Paralogous translation factors target distinct mRNAs to differentially regulate tolerance to oxidative stress in yeast.

Translation initiation factor 4G (eIF4G) is an integral component of the eIF4F complex which is key to translation initiation for most eukaryotic mRNAs. Many eIF4G isoforms have been described in diverse eukaryotic organisms but we currently have a poor understanding of their functional roles and whether they regulate translation in an mRNA specific manner. The yeast Saccharomyces cerevisiae expresses two eIF4G isoforms, eIF4G1 and eIF4G2, that have previously been considered as functionally redundant with any phenotypic differences arising due to alteration in eIF4G expression levels.

Inhibiting ERK5 overcomes breast cancer resistance to anti-HER2 therapy by targeting the G1/S cell cycle transition.

Targeting the human epidermal growth factor receptor 2 (HER2) became a landmark in the treatment of HER2-driven breast cancer. Nonetheless, the clinical efficacy of anti-HER2 therapies can be short-lived and a significant proportion of patients ultimately develop metastatic disease and die. One striking consequence of oncogenic activation of HER2 in breast cancer cells is the constitutive activation of the extracellular-regulated protein kinase 5 (ERK5) through its hyperphosphorylation.

Discovery of a Gatekeeper Residue in the C-Terminal Tail of the Extracellular Signal-Regulated Protein Kinase 5 (ERK5).

The extracellular signal-regulated protein kinase 5 (ERK5) is a non-redundant mitogen-activated protein kinase (MAPK) that exhibits a unique C-terminal extension which comprises distinct structural and functional properties. Here we sought to elucidate the significance of phosphoacceptor sites in the C-terminal transactivation domain of ERK5. We have found that Thr acted as a functional gatekeeper residue controlling C-terminal-mediated nuclear translocation and transcriptional enhancement.

The mTOR-S6 kinase pathway promotes stress granule assembly.

Stress granules are cytoplasmic mRNA-protein complexes that form upon the inhibition of translation initiation and promote cell survival in response to environmental insults. However, they are often associated with pathologies, including neurodegeneration and cancer, and changes in their dynamics are implicated in ageing. Here we show that the mTOR effector kinases S6 kinase 1 (S6K1) and S6 kinase 2 (S6K2) localise to stress granules in human cells and are required for their assembly and maintenance after mild oxidative stress.

Ribonucleoprotein bodies are phased in.

Intracellular compartments are necessary for the regulation of many biochemical processes that ensure cell survival, growth and proliferation. Compartmentalisation is commonly achieved in organelles with defined lipid membranes, such as mitochondria, endoplasmic reticulum or the Golgi apparatus. While these organelles are responsible for many localised biochemical processes, recent evidence points to another class of compartments that lack membrane boundaries.

Mitochondrial Proteins Moonlighting in the Nucleus.

Mitochondria function as cellular energy generators, producing the fuel required to drive biological processes. The response of cells to mitochondrial activity or dysfunction regulates their survival, growth, proliferation, and differentiation. Several proteins that contain mitochondrial-targeting sequences (MTS) also reside in the nucleus and there is increasing evidence that the nuclear translocation of mitochondrial proteins represents a novel pathway by which mitochondria signal their status to the cell.

A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity.

The coordinated regulation of mitochondrial and nuclear activities is essential for cellular respiration and its disruption leads to mitochondrial dysfunction, a hallmark of ageing. Mitochondria communicate with nuclei through retrograde signalling pathways that modulate nuclear gene expression to maintain mitochondrial homeostasis. The monooxygenase CLK-1 (human homologue COQ7) was previously reported to be mitochondrial, with a role in respiration and longevity.

A new role for an old enemy.

Drugs that change the shape of AKT, a protein kinase that promotes tumor growth, may be more effective than drugs that only target its enzymatic activity.

Targeting apoptosis signalling kinase-1 (ASK-1) does not prevent the development of neuropathy in streptozotocin-induced diabetic mice.

Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38. ASK1 may be activated by a variety of extracellular and intracellular stimuli. MAP kinase activation in the sensory nervous system as a result of diabetes has been shown in numerous preclinical and clinical studies.

Regulation of axon growth by the JIP1-AKT axis.

The polarisation of developing neurons to form axons and dendrites is required for the establishment of neuronal connections leading to proper brain function. The protein kinase AKT and the MAP kinase scaffold protein JNK-interacting protein-1 (JIP1) are important regulators of axon formation. Here we report that JIP1 and AKT colocalise in axonal growth cones of cortical neurons and collaborate to promote axon growth.

