The transmission of extracellular signals into their intracellular targets is mediated by a network of interacting proteins that regulate a large number of cellular processes. Cumulative efforts from many laboratories over the past decade have allowed the elucidation of one such signaling mechanism, which involves activations of several membranal signaling molecules followed by a sequential stimulation of several cytoplasmic protein kinases collectively known as mitogen-activated protein kinase (MAPK) signaling cascade. Up to six tiers in this cascade contribute to the amplification and specificity of the transmitted signals that eventually activate several regulatory molecules in the cytoplasm and in the nucleus to initiate cellular processes such as proliferation, differentiation, and development. Moreover, because many oncogenes have been shown to encode proteins that transmit mitogenic signals upstream of this cascade, the MAPK pathway provides a simple unifying explanation for the mechanism of action...

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fasebj.9.9.7601337

The MAPK signaling cascade.

Widmann, Christian, Spencer Gibson, Matthew B. Jarpe, and Gary L. Johnson. Mitogen-Activated Protein Kinase: Conservation of a Three-Kinase Module From Yeast to Human. Physiol. Rev. 79: 143–180, 19...

Mitogen-Activated Protein Kinase: Conservation of a Three-Kinase Module From Yeast to Human

DNA methylation is among the best studied epigenetic modifications and is essential to mammalian development. Although the methylation status of most CpG dinucleotides in the genome is stably propagated through mitosis, improvements to methods for measuring methylation have identified numerous regions in which it is dynamically regulated. In this Review, we discuss key concepts in the function of DNA methylation in mammals, stemming from more than two decades of research, including many recent studies that have elucidated when and where DNA methylation has a regulatory role in the genome. We include insights from early development, embryonic stem cells and adult lineages, particularly haematopoiesis, to highlight the general features of this modification as it participates in both global and localized epigenetic regulation.

DNA methylation: roles in mammalian development

MAPK families play an important role in complex cellular programs like proliferation, differentiation, development, transformation, and apoptosis. At least three MAPK families have been characterized: extracellular signal-regulated kinase (ERK), Jun kinase (JNK/SAPK) and p38 MAPK. The above effects are fulfilled by regulation of cell cycle engine and other cell proliferation related proteins. In this paper we discussed their functions and cooperation with other signal pathways in regulation of cell proliferation.

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MAPK signal pathways in the regulation of cell proliferation in mammalian cells.

Publisher Summary The chapter introduces the mitogen-activated protein (MAP) kinase (MAPK) module. The identification of MAP kinase pathways exemplifies the power of combining biochemical and genetic approaches to molecular problems. The chapter discusses the mammalian MAPK pathways—ERKl/2 and MKKl/2 pathways—and stress-activated protein kinase pathways. The regulation of MAPK pathways by protein phosphatases is discussed in the chapter describing in detail about dual specificity phosphatases, serinenhreonine phosphatases, and protein tyrosine phosphatases. The chapter explores the cellular substrates of MAP kinases, wherein it discusses about protein kinase substrates for MAPKS, nuclear transcription factors, signaling components, and cytoskeletal proteins. Responses to MAPK pathways, regulation of cell growth and transformation, and regulation of cell differentiation and development have also been summarized in the chapter. The chapter describes the yeast MAPK pathways of saccharomyces cerevisiae (Budding Yeast) and Schizosaccharomyces pombe (Fission Yeast). The chapter provides the description of the intracellular targeting and spatial regulation of MAPK pathway components, signaling complexes, and the nuclear translocation of MAPK and MKK. Eukaryotic MAPK cascades provide excellent examples of signal transduction mechanisms that embody key principles common to many, if not all, signaling pathways. Many fundamental questions remain for future studies to investigate the mechanisms by which these pathways are regulated as well as the cellular responses that they control.

Signal transduction through MAP kinase cascades.

