When vertebrate cells exit mitosis various cellular structures are re-organized to build functional interphase cells 1 . This depends on Cdk1 (cyclin dependent kinase 1) inactivation and subsequent dephosphorylation of its substrates 2-4 . Members of the protein phosphatase 1 and 2A (PP1 and PP2A) families can dephosphorylate Cdk1 substrates in biochemical extracts during mitotic exit 5,6 , but how this relates to postmitotic reassembly of interphase structures in intact cells is not known. Here, we use a live-cell imaging assay and RNAi knockdown to screen a genome-wide library of protein phosphatases for mitotic exit functions in human cells. We identify a trimeric PP2A-B55 complex as a key factor in mitotic spindle breakdown and postmitotic reassembly of the nuclear envelope, Golgi apparatus and decondensed chromatin. Using a chemically induced mitotic exit assay, we find that PP2A-B55 functions downstream of Cdk1 inactivation. PP2A-B55 isolated from mitotic cells had reduced phosphatase activity towards the Cdk1 substrate, histone H1, and was hyper-phosphorylated on all subunits. Mitotic PP2A complexes co-purified with the nuclear transport factor importin-1, and RNAi depletion of importin-1 delayed mitotic

Protein phosphatase type 2A (PP2A) enzymes constitute a large family of Ser/Thr phosphatases with multiple functions in cellular signaling and physiology. The composition of heterotrimeric PP2A holoenzymes, resulting from the combinatorial assembly of a catalytic C subunit, a structural A subunit, and regulatory B‐type subunit, provides the essential determinants for substrate specificity, subcellular targeting, and fine‐tuning of phosphatase activity, largely explaining why PP2A is functionally involved in so many diverse physiological processes, sometimes in seemingly opposing ways. In this review, we highlight how PP2A holoenzyme biogenesis and enzymatic activity are controlled by a sophisticatedly coordinated network of five PP2A modulators, consisting of α4, phosphatase 2A phosphatase activator (PTPA), leucine carboxyl methyl transferase 1 (LCMT1), PP2A methyl esterase 1 (PME‐1) and, potentially, target of rapamycin signaling pathway regulator‐like 1 (TIPRL1), which serve to prevent promiscuous phosphatase activity until the holoenzyme is completely assembled. Likewise, these modulators may come into play when PP2A holoenzymes are disassembled following particular cellular stresses. Malfunctioning of these cellular control mechanisms contributes to human disease. The potential therapeutic benefits or pitfalls of interfering with these regulatory mechanisms will be briefly discussed.

Protein phosphatases of the type 2A family (PP2A) represent a major fraction of cellular Ser/Thr phosphatase activity in any given human tissue. In this review, we describe how the holoenzymic nature of PP2A and the existence of several distinct PP2A composing subunits allow for the generation of multiple structurally and functionally different PP2A complexes, explaining why PP2A is involved in the regulation of so many diverse cell biological and physiological processes. Moreover, in human disease, most notably in several cancers and Alzheimer's Disease, PP2A expression and/or activity have been found significantly decreased, underscoring its important functions as a major tumor suppressor and tau phosphatase. Hence, several recent preclinical studies have demonstrated that pharmacological restoration of PP2A activity, as well as pharmacological PP2A inhibition, under certain conditions, may be of significant future therapeutic value.

The mammary gland undergoes important anatomical and physiological changes from embryogenesis through puberty, pregnancy, lactation and involution. These steps are under the control of a complex network of molecular factors, in which epigenetic mechanisms play a role that is increasingly well described. Recently, studies investigating epigenetic modifications and their impacts on gene expression in the mammary gland have been performed at different physiological stages and in different mammary cell types. This has led to the establishment of a role for epigenetic marks in milk component biosynthesis. This review aims to summarize the available knowledge regarding the involvement of the four main molecular mechanisms in epigenetics: DNA methylation, histone modifications, polycomb protein activity and non-coding RNA functions.