14), to regulate pVHL, beta-catenin and by that canonical WNT signaling on multiple levels (7, 9)(11), or to be involved in cell cycle regulation through a Plk1/CK1 kinase module(27, 28). In addition, altered expression of JADE proteins has been identified in several tumor entities, in line with their protein-protein interactions with several tumor suppressors, including pVHL and Ing4 (6, 24).…”