PPM1D controls nucleolar formation by up-regulating phosphorylation of nucleophosmin

Abstract

An increase of nucleolar number and size has made nucleoli essential markers for cytology and tumour development. However, the underlying basis for their structural integrity and abundance remains unclear. Protein phosphatase PPM1D was found to be up-regulated in different carcinomas including breast cancers. Here, we demonstrate for the first time that PPM1D regulates nucleolar formation via inducing an increased phosphorylation of the nucleolar protein NPM. We show that PPM1D overexpression induces an increase in the nucleolar number regardless of p53 status. We also demonstrated that specific sequential phosphorylation of NPM is important for nucleolar formation and that PPM1D is a novel upstream regulator of this phosphorylation pathway. These results enhance our understanding of the molecular mechanisms that govern nucleoli formation by demonstrating that PPM1D regulates nucleolar formation by regulating NPM phosphorylation status through a novel signalling pathway, PPM1D-CDC25C-CDK1-PLK1.

Lamin B2 Modulates Nucleolar Morphology, Dynamics, and Function

“…However, the majority of nucleolar proteins remain uncharacterized in terms of their potential to modulate nucleolar structure and function. Upstream binding factor (UBF), nucleolin, and nucleophosmin are well-characterized nucleolar proteins that are essential for nucleolar formation and morphology ( 18 – 21 ). Fibrillarin and nucleophosmin, which are associated with ribosome biogenesis, phase-separate from the soluble nucleoplasm into nucleoli in an rRNA-dependent manner ( 22 , 23 ).…”

Phosphoproteome Profiling Reveals Multifunctional Protein NPM1 as part of the Irradiation Response of Tumor Cells

“…NPM1 is a classical phosphoprotein which is regulated by phosphorylation and dephosphorylation to a great extent [9] , [63] , [64] . It is well established that NPM1 is involved in cellular proliferation and also in tumorigenesis [35] , [65] , and it is frequently overexpressed, mutated, or rearranged in tumor cells [33] . NPM1 has versatile cellular functions, and several of them are known to be relevant for malignant degeneration and progression, among them ribosomal biogenesis [15] and licensing of centrosomal duplication, thus assuring of genomic stability [17] , DNA repair processes [18] , [56] , [66] , [67] , [68] , and apoptosis [28] , [69] .…”

ATR signalling mediates the prosurvival function of phospho-NPM against PIDDosome mediated cell death

“…Phosphorylation of NPM is regulated by PPM1D phosphatase (26). PPM1D overexpression upregulates the phosphorylation of NPM at S4 and T199 resulting into increased nucleolar number, a hallmark of cancer cell (26).…”

“…Phosphorylation of NPM is regulated by PPM1D phosphatase (26). PPM1D overexpression upregulates the phosphorylation of NPM at S4 and T199 resulting into increased nucleolar number, a hallmark of cancer cell (26). PP1β is known to dephosphorylate pNPM(T199) and facilitate activation of E2F1 responsive genes in response to DNA damage (27).…”

“…PPM1D phosphatase upregulation results into increased level of pNPM and hence increased nucleolar number, a hallmark of cancer cell. A signaling pathway involving PPM1D-CDC25C-CDK1-PLK1 axis leads to the upregulation of pNPM levels in the cell (26). PP1β is a protein phosphatase involved in regulation of cellular processes like cell cycle progression, glycogen metabolism and abundantly found in liver and muscle cells.…”