Mitogen-activated protein kinases (MAPKs) are important signal transducing enzymes, unique to eukaryotes, that are involved in many facets of cellular regulation. Initial research concentrated on defining the components and organization of MAPK signalling cascades, but recent studies have begun to shed light on the physiological functions of these cascades in the control of gene expression, cell proliferation and programmed cell death.

/pdf/mammalian-map-kinase-signalling-cascades-2wtn4qrixr.pdf

Mammalian MAP kinase signalling cascades

The evolutionarily conserved checkpoint protein kinase, TOR (target of rapamycin), has emerged as a major effector of cell growth and proliferation via the regulation of protein synthesis. Work in the last decade clearly demonstrates that TOR controls protein synthesis through a stunning number of downstream targets. Some of the targets are phosphorylated directly by TOR, but many are phosphorylated indirectly. In this review, we summarize some recent developments in this fast-evolving field. We describe both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis. We also summarize the roles of mTOR in the control of cell growth and proliferation, as well as its relevance to cancer and synaptic plasticity.

/pdf/upstream-and-downstream-of-mtor-2v5cvgfhmb.pdf

Upstream and downstream of mTOR

Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases (MKs; formerly known as MAPKAP kinases). The MKs are related serine/threonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress-activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2 and 3, and MK5. In the last 5 years, several MK substrates have been identified, which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice, the identities of the MK substrates indicate that they play important roles in diverse biological processes, including mRNA translation, cell proliferation and survival, and the nuclear genomic response to mitogens and cellular stresses. In this article, we review the existing data on the MKs and discuss their physiological functions based on recent discoveries.

/pdf/erk-and-p38-mapk-activated-protein-kinases-a-family-of-xi88207cal.pdf

Erk and p38 mapk-activated protein kinases: a family of protein kinases with diverse biological functions

SUMMARY The mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs by relaying extracellular signals to intracellular responses. In mammals, there are more than a dozen MAPK enzymes that coordinately regulate cell proliferation, differentiation, motility, and survival. The best known are the conventional MAPKs, which include the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases 1 to 3 (JNK1 to -3), p38 (α, β, γ, and δ), and ERK5 families. There are additional, atypical MAPK enzymes, including ERK3/4, ERK7/8, and Nemo-like kinase (NLK), which have distinct regulation and functions. Together, the MAPKs regulate a large number of substrates, including members of a family of protein Ser/Thr kinases termed MAPK-activated protein kinases (MAPKAPKs). The MAPKAPKs are related enzymes that respond to extracellular stimulation through direct MAPK-dependent activation loop phosphorylation and kinase activation. There are five MAPKAPK subfamilies: the p90 ribosomal S6 kinase (RSK), the mitogen- and stress-activated kinase (MSK), the MAPK-interacting kinase (MNK), the MAPK-activated protein kinase 2/3 (MK2/3), and MK5 (also known as p38-regulated/activated protein kinase [PRAK]). These enzymes have diverse biological functions, including regulation of nucleosome and gene expression, mRNA stability and translation, and cell proliferation and survival. Here we review the mechanisms of MAPKAPK activation by the different MAPKs and discuss their physiological roles based on established substrates and recent discoveries.

Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases

Huntington disease is one of nine inherited neurodegenerative disorders caused by a polyglutamine tract expansion. Expanded polyglutamine proteins accumulate abnormally in intracellular aggregates. Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains. Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments. This protects against polyglutamine toxicity, as the specific mTOR inhibitor rapamycin attenuates huntingtin accumulation and cell death in cell models of Huntington disease, and inhibition of autophagy has the converse effects. Furthermore, rapamycin protects against neurodegeneration in a fly model of Huntington disease, and the rapamycin analog CCI-779 improved performance on four different behavioral tasks and decreased aggregate formation in a mouse model of Huntington disease. Our data provide proof-of-principle for the potential of inducing autophagy to treat Huntington disease.

/pdf/inhibition-of-mtor-induces-autophagy-and-reduces-toxicity-of-32ebr5onpq.pdf

Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease.

The critical role of the MAP kinase pathway in meiosis II in Xenopus oocytes is mediated by p90Rsk

Before fertilization, vertebrate eggs are arrested in metaphase of meiosis II by cytostatic factor (CSF), an activity that requires activation of the mitogen-activated protein kinase (MAPK) pathway. To investigate whether CSF arrest is mediated by the protein kinase p90Rsk, which is phosphorylated and activated by MAPK, a constitutively activated (CA) form of Rsk was expressed in Xenopus embryos. Expression of CA Rsk resulted in cleavage arrest, and cytological analysis showed that arrested blastomeres were in M phase with prominent spindles characteristic of meiotic metaphase. Thus, Rsk appears to be the mediator of MAPK-dependent CSF arrest in vertebrate unfertilized eggs.

http://science.sciencemag.org/content/sci/286/5443/1365.full.pdf

Induction of metaphase arrest in cleaving Xenopus embryos by the protein kinase p90Rsk.

Bub1 is activated by the protein kinase p90(Rsk) during Xenopus oocyte maturation.

https://www.cell.com/current-biology/pdf/S0960-9822(02)00894-1.pdf

The Spindle Checkpoint Kinase Bub1 and Cyclin E/Cdk2 Both Contribute to the Establishment of Meiotic Metaphase Arrest by Cytostatic Factor

In mammalian cells, p70S6K plays a key role in translational control of cell proliferation in response to growth factors. Because of the reliance on translational control in early vertebrate development, we cloned a Xenopus homolog of p70S6K and investigated the activity profile of p70S6K during Xenopus oocyte maturation and early embryogenesis. p70S6K activity is high in resting oocytes and decreases to background levels upon stimulation of maturation with progesterone. During embryonic development, three peaks of activity were observed: immediately after fertilization, shortly before the midblastula transition, and during gastrulation. Rapamycin, an inhibitor of p70S6K activation, caused oocytes to undergo germinal vesicle breakdown earlier than control oocytes, and sensitivity to progesterone was increased. Injection of a rapamycin-insensitive, constitutively active mutant of p70S6K reversed the effects of rapamycin. However, increases in S6 phosphorylation were not significantly affected by rapamycin during maturation. mos mRNA, which does not contain a 5′-terminal oligopyrimidine tract (5′-TOP), was translated earlier, and a larger amount of Mos protein was produced in rapamycin-treated oocytes. In fertilized eggs rapamycin treatment increased the translation of the Cdc25A phosphatase, which lacks a 5′-TOP. Translation assays in vivo using both DNA and RNA reporter constructs with the 5′-TOP from elongation factor 2 showed decreased translational activity with rapamycin, whereas constructs without a 5′-TOP or with an internal ribosome entry site were translated more efficiently upon rapamycin treatment. These results suggest that changes in p70S6K activity during oocyte maturation and early embryogenesis selectively alter the translational capacity available for mRNAs lacking a 5′-TOP region.

Markus S. Schwab

Papers

The critical role of the MAP kinase pathway in meiosis II in Xenopus oocytes is mediated by p90Rsk

Induction of metaphase arrest in cleaving Xenopus embryos by the protein kinase p90Rsk.

Bub1 is activated by the protein kinase p90(Rsk) during Xenopus oocyte maturation.

The Spindle Checkpoint Kinase Bub1 and Cyclin E/Cdk2 Both Contribute to the Establishment of Meiotic Metaphase Arrest by Cytostatic Factor

p70(S6K) controls selective mRNA translation during oocyte maturation and early embryogenesis in Xenopus laevis.