MAP kinase becomes stably activated at metaphase and is associated with microtubule-organizing centers during meiotic maturation of mouse oocytes

At fertilization, the highly condensed and transcriptionally inert chromatin of the spermatozoa becomes remodelled into the decondensed and transcriptionally competent chromatin of the male pronucleus. The chromatin initially becomes dispersed and then transiently recondenses into a small mass upon entry into the ooplasm. This morphological change is coincident with and likely dependent on the replacement of the sperm-specific protamines by oocyte-supplied histones and the organization of the chromatin into nucleosomes. The chromatin then extensively decondenses within the male pronucleus and acquires many of the proteins that are associated with the maternal chromatin. Nonetheless, the paternal chromatin manifests distinct characteristics, including transient hyperacetylation of histone H4, increased transcription of endogenous and microinjected genes, and replication-independent demethylation of DNA. Sperm chromatin remodelling is controlled by an oocyte activity that appears during meiotic maturation and disappears approximately 3 h after activation (release from metaphase II arrest), and which requires factors associated with the germinal vesicle of the oocyte. The molecular components of this activity remain largely unknown. In frogs, nucleoplasmin is required to assemble histones H2A and H2B onto the paternal chromatin. Evidence is presented that related proteins may perform similar functions in mammals. Identifying the mechanisms that underlie sperm chromatin remodelling at fertilization may be relevant for understanding reprogramming of somatic cell nuclei after transfer into oocytes.

/pdf/remodelling-the-paternal-chromatin-at-fertilization-in-2mq1ycqnz0.pdf

Remodelling the paternal chromatin at fertilization in mammals.

Dynamics of Dnmt1 methyltransferase expression and intracellular localization during oogenesis and preimplantation development.

Successful implantation relies on precisely orchestrated and reciprocal signaling between the implanting blastocyst and the receptive uterus. We have examined the role of the Wnt/β-catenin signaling pathway during the process of implantation and demonstrate that this pathway is activated during two distinct stages. Wnt/β-catenin signaling is first transiently activated in circular smooth muscle forming a banding pattern of activity within the uterus on early day 4. Subsequently, activation is restricted to the luminal epithelium at the prospective site of implantation. Activation at both sites requires the presence of the blastocyst. Furthermore, inhibition of Wnt/β-catenin signaling interferes with the process of implantation. Our results demonstrate that the Wnt/β-catenin signaling pathway plays a central role in coordinating uterus–embryo interactions required for implantation.

https://www.pnas.org/content/pnas/102/24/8579.full.pdf

Uterine Wnt/β-catenin signaling is required for implantation

β-Catenin signaling has been shown to be involved in triggering axis formation in several organisms, including Xenopus and zebrafish. Genetic analysis has demonstrated that the Wnt/β-catenin signaling pathway is also involved in axis formation in the mouse, since a targeted deletion of β-catenin results in embryos that have a block in anterior–posterior axis formation, fail to initiate gastrulation, and do not form mesoderm. However, because β-catenin is ubiquitously expressed, the precise time and cell types in which this signaling pathway is active during early embryonic development remain unknown. Thus, to better understand the role of the Wnt/β-catenin signaling pathway in axis formation and mesoderm specification, we have examined both the distribution and signaling activity of β-catenin during early embryonic development in the mouse. We show that the N-terminally nonphosphorylated form of β-catenin as well as β-catenin signaling is first detectable in the extraembryonic visceral endoderm in day 5.5 embryos. Before the initiation of gastrulation at day 6.0, β-catenin signaling is asymmetrically distributed within the epiblast and is localized to a small group of cells adjacent to the embryonic–extraembryonic junction. At day 6.5 and onward, β-catenin signaling was detected in the primitive streak and mature node. Thus, β-catenin signaling precedes primitive streak formation and is present in epiblast cells that will go on to form the primitive streak. These results support a critical role for the Wnt/β-catenin pathway in specifying cells to form the primitive streak and node in the mammalian embryo as well as identify a novel domain of Wnt/β-catenin signaling activity during early embryogenesis. Developmental Dynamics 231:416–424, 2004. © 2004 Wiley-Liss, Inc.

Hugh J. Clarke

Papers

MAP kinase becomes stably activated at metaphase and is associated with microtubule-organizing centers during meiotic maturation of mouse oocytes

Remodelling the paternal chromatin at fertilization in mammals.

Dynamics of Dnmt1 methyltransferase expression and intracellular localization during oogenesis and preimplantation development.

Uterine Wnt/β-catenin signaling is required for implantation

β-catenin signaling marks the prospective site of primitive streak formation in the mouse embryo