A new regulator of caveolae signalling.

Cavin-3 regulates metabolism and cell proliferation by coordinating the activities of growth factor signalling cascades.

MAP kinase signalling cascades and transcriptional regulation.

The MAP kinase (MAPK) signalling pathways play fundamental roles in a wide range of cellular processes and are often deregulated in disease states. One major mode of action for these pathways is in controlling gene expression, in particular through regulating transcription. In this review, we discuss recent significant advances in this area.

Docking interactions of the JNK scaffold protein WDR62.

JNK (c-Jun N-terminal kinase) is part of a MAPK (mitogen-activated protein kinase) signalling cascade. Scaffold proteins simultaneously associate with various components of the MAPK signalling pathway and play a crucial role in signal transmission and MAPK regulation. WDR62 (WD repeat domain 62) is a JNK scaffold protein.

A central role for p38 MAPK in the early transcriptional response to stress.

The mitogen-activated protein kinase p38 (p38 MAPK) is activated by a number of stresses. A recent study in BMC Genomics has uncovered the early transcriptional responses to three types of stress and has demonstrated a central role for p38 MAPK in mediating these responses. See research article http://www.

Mouse ACF7 and drosophila short stop modulate filopodia formation and microtubule organisation during neuronal growth.

Spectraplakins are large actin-microtubule linker molecules implicated in various processes, including gastrulation, wound healing, skin blistering and neuronal degeneration. Expression data for the mammalian spectraplakin ACF7 and genetic analyses of the Drosophila spectraplakin Short stop (Shot) suggest an important role during neurogenesis. Using three parallel neuronal culture systems we demonstrate that, like Shot, ACF7 is essential for axon extension and describe, for the first time, their subcellular functions during axonal growth.

Analyzing mitogen-activated protein kinase (MAPK) activities in T cells.

The recognition of peptide antigens by T cells through their antigen receptors (T cell receptors, or TCR), together with the ligation of additional surface molecules called costimulatory receptors, rapidly induces interactive signaling pathways that lead to transcriptional initiation at genes such as that of the autocrine growth factor interleukin 2 (IL-2). Activation of the ERK and JNK subfamilies of MAPK mediates some of these signals. This unit presents procedures for a solid-phase kinase assay and immune-complex kinase assay to measure JNK and ERK activities, respectively, in T cells that have been appropriately stimulated.

The beta-arrestin-2 scaffold protein promotes c-Jun N-terminal kinase-3 activation by binding to its nonconserved N terminus.

The c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathway mediates stress responses in cells. JNK activity is regulated by a protein kinase cascade consisting of a MAPK kinase (MKK) and a MAPK kinase kinase (MAPKKK). beta-Arrestin-2 acts as a scaffold by directly binding to the JNK3 isoform and also by recruiting MKK4 and the MAPKKK apoptosis-signaling kinase-1 (ASK1).

The JIP1 scaffold protein regulates axonal development in cortical neurons.

The development of neuronal polarity is essential for the determination of neuron connectivity and for correct brain function. The c-Jun N-terminal kinase (JNK)-interacting protein-1 (JIP1) is highly expressed in neurons and has previously been characterized as a regulator of JNK signaling.JIP1 has been shown to localize to neurites in various neuronal models, but the functional significance of this localization is not fully understood [1-4].

Regulation of p73-mediated apoptosis by c-Jun N-terminal kinase.

The JNK (c-Jun N-terminal kinase)/mitogen-activated protein kinase signalling pathway is a major mediator of stress responses in cells, including the response to DNA damage. DNA damage also causes the stabilization and activation of p73, a member of the p53 family of transcription factors. p73, like p53, can mediate apoptosis by up-regulating the expression of pro-apoptotic genes, including Bax (Bcl2-associated X protein) and PUMA (p53 up-regulated modulator of apoptosis).

Regulation of gene transcription by mitogen-activated protein kinase signaling pathways.

Mitogen-activated protein kinase (MAPK) signaling pathways are key mediators of eukaryotic transcriptional responses to extracellular signals. These pathways control gene expression in a number of ways including the phosphorylation and regulation of transcription factors, co-regulatory proteins and chromatin proteins. MAPK pathways therefore target multiple components of transcriptional complexes at gene promoters and can regulate DNA binding, protein stability, cellular localization, transactivation or repression, and nucleosome structure.